5.2: Reactions: favorable, unfavorable, and their dynamics - Biology

5.2: Reactions: favorable, unfavorable, and their dynamics - Biology

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As we will see, biological systems are extremely complex; both their overall structural elements and many of their molecular components (including DNA) are the products of thermodynamically unfavorable processes and reactions. Here we will consider the thermodynamics of these processes.

Thinking about energy: Thermodynamics is at its core about energy and changes in energy. This leads to the non-trivial question, what is energy? Energy comes in many forms. There is energy associated with the movement and vibrations of objects with mass. At the atomic and molecular level there is energy associated with the (quantum) state of electrons. There is energy associated with fields that depends upon an object’s nature (for example its mass or electrical charge) and its position within the field. There is the energy associated with electromagnetic radiation, the most familiar form is visible light, but electromagnetic radiation extends from microwaves to X-rays. Finally, there is the energy that is present in the very nature of matter, such energy is described by the equation:

e (energy) = m (mass) x c2 (c = speed of light)

To illustrate this principle, we can call on our day-to-day experiences. Energy can be used to make something move. Imagine a system of a box sitting on a rough floor. You shove the box so that it moves and then you stop pushing – the box travels a short distance and then stops. The first law of thermodynamics is that the total energy in a system is constant. So the question is where has the energy gone? One answer might be that the energy was destroyed. This is wrong. Careful observations lead us to deduce that the energy still exists but that it has been transformed. One obvious change is the transformation of energy from a mechanical force to some other form, so what are those other forms? It is unlikely that the mass of the box has increased, so we have to look at more subtle forms – the most likely is heat. The friction generated by moving the box represents an increase in the movements of the molecules of the box and the floor over which the box moved. Through collisions and vibrations, this energy will, over time, be distributed throughout the system. This thermal motion can be seen in what is known as Brownian motion. In 1905, Albert Einstein explained Brownian motion in terms of the existence, size, and movements of molecules148.

In the system we have been considering, the concentrated energy used to move the box has been spread out throughout the system. While one could use the push to move something (to work), the diffuse thermoenergy cannot be used to do work. While the total amount of energy is conserved, its ability to do things has been decrease (almost abolished). This involves the concept of entropy, which we will turn to next.

TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics

Wen-Chien Chou, Sheng-Chieh Chou, Chieh-Yu Liu, Chien-Yuan Chen, Hsin-An Hou, Yuan-Yeh Kuo, Ming-Cheng Lee, Bor-Sheng Ko, Jih-Luh Tang, Ming Yao, Woei Tsay, Shang-Ju Wu, Shang-Yi Huang, Szu-Chun Hsu, Yao-Chang Chen, Yi-Chang Chang, Yi-Yi Kuo, Kuan-Ting Kuo, Fen-Yu Lee, Ming-Chi Liu, Chia-Wen Liu, Mei-Hsuan Tseng, Chi-Fei Huang, Hwei-Fang Tien TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics. Blood 2011 118 (14): 3803–3810. doi:

5.2: Reactions: favorable, unfavorable, and their dynamics - Biology

Bacterial membrane potential is dynamic, with the ability to hyperpolarize and depolarize.

The dynamics of bacterial membrane potential mediate signaling at the single-cell and biofilm levels.

Bacterial electrophysiology is different from neural electrophysiology because of the size of bacteria and their membrane structure.

Techniques have been developed and utilized to measure bacterial membrane potential quantitatively and temporally.

All cellular membranes have the functionality of generating and maintaining the gradients of electrical and electrochemical potentials. Such potentials were generally thought to be an essential but homeostatic contributor to complex bacterial behaviors. Recent studies have revised this view, and we now know that bacterial membrane potential is dynamic and plays signaling roles in cell–cell interaction, adaptation to antibiotics, and sensation of cellular conditions and environments. These discoveries argue that bacterial membrane potential dynamics deserve more attention. Here, we review the recent studies revealing the signaling roles of bacterial membrane potential dynamics. We also introduce basic biophysical theories of the membrane potential to the microbiology community and discuss the needs to revise these theories for applications in bacterial electrophysiology.


Genetic diversity and population properties

We collected DNA re-sequencing data for 1961 cottons for a genomic variation analysis with an average depth of

14.8× for each [3,4,5,6, 16, 33, 34]. After discarding duplicated accessions, a total of 1913 cotton accessions were used for SNP and InDel analysis, which included 256 G. hirsutum landraces (Ghlandraces), 438 improved G. hirsutum cultivars from the USA and other countries (GhImpUSO), 929 improved G. hirsutum cultivars from China (GhImpCHN), 261 G. barbadense accessions, and 29 other Gossypium species that were used as outgroup (Additional file 1: Table S1). We aligned these data against the reference genome of G. hirsutum acc. “TM-1” [12] and identified 63,084,975 SNPs and 12,354,432 small insertions or deletions (InDels length ≤ 20 bp), in which the core variation dataset includes 19,246,497 SNPs and 4,815,125 InDels with a minor allele frequency (MAF) ≥ 0.01 and more than five accessions having homozygous variations (Table 1 Additional file 1: Tables S2-S6 Additional file 3). Based on core SNP data, we investigated the population structure of G. hirsutum and G. barbadense. Neighbor-joining tree analysis showed the 1913 accessions classify into 12 clades. G. hirsutum accessions form 8 clades, G. barbadense accessions form 3 clades, and other species form 1 clade (Fig. 1a Additional file 2: Figure S1). Population analysis showed that G. barbadense accessions were separated from the G. hirsutum landraces, GhImpUSO and GhImpCHN (Fig. 1b, c Additional file 2: Figure S2). G. hirsutum nucleotide diversity (π) is estimated at 1.07 × 10 − 3 in landraces, 3.74 × 10 − 4 in GhImpUSO, 3.34 × 10 − 4 in GhImpCHN, and 1.01 × 10 − 3 in G. barbadense (Additional file 2: Figure S3), similar to the recent studies in cotton [3,4,5,6, 34] (Fig. 1d).

Population structure and genetic diversity in G. hirsutum and G. barbadense accessions. a The unweighted neighbor-joining phylogenetic tree of 1913 cotton accessions was constructed based on 20,000 random SNPs from core SNPs. The G. tomentosum (AD3), G. mustelinum (AD4), G. darwinii (AD5), G. ekmanianum (AD6), G. stephensii (AD7) of tetraploid species, G. arboreum (A2) and G. davidsonii (D3-d) of diploid species serve as outgroup. b Principal component analysis (PCA) plot of the first two components for all accessions. c STRUCTURE analysis of all cotton accessions with different numbers of clusters K = 6 and K = 12 (K = 12 is optimal value). The x-axis lists the outgroup species (gray), G. barbadense (blue), G. hirsutum landrace accessions (orange), and G. hirsutum improved accessions (green) respectively, and the y-axis quantifies genetic diversity in each accession. The other structure results are shown in the Additional file 2: Figure S2. d Nucleotide diversity (π) and fixation index divergence (Fst) across the five groups. e The number of deletions, duplications, inversions, and translocations in five populations (two-sided Wilcoxon rank-sum test for adjacent groups, P < 0.001). Each node represents one accession. In this analysis, the number of SVs was shown with the TM-1 reference genome

We used 742 cotton accessions with a high sequencing depth (> 10×) against the G. hirsutum “TM-1” reference genome (Additional file 1: Table S1 Additional file 3) and identified 32,099 deletions, 7576 duplications, 1112 inversions, and 357 translocations (Additional file 1: Table S7). There are more SVs in Ghlandrace than that GhImpUSO and GhImpCHN groups (Fig. 1e). In addition, 173,166 (MAF ≥ 0.01) copy number variations (CNVs) were identified in the 742 accessions, including 82,431 in the landraces, 59,309 in the GhImpUSO, and 38,057 in the GhImpCHN group (Additional file 1: Table S8). Population genetic properties of CNVs in 742 accessions showed that G. hirsutum landraces were clearly separated from the improved accessions, similar to SNP-based result, but were clustered together with the GhImpUSO and GhImpCHN accessions (Additional file 2: Figure S4). These results suggested that high-confidence CNVs have strong divergence between G. hirsutum landrace and improved population and can be used to discover complex quantitative trait loci (QTLs). This comprehensive variome dataset provides a genomic resource for cotton population genetics, domestication analysis, and agronomic allele identification (Additional file 2: Figure S5).

Evidence for genomic divergence during domestication and improvement

Domestication-related traits arise from selected genetic variation in wild species, affecting seed size, flowering time, yield, quality, and crop adaptation [35,36,37]. To identify potential selection signals during cotton domestication, we scanned genetic variations with allele frequency differentiation in nucleotide diversity by comparing each cultivated group with its corresponding wild group. We identified 76 domestication sweep regions (DSRs) using πLandraceImproved (ratio ≥ 15) and a likelihood method (XP-CLR, Top 5%) (Additional file 2: Figure S6a), occupying 66.8 Mb in the A subgenome and 51.4 Mb in the D subgenome associated with 837 and 1272 genes, including 274 homologous gene pairs (Fig. 2a). Compared with previous studies with small numbers of accessions [3,4,5], this domestication selection analysis identified 31 novel DSRs occupying 43.6 Mb (Additional file 1: Table S9). Some fiber-related and known domesticated genes were differentially expressed between wild/landraces and improved cultivars (Additional file 2: Figure S6b, c). The domestication selected genes were involved in stress response, cell wall regulation, jasmonic acid, ethylene, and circadian rhythm process (Additional file 2: Figure S7). Further manipulation of these genes in plant hormone pathway and stress response pathway may help illustrate their putative regulatory role in fiber quality improvement and environmental adaptation during cotton domestication [3, 38, 39]. We also identified 120 Mb (πGhImpUSOGhImpCHN ≥ 2) with improvement signals, including 1006 selected genes in the A subgenome and 2369 in the D subgenome with 353 homologous gene pairs (Fig. 2a Additional file 2: Figure S6d), and 79.5% (95.4 Mb) of the improvement selection regions were not identified previously [5] (Additional file 1: Table S10). Of note is the observation that 19 Mb of sequence was screened with both domestication and improvement selection signals, in which the D subgenome (441 genes) has more genes than the A subgenome (50 genes) (Additional file 1: Table S11). These data suggest that D subgenome has stronger SNP-based selection signals in both domestication and improvement processes.

Multiple-scale variation for subgenomic divergence and GWAS on agronomic traits during cotton domestication. a Circos plot showing the SNP- and SV-based selection signals and QTLs during cotton domestication and improvement. The selection region was calculated in a 1-Mb sliding window with a step size of 200 kb. I–VIII, Circos plot from outer to inter tracks showing gene density (I), snpQTLs (II), cnvQTLs (III), the ratio of nucleotide diversity (π) based on SNPs between 256 landraces and 1364 improved accessions for domestication (IV), the ratio of nucleotide diversity (π) based on SNPs between 438 GhImpUSO accessions and 929 GhImpCHN accessions for improvement (V), the relative SV allele difference in the comparisons between landrace and improved accessions (VI), and between GhImpUSO and GhImpCHN (VII). The track (VIII) represents the domesticated homologous. Upper and lower panels (VI) represent deletion and duplication variation allele difference, respectively. The snpQTLs were identified using the meta-GWAS analysis of 890 cotton accessions. The outermost circle of the circos plot purple and yellow font shows pleiotropic snpQTLs (psnpQTLs) and pleiotropic cnvQTLs (pcnvQTLs), respectively. b–i Selective signals of copy number variations (CNVs) between the A (b) and D (f) subgenome during domestication. The horizontal gray dashed lines show the domestication signal threshold with the ratio of nucleotide diversity between wild/landrace and improved cotton accessions (πlandraceImproved > 200). c–e and g–i Six CNV-based GWAS hits that overlapped with domestication selection signals are shown for seed index (SI) (c), fiber length (FL) (d), boll weight (BW) (e), fiber uniformity (FU) (g), fiber elongation (FE) (h), and flowering date (FD) (i). The threshold of cnvQTL line was -log10 P = 4.4. The violin plot showed phenotypic variation with the lead CNV genotype. The numbers in the violin plot show the number of accessions for each copy. The significance difference was calculated with two-sided Wilcoxon rank-sum test (**P < 0.01, *P < 0.05)

Domestication is a driver for CNV allele frequency difference between wild/landrace and domesticated groups [37]. In total, 286 non-redundant CNV-based regions were identified with selection signals during cotton domestication, comprising 297 Mb in the A subgenome (Fig. 2b) and 105 Mb in the D subgenome (Fig. 2f). About 55% (65 Mb of 118 Mb) of SNP-based domestication signals overlapped CNV-based domestication sweeps (Additional file 1: Table S12). In total, 217 CNV regions were identified with improvement selection signals, comprising 156 Mb in the A subgenome and 133 Mb in the D subgenome. About 44% (52 Mb of 120 Mb) of SNP-based improvement signals overlapped the CNV-based improvement signals (Additional file 1: Table S13). In total, we identified 329 Mb (covering 6339 genes) of sequences in the A subgenome and 127 Mb (4955 genes) in the D subgenome with both SNP- and CNV-based domestication signals. A total of 173 Mb (5526 genes) and 184 Mb (8405 genes) of sequences have improvement signals in the A and D subgenomes. The identification of selection signals during domestication and improvement can facilitate to further identify genetic loci of important agronomic traits.

To identify QTLs for selection signals associated with agronomic traits, we conducted a genome-wide association study (GWAS) meta-analysis of 890 G. hirsutum accessions from three independent experimental cases with multiple environments (Additional file 3) [3, 5, 6]. Using the genotypic data of 2,291,437 high-quality SNPs with MAF ≥ 0.05 in 890 accessions, we identified 2952 significant SNPs (0.05/2,291,437 P < 2.18 × 10 − 8 ) associated with fiber quality-related traits. After strict filtering, 91 major fiber-related QTLs were located, including 11 for fiber length (FL), 17 for fiber elongation (FE), 15 for fiber strength (FS), 19 for fiber length uniformity (FU), 10 for fiber micronaire (FM), 7 for fiber maturity (MAT), and 12 for spinning consistency index (SCI) (Additional file 1: Table S14 and Additional file 2: Figure S8). We also identified 31 yield-related and 3 flowering date (FD)-related QTLs. In total, 125 major QTLs with 4751 candidate genes for 15 agronomic traits were identified, in which 78 were consistent with previous studies [3, 5, 6, 15, 40, 41] and the other 47 were newly detected in meta-analysis (Additional file 1: Table S14). In the 125 QTLs, 14 have selection signals during domestication and improvement (Additional file 1: Table S15). In addition, twenty-one QTL loci showed pleiotropic effects on fiber quality, yield, and flowering date (Fig. 2a Additional file 1: Table S16). For example, lint percentage (LP), fiber weight per boll (FWPB), and lint index (LI) are components of yield trait, with major QTLs co-localized on chromosome D02 (Additional file 2: Figure S9a). The LP, FD, and whole growth period (WGP) for flowering time traits have co-located QTLs on chromosome D03 (Additional file 2: Figure S9b).

We focused on novel QTLs related to fiber elongation that were identified in meta-GWAS. A novel QTL (mqFE253) was located on the D05 chromosome (at 11.3–12.5 Mb of genomic region). The 64 candidate genes were predicted by integrating haplotype analysis, gene expression, and functional annotation (Additional file 2: Figure S10). One candidate gene (Ghir_D05G013680, GhIDD7), encoding an indeterminate-domain 7 transcription factor, was differentially expressed in four fiber developmental stages (Additional file 2: Figure S10f). Accessions representing two main haplotypes of the 5′ UTR region showed a significant difference in fiber elongation and fiber length (Additional file 2: Figure S11a-b). After knock-out of GhIDD7, the mature fiber was significantly shorter than that in wild type plants (25.8 ± 0.3 vs. 27.1 ± 0.1) (Additional file 2: Figure S11c, d, e). These results indicated that GhIDD7 was a previously uncharacterized gene contributing to fiber quality-related trait.

GWAS analysis of 26,831 high-confidence CNVs (MAF ≥ 0.05) in 419 G. hirsutum accessions revealed 370 significant CNVs for 50 QTLs (cnvQTLs) (Additional file 1: Table S17), of which 5 showed pleiotropic effects on both fiber quality and lint yield (Fig. 2a). Thirteen cnvQTLs overlapped with SNP-based QTLs (snpQTLs), and the other 37 cnvQTLs are only identified by CNVs. Of these cnvQTLs, 15 overlapped with domestication sweeps and 10 overlapped with improvement selection signals (Additional file 1: Table S18). The phenotypic data exhibit a significant difference in cotton accessions with different copy numbers of lead CNV (Fig. 2c–e, g–i Additional file 2: Figure S12). For example, a seed index (SI) association with domestication signal was identified on the A06 chromosome (Fig. 2c). A fiber length (FL) association with domestication signal was located on the A10 chromosome, and FL with 2 duplication copies was significantly longer than that with 0 copy (reference) allele (P < 0.01) (Fig. 2d). The lead CNV-involved LD region has 78 candidate coding genes, in which some are involved in cotton fiber development, such as UDP-glucose pyrophosphorylase 3 (Ghir_A10G024310, UGP3) and AP2/B3-like transcriptional factor (Ghir_A10G023950). Another example shows a fiber maturity (MAT) association with improvement selection signal was located on the A12 chromosome (Additional file 2: Figure S13a, b, c). This association has one candidate gene encoding xyloglucan endotransglucosylase/hydrolase 5 (Ghir_A12G008500, XTH5). In the D subgenome, three cnvQTLs with strong selection signals were found to be associated with FD, FWPB, and FS on the D03, D06, and D07 chromosomes (Additional file 2: Figure S13d, e, f, g). These results provide a number of cnvQTL candidates that may be applied to cultivate desirable traits in future breeding.

Pan-genomes of G. hirsutum and G. barbadense species

We used a reference-guided assembly approach [21] to construct pan-genomes of G. hirsutum and G. barbadense. The sequencing data of 1581 G. hirsutum (251 landraces, 424 GhImpUSO and 906 GhImpCHN) and 226 G. barbadense improved accessions were aligned to the “TM-1” and “3–79” reference genomes, respectively [12]. About 5800 million unmapped reads from G. hirsutum and 1127 million unmapped reads from G. barbadense were subject to de novo assembly (Additional file 2: Figure S14, S15), producing 5,047,083,790 bp and 1,517,253,311 bp of contig sequence respectively, with a minimum length of 500 bp (Additional file 1: Table S19). After removing redundancies, 3704 Mb and 1422 Mb non-reference sequences with a contig N50 of 1530 bp (G. hirsutum) and 1108 bp (G. barbadense) passed all filtering steps for the final non-reference genomes (Additional file 1: Table S20). The final 1041 Mb and 309 Mb non-reference sequences in G. hirsutum and G. barbadense with a contig length of more than 1000 bp were used for predicting protein-coding genes (Additional file 2: Figure S16). We obtained 32,569 G. hirsutum genes (65,679 transcripts) and 8851 G. barbadense genes (12,076 transcripts) (Additional file 1: Tables S21-S22). The final G. hirsutum pan-genome (Ghpan-genome) is 3388 Mb with 102,768 genes (2347 Mb with 70,199 genes in the “TM-1” reference genome) and G. barbadense (Gbpan-genome) is 2575 Mb with 80,148 genes (2266 Mb with 71,297 genes in the “3–79” reference genome) (Additional file 2: Figure S17).

The coverage of the Ghpan-genome was investigated using PacBio reads of 10 representative accessions, including G. hirsutum yucatanense, G. hirsutum richmondi, G. hirsutum morrilli from the wild/landraces, the Acala, Paymaster 54, Stoneville 2B from the GhImpUSO group, and Simian 3, CRI 7, Xinluzao 42, and Xuzhou 142 from the GhImpCHN group (Additional file 1: S23-S25 Additional file 2: Figure S18). After de novo assembly (Additional file 3), more than 93% of assembled contigs were mapped to the TM-1 reference genome. Approximately 18.9 Mb of unmapped contigs (a total of 641 Mb contigs from 10 accessions that were not mapped on the TM-1 reference genome) were aligned to the non-reference sequences of 1581 G. hirsutum accessions (the average non-reference sequence length is

655 kb 1041 Mb/1581 Mb). The PacBio-based assemblies provide evidence for non-reference genome sequences in G. hirsutum, indicating that our pipeline of pan-genome construction can retrieve PAVs in a large germplasm population. Some high-frequency PAVs were also verified by PCR in 23 representative accessions (Additional file 2: Figure S19).

For the G. hirsutum population, we mapped re-sequencing reads against 102,768 pan genes, which resulted in 17,100 genes (16.64%, singleton) in 561 accessions (sequencing depth < 5) and 85,667 genes in 1020 accessions (depth > 5). The 1020 G. hirsutum accessions include 63,489 core genes shared by all G. hirsutum accessions, 5941 (5.78%) softcore genes in 990–1019 accessions (97–100%), 3803 (3.7%) shell genes in 11–989 accessions (1–97%), and 12,434 (12.1%) clouds in less than 10 accessions (0–1%) (Fig. 3a, b). For the G. barbadense pan-genome, the 1536 singleton genes only occurred in 49 low-depth accessions. We used 78,612 pan genes that occurred in 177 accessions for further PAV analysis. The 177 G. barbadense accessions include 68,789 (85.8%) core genes, 1796 (2.24%) softcore genes in 172–176 accessions (97–100%), 5867 (7.32%) shell genes in 4–171 accessions (2–97%), and 2160 (2.75%) clouds in less than 3 accessions (0–2%) (Fig. 3c, d). Modeling of pan-genome size with iteratively random sampling suggests that the Ghpan-genome has an average of 81,688 pan genes and an average of 65,595 core genes in 398 accessions (Fig. 3e). The Gbpan-genome has an average of 78,607 pan genes and 69,563 core genes in 59 accessions for modeling saturation (Fig. 3f). Therefore, the size of core-genome decreased and pan-genome increased with the increase of population size. GO analysis showed that core genes were involved in cellular metabolic process and development, whereas the variable genes were involved in “defense response,” “response to stress,” and “signaling transduction in environment fitness” (Additional file 2: Figure S20).

Pan-genomes of G. hirsutum and G. barbadense species. a Gene number and presence frequency in G. hirsutum pan genes. The pie chart corresponds to the core (present in all accessions), softcore, shell, and cloud genes. The singleton genes in low-depth (< 5) accessions were excluded for further PAV analysis. The variable genes are divided into reference and non-reference genes in Additional file 2: Figure S17. b 1020 G. hirsutum accessions heatmap showed presence and absence of variable PAVs. c Gene number and presence frequency in G. barbadense pan genes. d 177 G. barbadense accessions heatmap showed presence and absence of variable PAVs. e, f Saturation curve modeling the increase of pan-genome size and decrease of core-genome size in 1020 G. hirsutum (e) and 177 G. barbadense (f). The error bar was calculated based on 1000 random combinations with five replicates of cotton genomes. The top and bottom edges in purple and red represent the maximum and minimum gene number. The solid lines represent the number of pan genes and core genes

We next investigated the genomic characteristics of core and variable genes between A and D subgenome. Core genes have higher expression levels than variable genes in both G. hirsutum and G. barbadense (Additional file 2: Figure S21). Interestingly, A subgenomic variable genes have higher expression levels than D subgenomic genes (Fig. 4a). Variable genes have a higher adjacent (2 kb) TE insertion probability than core genes, especially for the Gypsy class (Additional file 2: Figure S22). The variable genes in the D subgenome have a higher ratio than those in the A subgenome (Fig. 4b). Evolutionary selection analysis showed that more variable genes have undergone positive selection than core genes in both G. hirsutum and G. barbadense, especially in the D subgenome (Fig. 4c). Furthermore, variable genes have a larger nucleotide diversity than core genes, and more variable genes in the D subgenome have a higher diversity (P < 0.001) (Fig. 4d Additional file 2: Figure S23). These data indicated that D subgenomic variable genes had a faster evolutionary rate than A subgenomic genes.

Comparison of core and variable genes in A and D subgenomes. a Expression levels of core and variable genes in G. hirsutum and G. barbadense. The softcore genes are represented by “Soft.” b Ratio of transposable element (TE) insertion frequency in upstream 2 kb of core and variable genes in the A and D subgenomes. c Ratio of nonsynonymous/synonymous (Ka/Ks) mutations of core and variable genes. d SNP diversity of core and variable genes. The comparison of gene expression, TE, and SNP diversity between core and variable genes were carried out using a two-sided Kolmogorov-Smirnov test (*P < 0.05, **P < 0.01, ***P < 0.001)

PAV selection during domestication and improvement

To establish landscape of selective PAVs between landrace and improved cotton, we compared PAV frequency between the landrace, GhImpUSO, and GhImpCHN groups. The landrace group has more variable genes than improved cultivars, suggesting a general trend of gene loss during cotton domestication (Fig. 5a). PCA and phylogenetic analysis of PAVs suggest that the landrace group was separated from the improved cultivar group (Fig. 5b, c). The landraces originating from native America had a population mixture with American cultivated cotton in genetic composition, consistent with the clustering analysis of high-confidence SNPs (Additional file 2: Figure S24). To control the false-positive rate, eight landraces and thirty-four GhImpUSO accessions in a mixed population structure with uncertain origin were excluded from further analysis.

PAV selection signals during cotton domestication and improvement. a Gene number among the G. hirsutum landrace and improved accessions. The Wilcoxon rank-sum test (P < 0.001) was used for the significant statistics. b PCA analysis of 1020 accessions based on shell PAVs. c Maximum-likelihood phylogenetic tree and population structure with different number of clusters (K = 2, 3, and 4) in 1020 G. hirsutum accessions using 3803 shell PAVs. The population structure is sorted according to the phylogenetic tree. d, e Comparison of significant gene presence frequency between the landrace versus GhImpUSO group (domestication) and GhImpUSO versus GhImpCHN group (improvement) (FDR < 0.001, two-sided Fisher’s exact test). f Numbers of favorable and unfavorable genes during domestication and improvement. g, h PAV presence frequency of favorable and unfavorable genes during domestication and improvement. i, j GO enrichment analysis of favorable gene (i) and unfavorable gene (j) gain and loss during domestication and improvement

To identify PAV-related genes with selection signals during domestication and improvement, we performed two comparisons between 182 landraces and 206 GhImpUSO accessions using the presence frequency of variable genes, for “domestication” (Fig. 5d Additional file 2: Figure S25), and between 206 GhImpUSO and 592 GhImpCHN accessions for “improvement” (Fig. 5e). The genes with a significant change of presence frequency (FDR < 0.001 and frequency fold change > 2 for “unfavorable gene” or < 0.5 for “favorable gene”) were regarded as selected genes. Genes with higher presence frequency in landrace than in GhImpUSO, and higher presence frequency in GhImpUSO than in GhImpCHN were potentially “unfavorable gene,” while genes with reverse patterns of presence frequency were “favorable gene.” We identified 2785 and 7867 favorable genes with allele gain, and 6753 and 3866 unfavorable genes with allele loss during domestication and improvement, respectively (Additional file 1: Tables S26, S27). GO enrichment analysis showed that favorable genes were enriched in oxidation-reduction-related process, whereas unfavorable genes were enriched in fatty acid biosynthesis and gene regulation. The favorable and unfavorable genes were divided into four comparisons according to the presence frequency in three groups during domestication and improvement (Fig. 5f). The continuous selection of 337 favorable genes with both domestication and improvement signals may be elite candidates for breeding, whereas 308 unfavorable genes exhibiting lower presence frequencies in the GhImpCHN group represent loss alleles (Fig. 5g Additional file 1: Table S28). More unfavorable genes than favorable were eliminated during cotton breeding (Fig. 5h). Favorable gain genes participated in transmembrane transport and oxidation-reduction process, whereas favorable loss genes involved in electron transport chain and secondary metabolic process (Fig. 5i, j). Unfavorable gain genes had no significantly enriched process during improvement (Fig. 5j). These analyses showed that many unfavorable gene were lost during domestication and considerable favorable genes were retained during improvement process.

Genes for related traits using pan-genome dataset

Based on the above data, we propose a summary chart for cotton natural selection, domestication, and improvement (Fig. 6a). We identified nearly 456 Mb (19.4% of the assembled reference genome) and 357 Mb (15.2%) of sequences with domestication and improvement signals, through the integrated SNP, CNV, and PAV maps (Additional file 1: Table S29). There are 21,169 genes located in domestication regions, some of which have been demonstrated to be involved in the regulation of flowering date, morphology, and fiber development. For the flowering date, a significant GWAS peak on chromosome D03 has two candidate genes encoding a COP1-interactive protein [6] (CIPI, Ghir_D03G008950) and a CONSTANS-like protein [42] (COL2, Ghir_D03G011010), which are required for adaptation change in landrace cotton to cultivated varieties in different geographical areas with different photoperiods. Further investigation of causal SNP alleles shows that the ancestral alleles are mainly distributed in landraces, with lower allele frequencies in improved cultivars (Fig. 6b). Similarly, we found that landrace and improved groups exhibited allele differentiation in LATE MERISTEM IDENTITY1 [43] (LMI1, Ghir_D01G021810) that regulates leaf shapes, and in the basic helix-loop-helix protein gene GRF (Ghir_A12G025340) that is a candidate gene for cotton glandular QTL [44] (Fig. 6b). Some genes responsible for fiber development that experienced domestication and improvement selection were also detected by the geographical differentiation analysis. KCS2 (Ghir_D10G015750) and CesA6 (Ghir_D03G004880), responsible for fiber elongation [45,46,47,48], were subject to domestication and improvement selection (Fig. 6b). The domestication gene PRF3 (Ghir_D13G021640) has a strongly mutated allele in improved cultivars [49].

An available pan-genome dataset for cotton breeding. a A four-step model of variation during cotton domestication and breeding. b The spectrum of gene allele frequencies at the causal SNP polymorphisms of COL2, CIP1, PRF3, LMI1, GRF, KCS2, and CesA6 in landrace and two geographic groups. c The spectrum of domesticated PAV allele frequ encies of seven genes in landrace and two geographic groups. d An example of functional PAV located on the A08 chromosome. The dashed line in Manhattan plot indicates the threshold for GWAS signals (P < 2.62 × 10 − 8 −log P > 7.6). This locus includes four QTLs (lint percentage (LP), fiber weight per boll (FWPB), fiber micronaire (FM), fiber strength (FS)). e Four QTLs were displayed in a panel of multiple accessions. The two dashed lines represent GWAS thresholds for CNV (−log P > 6.45) and SNP (−log P > 4.42), respectively. f the phenotypic difference between presence and absence groups. The numbers below the violin plots show the accession numbers. The significance difference was calculated with a two-sided Wilcoxon rank-sum test (***P < 0.001, **P < 0.01). g Presence frequencies of Ghir_A08G006710 in 182 landrace, 206 GhImpUSO, and 592 GhImpCHN accessions

Pan-genome analysis uncovered favorable and unfavorable gene alleles during domestication and improvement, providing novel candidate genes for functional investigation (Fig. 5). For genes favorable to cotton improvement selection, SCD (short chain dehydrogenase, GhirPan.00056999), ST (sugar transporter, GhirPan.00054328), and RbfA (ribosome-binding factor A, GhirPan.00033905) have the lowest frequency in wild population and highest in domesticated cultivars (Fig. 6c Additional file 2: Figure S26). Some favorable genes exhibiting a decrease of frequency in the improvement process could be eliminated (308 genes), having almost the same allele frequency between wild and cultivated accessions, such as DXS (deoxyxylulose-5-phosphate synthase, Ghir_Scaffold1882G000030) and COX3 (cytochrome oxidase subunit 3, Ghir_Scaffold1273G00008). Genes unfavorable during domestication showed increased (182 genes) or decreased (5405 genes) frequency in the GhImpCHN group, such as RLP9 (receptor like protein 9, Ghir_D13G022380) and ZBD (Zinc-binding dehydrogenase, GhirPan.00044196) (Fig. 6c).

To determine the contribution of PAV to agronomic traits, we identified PAV-associated SNPs for 1196 PAVs (MAF ≥ 0.02) in 415 accessions (4 accessions were discarded from 419) using 1,904,926 SNPs and obtained 56,486 significant SNPs (P < 2.62 × 10 − 8 ) associated with 864 (72.2%) PAVs. Of these PAVs, 124 were overlapped with 89 trait-QTLs (Additional file 1: Table S30 Additional file 2: Figure S27). One representative PAV (Ghir_A08G006710, 543 bp, an uncharacterized gene in G. hirsutum) is located on chromosome A08 (Fig. 6d, Additional file 2: Figure S28). This hotspot region contained two yield-related (LP, FWPB) QTLs and two fiber quality-related (FM, FS) QTLs (Fig. 6e). These accessions with the presence haplotype of this gene showed significantly increased appearance of LP and FWPB traits than those with the absence haplotype, but no difference for FS and FM traits (Fig. 6f). Further presence frequency analysis showed that Ghir_A08G006710 was present in nearly all landrace and GhImpUSO accessions, but was absent in only a few GhImpCHN accessions (Fig. 6g). Interestingly, in the population RNA-Seq data of 15 DPA fiber [15], absence of this gene in 18 accessions was accompanied by significant low expression of an adjacent gene Ghir_A08G006730 (locating at upstream

61 kb, encoding an AUX/IAA transcriptional regulator family protein) compared with that representing presence of this gene in 233 accessions, supported by the change of IAA content in fibers of representative accessions (Additional file 2: Figure S29, S30). These results implied that this gene represented a recent loss event with a potential regulatory role in other gene expression during cotton improvement. These PAV localization and QTL analyses may improve the efficiency of identifying favorable genes associated with desirable agronomic traits.

  • Dedication
  • About the authors
  • Preface
  • Acknowledgments
  • Part I. The Molecular Design of Life
    • Chapter 1. Prelude: Biochemistry and the Genomic Revolution
      • 1.1. DNA Illustrates the Relation between Form and Function
        • 1.1.1. DNA Is Constructed from Four Building Blocks
        • 1.1.2. Two Single Strands of DNA Combine to Form a Double Helix
        • 1.1.3. RNA Is an Intermediate in the Flow of Genetic Information
        • 1.1.4. Proteins, Encoded by Nucleic Acids, Perform Most Cell Functions
        • 1.3.1. Reversible Interactions of Biomolecules Are Mediated by Three Kinds of Noncovalent Bonds
        • 1.3.2. The Properties of Water Affect the Bonding Abilities of Biomolecules
        • 1.3.3. Entropy and the Laws of Thermodynamics
        • 1.3.4. Protein Folding Can Be Understood in Terms of Free-Energy Changes
        • Stereochemical Renderings
        • Fischer Projections
        • Key Terms
        • 2.1. Key Organic Molecules Are Used by Living Systems
          • 2.1.1. Many Components of Biochemical Macromolecules Can Be Produced in Simple, Prebiotic Reactions
          • 2.1.2. Uncertainties Obscure the Origins of Some Key Biomolecules
          • 2.2.1. The Principles of Evolution Can Be Demonstrated in Vitro
          • 2.2.2. RNA Molecules Can Act As Catalysts
          • 2.2.3. Amino Acids and Their Polymers Can Play Biosynthetic and Catalytic Roles
          • 2.2.4. RNA Template-Directed Polypeptide Synthesis Links the RNA and Protein Worlds
          • 2.2.5. The Genetic Code Elucidates the Mechanisms of Evolution
          • 2.2.6. Transfer RNAs Illustrate Evolution by Gene Duplication
          • 2.2.7. DNA Is a Stable Storage Form for Genetic Information
          • 2.3.1. ATP, a Common Currency for Biochemical Energy, Can Be Generated Through the Breakdown of Organic Molecules
          • 2.3.2. Cells Were Formed by the Inclusion of Nucleic Acids Within Membranes
          • 2.3.3. Compartmentalization Required the Development of Ion Pumps
          • 2.3.4. Proton Gradients Can Be Used to Drive the Synthesis of ATP
          • 2.3.5. Molecular Oxygen, a Toxic By-Product of Some Photosynthetic Processes, Can Be Utilized for Metabolic Purposes
          • 2.4.1. Filamentous Structures and Molecular Motors Enable Intracellular and Cellular Movement
          • 2.4.2. Some Cells Can Interact to Form Colonies with Specialized Functions
          • 2.4.3. The Development of Multicellular Organisms Requires the Orchestrated Differentiation of Cells
          • 2.4.4. The Unity of Biochemistry Allows Human Biology to Be Effectively Probed Through Studies of Other Organisms
          • Key Organic Molecules Are Used by Living Systems
          • Evolution Requires Reproduction, Variation, and Selective Pressure
          • Energy Transformations Are Necessary to Sustain Living Systems
          • Cells Can Respond to Changes in Their Environments
          • Key Terms
          • Where to start
          • Books
          • Prebiotic chemistry
          • In vitro evolution
          • Replication and catalytic RNA
          • Transition from RNA to DNA
          • Membranes
          • Multicellular organisms and development
          • 3.1. Proteins Are Built from a Repertoire of 20 Amino Acids
          • 3.2. Primary Structure: Amino Acids Are Linked by Peptide Bonds to Form Polypeptide Chains
            • 3.2.1. Proteins Have Unique Amino Acid Sequences That Are Specified by Genes
            • 3.2.2. Polypeptide Chains Are Flexible Yet Conformationally Restricted
            • 3.3.1. The Alpha Helix Is a Coiled Structure Stabilized by Intrachain Hydrogen Bonds
            • 3.3.2. Beta Sheets Are Stabilized by Hydrogen Bonding Between Polypeptide Strands
            • 3.3.3. Polypeptide Chains Can Change Direction by Making Reverse Turns and Loops
            • 3.6.1. Amino Acids Have Different Propensities for Forming Alpha Helices, Beta Sheets, and Beta Turns
            • 3.6.2. Protein Folding Is a Highly Cooperative Process
            • 3.6.3. Proteins Fold by Progressive Stabilization of Intermediates Rather Than by Random Search
            • 3.6.4. Prediction of Three-Dimensional Structure from Sequence Remains a Great Challenge
            • 3.6.5. Protein Modification and Cleavage Confer New Capabilities
            • Proteins Are Built from a Repertoire of 20 Amino Acids
            • Primary Structure: Amino Acids Are Linked by Peptide Bonds to Form Polypeptide Chains
            • Secondary Structure: Polypeptide Chains Can Fold into Regular Structures Such as the Alpha Helix, the Beta Sheet, and Turns and Loops
            • Tertiary Structure: Water-Soluble Proteins Fold into Compact Structures with Nonpolar Cores
            • Quaternary Structure: Polypeptide Chains Can Assemble into Multisubunit Structures
            • The Amino Acid Sequence of a Protein Determines Its Three-Dimensional Structure
            • Key Terms
            • Ionization of Water
            • Definition of Acid and Base
            • Definition of pH and pK
            • Henderson-Hasselbalch Equation
            • Buffers
            • pKa Values of Amino Acids
            • Media Problem
            • Where to start
            • Books
            • Conformation of proteins
            • Alpha helices, beta sheets, and loops
            • Domains
            • Protein folding
            • Covalent modification of proteins
            • Molecular graphics
            • 4.1. The Purification of Proteins Is an Essential First Step in Understanding Their Function
              • 4.1.1. The Assay: How Do We Recognize the Protein That We Are Looking For?
              • 4.1.2. Proteins Must Be Released from the Cell to Be Purified
              • 4.1.3. Proteins Can Be Purified According to Solubility, Size, Charge, and Binding Affinity
              • 4.1.4. Proteins Can Be Separated by Gel Electrophoresis and Displayed
              • 4.1.5. A Protein Purification Scheme Can Be Quantitatively Evaluated
              • 4.1.6. Ultracentrifugation Is Valuable for Separating Biomolecules and Determining Their Masses
              • 4.1.7. The Mass of a Protein Can Be Precisely Determined by Mass Spectrometry
              • 4.2.1. Proteins Can Be Specifically Cleaved into Small Peptides to Facilitate Analysis
              • 4.2.2. Amino Acid Sequences Are Sources of Many Kinds of Insight
              • 4.2.3. Recombinant DNA Technology Has Revolutionized Protein Sequencing
              • 4.3.1. Antibodies to Specific Proteins Can Be Generated
              • 4.3.2. Monoclonal Antibodies with Virtually Any Desired Specificity Can Be Readily Prepared
              • 4.3.3. Proteins Can Be Detected and Quantitated by Using an Enzyme-Linked Immunosorbent Assay
              • 4.3.4. Western Blotting Permits the Detection of Proteins Separated by Gel Electrophoresis
              • 4.3.5. Fluorescent Markers Make Possible the Visualization of Proteins in the Cell
              • 4.5.1. Nuclear Magnetic Resonance Spectroscopy Can Reveal the Structures of Proteins in Solution
              • 4.5.2. X-Ray Crystallography Reveals Three-Dimensional Structure in Atomic Detail
              • The Purification of Proteins Is an Essential Step in Understanding Their Function
              • Amino Acid Sequences Can Be Determined by Automated Edman Degradation
              • Immunology Provides Important Techniques with Which to Investigate Proteins
              • Peptides Can Be Synthesized by Automated Solid-Phase Methods
              • Three-Dimensional Protein Structure Can Be Determined by NMR Spectroscopy and X-Ray Crystallography
              • Key Terms
              • Chapter Integration Problems
              • Data Interpretation Problems
              • Where to start
              • Books
              • Protein purification and analysis
              • Ultracentrifugation and mass spectrometry
              • X-ray crystallography and spectroscopy
              • Monoclonal antibodies and fluorescent molecules
              • Chemical synthesis of proteins
              • 5.1. A Nucleic Acid Consists of Four Kinds of Bases Linked to a Sugar-Phosphate Backbone
                • 5.1.1. RNA and DNA Differ in the Sugar Component and One of the Bases
                • 5.1.2. Nucleotides Are the Monomeric Units of Nucleic Acids
                • 5.2.1. The Double Helix Is Stabilized by Hydrogen Bonds and Hydrophobic Interactions
                • 5.2.2. The Double Helix Facilitates the Accurate Transmission of Hereditary Information
                • 5.2.3. The Double Helix Can Be Reversibly Melted
                • 5.2.4. Some DNA Molecules Are Circular and Supercoiled
                • 5.2.5. Single-Stranded Nucleic Acids Can Adopt Elaborate Structures
                • 5.3.1. DNA Polymerase Catalyzes Phosphodiester-Bond Formation
                • 5.3.2. The Genes of Some Viruses Are Made of RNA
                • 5.4.1. Several Kinds of RNA Play Key Roles in Gene Expression
                • 5.4.2. All Cellular RNA Is Synthesized by RNA Polymerases
                • 5.4.3. RNA Polymerases Take Instructions from DNA Templates
                • 5.4.4. Transcription Begins near Promoter Sites and Ends at Terminator Sites
                • 5.4.5. Transfer RNA Is the Adaptor Molecule in Protein Synthesis
                • 5.5.1. Major Features of the Genetic Code
                • 5.5.2. Messenger RNA Contains Start and Stop Signals for Protein Synthesis
                • 5.5.3. The Genetic Code Is Nearly Universal
                • 5.6.1. RNA Processing Generates Mature RNA
                • 5.6.2. Many Exons Encode Protein Domains
                • A Nucleic Acid Consists of Four Kinds of Bases Linked to a Sugar-Phosphate Backbone
                • A Pair of Nucleic Acid Chains with Complementary Sequences Can Form a Double-Helical Structure
                • DNA Is Replicated by Polymerases That Take Instructions from Templates
                • Gene Expression Is the Transformation of DNA Information into Functional Molecules
                • Amino Acids Are Encoded by Groups of Three Bases Starting from a Fixed Point
                • Most Eukaryotic Genes Are Mosaics of Introns and Exons
                • Key Terms
                • Chapter Integration Problems
                • Media Problem
                • Where to start
                • Books
                • DNA structure
                • DNA replication
                • Discovery of messenger RNA
                • Genetic code
                • Introns, exons, and split genes
                • Reminiscences and historical accounts
                • 6.1. The Basic Tools of Gene Exploration
                  • 6.1.1. Restriction Enzymes Split DNA into Specific Fragments
                  • 6.1.2. Restriction Fragments Can Be Separated by Gel Electrophoresis and Visualized
                  • 6.1.3. DNA Is Usually Sequenced by Controlled Termination of Replication (Sanger Dideoxy Method)
                  • 6.1.4. DNA Probes and Genes Can Be Synthesized by Automated Solid-Phase Methods
                  • 6.1.5. Selected DNA Sequences Can Be Greatly Amplified by the Polymerase Chain Reaction
                  • 6.1.6. PCR Is a Powerful Technique in Medical Diagnostics, Forensics, and Molecular Evolution
                  • 6.2.1. Restriction Enzymes and DNA Ligase Are Key Tools in Forming Recombinant DNA Molecules
                  • 6.2.2. Plasmids and Lambda Phage Are Choice Vectors for DNA Cloning in Bacteria
                  • 6.2.3. Specific Genes Can Be Cloned from Digests of Genomic DNA
                  • 6.2.4. Long Stretches of DNA Can Be Efficiently Analyzed by Chromosome Walking
                  • 6.3.1. Complementary DNA Prepared from mRNA Can Be Expressed in Host Cells
                  • 6.3.2. Gene-Expression Levels Can Be Comprehensively Examined
                  • 6.3.3. New Genes Inserted into Eukaryotic Cells Can Be Efficiently Expressed
                  • 6.3.4. Transgenic Animals Harbor and Express Genes That Were Introduced into Their Germ Lines
                  • 6.3.5. Gene Disruption Provides Clues to Gene Function
                  • 6.3.6. Tumor-Inducing Plasmids Can Be Used to Introduce New Genes into Plant Cells
                  • 6.4.1. Proteins with New Functions Can Be Created Through Directed Changes in DNA
                  • 6.4.2. Recombinant DNA Technology Has Opened New Vistas
                  • The Basic Tools of Gene Exploration
                  • Recombinant DNA Technology Has Revolutionized All Aspects of Biology
                  • Manipulating the Genes of Eukaryotes
                  • Novel Proteins Can Be Engineered by Site-Specific Mutagenesis
                  • Key Terms
                  • Chapter Integration Problem
                  • Chapter Integration and Data Analysis Problem
                  • Data Interpretation Problem
                  • Where to start
                  • Books on recombinant DNA technology
                  • DNA sequencing and synthesis
                  • Polymerase chain reaction (PCR)
                  • DNA arrays
                  • Introduction of genes into animal cells
                  • Genetic engineering of plants
                  • 7.1. Homologs Are Descended from a Common Ancestor
                  • 7.2. Statistical Analysis of Sequence Alignments Can Detect Homology
                    • 7.2.1. The Statistical Significance of Alignments Can Be Estimated by Shuffling
                    • 7.2.2. Distant Evolutionary Relationships Can Be Detected Through the Use of Substitution Matrices
                    • 7.2.3. Databases Can Be Searched to Identify Homologous Sequences
                    • 7.3.1. Tertiary Structure Is More Conserved Than Primary Structure
                    • 7.3.2. Knowledge of Three-Dimensional Structures Can Aid in the Evaluation of Sequence Alignments
                    • 7.3.3. Repeated Motifs Can Be Detected by Aligning Sequences with Themselves
                    • 7.3.4. Convergent Evolution: Common Solutions to Biochemical Challenges
                    • 7.3.5. Comparison of RNA Sequences Can Be a Source of Insight into Secondary Structures
                    • 7.5.1. Ancient DNA Can Sometimes Be Amplified and Sequenced
                    • 7.5.2. Molecular Evolution Can Be Examined Experimentally
                    • Homologs Are Descended from a Common Ancestor
                    • Statistical Analysis of Sequence Alignments Can Detect Homology
                    • Examination of Three-Dimensional Structure Enhances Our Understanding of Evolutionary Relationships
                    • Evolutionary Trees Can Be Constructed on the Basis of Sequence Information
                    • Modern Techniques Make the Experimental Exploration of Evolution Possible
                    • Key Terms
                    • Media Problem
                    • Book
                    • Sequence alignment
                    • Structure comparison
                    • Domain detection
                    • Evolutionary trees
                    • Ancient DNA
                    • Evolution in the laboratory
                    • Web sites
                    • 8.1. Enzymes Are Powerful and Highly Specific Catalysts
                      • 8.1.1. Many Enzymes Require Cofactors for Activity
                      • 8.1.2. Enzymes May Transform Energy from One Form into Another
                      • 8.1.3. Enzymes Are Classified on the Basis of the Types of Reactions That They Catalyze
                      • 8.2.1. The Free-Energy Change Provides Information About the Spontaneity but Not the Rate of a Reaction
                      • 8.2.2. The Standard Free-Energy Change of a Reaction Is Related to the Equilibrium Constant
                      • 8.2.3. Enzymes Alter Only the Reaction Rate and Not the Reaction Equilibrium
                      • 8.3.1. The Formation of an Enzyme-Substrate Complex Is the First Step in Enzymatic Catalysis
                      • 8.3.2. The Active Sites of Enzymes Have Some Common Features
                      • 8.4.1. The Significance of KM and Vmax Values
                      • 8.4.2. Kinetic Perfection in Enzymatic Catalysis: The kcat/KM Criterion
                      • 8.4.3. Most Biochemical Reactions Include Multiple Substrates
                      • 8.4.4. Allosteric Enzymes Do Not Obey Michaelis-Menten Kinetics
                      • 8.5.1. Competitive and Noncompetitive Inhibition Are Kinetically Distinguishable
                      • 8.5.2. Irreversible Inhibitors Can Be Used to Map the Active Site
                      • 8.5.3. Transition-State Analogs Are Potent Inhibitors of Enzymes
                      • 8.5.4. Catalytic Antibodies Demonstrate the Importance of Selective Binding of the Transition State to Enzymatic Activity
                      • 8.5.5. Penicillin Irreversibly Inactivates a Key Enzyme in Bacterial Cell-Wall Synthesis
                      • 8.6.1. Water-Soluble Vitamins Function As Coenzymes
                      • 8.6.2. Fat-Soluble Vitamins Participate in Diverse Processes Such as Blood Clotting and Vision
                      • Enzymes are Powerful and Highly Specific Catalysts
                      • Free Energy Is a Useful Thermodynamic Function for Understanding Enzymes
                      • Enzymes Accelerate Reactions by Facilitating the Formation of the Transition State
                      • The Michaelis-Menten Model Accounts for the Kinetic Properties of Many Enzymes
                      • Enzymes Can Be Inhibited by Specific Molecules
                      • Vitamins Are Often Precursors to Coenzymes
                      • Key Terms
                      • Data Interpretation Problems
                      • Chapter Integration Problems
                      • Media Problem
                      • Where to start
                      • Books
                      • Transition-state stabilization, analogs, and other enzyme inhibitors
                      • Catalytic antibodies
                      • Enzyme kinetics and mechanisms
                      • 9.1. Proteases: Facilitating a Difficult Reaction
                        • 9.1.1. Chymotrypsin Possesses a Highly Reactive Serine Residue
                        • 9.1.2. Chymotrypsin Action Proceeds in Two Steps Linked by a Covalently Bound Intermediate
                        • 9.1.3. Serine is Part of a Catalytic Triad That Also Includes Histidine and Aspartic Acid
                        • 9.1.4. Catalytic Triads Are Found in Other Hydrolytic Enzymes
                        • 9.1.5. The Catalytic Triad Has Been Dissected by Site-Directed Mutagenesis
                        • 9.1.6. Cysteine, Aspartyl, and Metalloproteases Are Other Major Classes of Peptide-Cleaving Enzymes
                        • 9.1.7. Protease Inhibitors Are Important Drugs
                        • 9.2.1. Carbonic Anhydrase Contains a Bound Zinc Ion Essential for Catalytic Activity
                        • 9.2.2. Catalysis Entails Zinc Activation of Water
                        • 9.2.3. A Proton Shuttle Facilitates Rapid Regeneration of the Active Form of the Enzyme
                        • 9.2.4. Convergent Evolution Has Generated Zinc-Based Active Sites in Different Carbonic Anhydrases
                        • 9.3.1. Cleavage Is by In-Line Displacement of 3′ Oxygen from Phosphorus by Magnesium-Activated Water
                        • 9.3.2. Restriction Enzymes Require Magnesium for Catalytic Activity
                        • 9.3.3. The Complete Catalytic Apparatus Is Assembled Only Within Complexes of Cognate DNA Molecules, Ensuring Specificity
                        • 9.3.4. Type II Restriction Enzymes Have a Catalytic Core in Common and Are Probably Related by Horizontal Gene Transfer
                        • 9.4.1. NMP Kinases Are a Family of Enzymes Containing P-Loop Structures
                        • 9.4.2. Magnesium (or Manganese) Complexes of Nucleoside Triphosphates Are the True Substrates for Essentially All NTP-Dependent Enzymes
                        • 9.4.3. ATP Binding Induces Large Conformational Changes
                        • 9.4.4. P-Loop NTPase Domains Are Present in a Range of Important Proteins
                        • Proteases: Facilitating a Difficult Reaction
                        • Carbonic Anhydrases: Making a Fast Reaction Faster
                        • Restriction Enzymes: Performing Highly Specific DNA Cleavage Reactions
                        • Nucleoside Monophosphate Kinases: Catalyzing Phosphoryl Group Exchange Without Promoting Hydrolysis
                        • Key Terms
                        • Mechanism Problem
                        • Media Problems
                        • Where to start
                        • Books
                        • Chymotrypsin and other serine proteases
                        • Other proteases
                        • Carbonic anhydrase
                        • Restriction enzymes
                        • NMP kinases
                        • 10.1. Aspartate Transcarbamoylase Is Allosterically Inhibited by the End Product of Its Pathway
                          • 10.1.1. ACTase Consists of Separable Catalytic and Regulatory Subunits
                          • 10.1.2. Allosteric Interactions in ATCase Are Mediated by Large Changes in Quaternary Structure
                          • 10.1.3. Allosterically Regulated Enzymes Do Not Follow Michaelis-Menten Kinetics
                          • 10.1.4. Allosteric Regulators Modulate the T-to-R Equilibrium
                          • 10.1.5. The Concerted Model Can Be Formulated in Quantitative Terms
                          • 10.1.6. Sequential Models Also Can Account for Allosteric Effects
                          • 10.2.1. Oxygen Binding Induces Substantial Structural Changes at the Iron Sites in Hemoglobin
                          • 10.2.2. Oxygen Binding Markedly Changes the Quaternary Structure of Hemoglobin
                          • 10.2.3. Tuning the Oxygen Affinity of Hemoglobin: The Effect of 2,3-Bisphosphoglycerate
                          • 10.2.4. The Bohr Effect: Hydrogen Ions and Carbon Dioxide Promote the Release of Oxygen
                          • 10.4.1. Phosphorylation Is a Highly Effective Means of Regulating the Activities of Target Proteins
                          • 10.4.2. Cyclic AMP Activates Protein Kinase A by Altering the Quaternary Structure
                          • 10.4.3. ATP and the Target Protein Bind to a Deep Cleft in the Catalytic Subunit of Protein Kinase A
                          • 10.5.1. Chymotrypsinogen Is Activated by Specific Cleavage of a Single Peptide Bond
                          • 10.5.2. Proteolytic Activation of Chymotrypsinogen Leads to the Formation of a Substrate-Binding Site
                          • 10.5.3. The Generation of Trypsin from Trypsinogen Leads to the Activation of Other Zymogens
                          • 10.5.4. Some Proteolytic Enzymes Have Specific Inhibitors
                          • 10.5.5. Blood Clotting Is Accomplished by a Cascade of Zymogen Activations
                          • 10.5.6. Fibrinogen Is Converted by Thrombin into a Fibrin Clot
                          • 10.5.7. Prothrombin Is Readied for Activation by a Vitamin K-Dependent Modification
                          • 10.5.8. Hemophilia Revealed an Early Step in Clotting
                          • 10.5.9. The Clotting Process Must Be Precisely Regulated
                          • Aspartate Transcarbamoylase Is Allosterically Inhibited by the End Product of Its Pathway
                          • Hemoglobin Transports Oxygen Efficiently by Binding Oxygen Cooperatively
                          • Isozymes Provide a Means of Regulation Specific to Distinct Tissues and Developmental Stages
                          • Covalent Modification Is a Means of Regulating Enzyme Activity
                          • Many Enzymes Are Activated by Specific Proteolytic Cleavage
                          • Key Terms
                          • Data Interpretation Problems
                          • Chapter Integration Problem
                          • Mechanism Problems
                          • Media Problem
                          • Where to start
                          • Aspartate transcarbamoylase and allosteric interactions
                          • Hemoglobin
                          • Covalent modification
                          • Protein kinase A
                          • Zymogen activation
                          • Protease inhibitors
                          • Clotting cascade
                          • 11.1. Monosaccharides Are Aldehydes or Ketones with Multiple Hydroxyl Groups
                            • 11.1.1. Pentoses and Hexoses Cyclize to Form Furanose and Pyranose Rings
                            • 11.1.2. Conformation of Pyranose and Furanose Rings
                            • 11.1.3. Monosaccharides Are Joined to Alcohols and Amines Through Glycosidic Bonds
                            • 11.2.1. Sucrose, Lactose, and Maltose Are the Common Disaccharides
                            • 11.2.2. Glycogen and Starch Are Mobilizable Stores of Glucose
                            • 11.2.3. Cellulose, the Major Structural Polymer of Plants, Consists of Linear Chains of Glucose Units
                            • 11.2.4. Glycosaminoglycans Are Anionic Polysaccharide Chains Made of Repeating Disaccharide Units
                            • 11.2.5. Specific Enzymes Are Responsible for Oligosaccharide Assembly
                            • 11.3.1. Carbohydrates May Be Linked to Proteins Through Asparagine (N-Linked) or Through Serine or Threonine (O-Linked) Residues
                            • 11.3.2. Protein Glycosylation Takes Place in the Lumen of the Endoplasmic Reticulum and in the Golgi Complex
                            • 11.3.3. N-Linked Glycoproteins Acquire Their Initial Sugars from Dolichol Donors in the Endoplasmic Reticulum
                            • 11.3.4. Transport Vesicles Carry Proteins from the Endoplasmic Reticulum to the Golgi Complex for Further Glycosylation and Sorting
                            • 11.3.5. Mannose 6-phosphate Targets Lysosomal Enzymes to Their Destinations
                            • 11.3.6. Glucose Residues Are Added and Trimmed to Aid in Protein Folding
                            • 11.3.7. Oligosaccharides Can Be “Sequenced”
                            • 11.4.1. Lectins Promote Interactions Between Cells
                            • 11.4.2. Influenza Virus Binds to Sialic Acid Residues
                            • Monosaccharides Are Aldehydes or Ketones with Multiple Hydroxyl Groups
                            • Complex Carbohydrates Are Formed by Linkage of Monosaccharides
                            • Carbohydrates Can Attach to Proteins to Form Glycoproteins
                            • Lectins Are Specific Carbohydrate-Binding Proteins
                            • Key Terms
                            • Chapter Integration Problem
                            • Where to start
                            • Books
                            • Structure of carbohydrate-binding proteins
                            • Glycoproteins
                            • Carbohydrates in recognition processes
                            • Carbohydrate sequencing
                            • 12.1. Many Common Features Underlie the Diversity of Biological Membranes
                            • 12.2. Fatty Acids Are Key Constituents of Lipids
                              • 12.2.1. The Naming of Fatty Acids
                              • 12.2.2. Fatty Acids Vary in Chain Length and Degree of Unsaturation
                              • 12.3.1. Phospholipids Are the Major Class of Membrane Lipids
                              • 12.3.2. Archaeal Membranes Are Built from Ether Lipids with Branched Chains
                              • 12.3.3. Membrane Lipids Can Also Include Carbohydrate Moieties
                              • 12.3.4. Cholesterol Is a Lipid Based on a Steroid Nucleus
                              • 12.3.5. A Membrane Lipid Is an Amphipathic Molecule Containing a Hydrophilic and a Hydrophobic Moiety
                              • 12.4.1. Lipid Vesicles Can Be Formed from Phospholipids
                              • 12.4.2. Lipid Bilayers Are Highly Impermeable to Ions and Most Polar Molecules
                              • 12.5.1. Proteins Associate with the Lipid Bilayer in a Variety of Ways
                              • 12.5.2. Proteins Interact with Membranes in a Variety of Ways
                              • 12.5.3. Some Proteins Associate with Membranes Through Covalently Attached Hydrophobic Groups
                              • 12.5.4. Transmembrane Helices Can Be Accurately Predicted from Amino Acid Sequences
                              • 12.6.1. The Fluid Mosaic Model Allows Lateral Movement but Not Rotation Through the Membrane
                              • 12.6.2. Membrane Fluidity Is Controlled by Fatty Acid Composition and Cholesterol Content
                              • 12.6.3. All Biological Membranes Are Asymmetric
                              • 12.7.1. Proteins Are Targeted to Specific Compartments by Signal Sequences
                              • 12.7.2. Membrane Budding and Fusion Underlie Several Important Biological Processes
                              • Many Common Features Underlie the Diversity of Biological Membranes
                              • Fatty Acids Are Key Constituents of Lipids
                              • There Are Three Common Types of Membrane Lipids
                              • Phospholipids and Glycolipids Readily Form Bimolecular Sheets in Aqueous Media
                              • Proteins Carry Out Most Membrane Processes
                              • Lipids and Many Membrane Proteins Diffuse Rapidly in the Plane of the Membrane
                              • Eukaryotic Cells Contain Compartments Bounded by Internal Membranes
                              • Key Terms
                              • Data Interpretation Problems
                              • Chapter Integration Problem
                              • Where to start
                              • Books
                              • Membrane lipids and dynamics
                              • Structure of membrane proteins
                              • Intracellular membranes
                              • 13.1. The Transport of Molecules Across a Membrane May Be Active or Passive
                                • 13.1.1. Many Molecules Require Protein Transporters to Cross Membranes
                                • 13.1.2. Free Energy Stored in Concentration Gradients Can Be Quantified
                                • 13.2.1. The Sarcoplasmic Reticulum Ca 2+ ATPase Is an Integral Membrane Protein
                                • 13.2.2. P-Type ATPases Are Evolutionarily Conserved and Play a Wide Range of Roles
                                • 13.2.3. Digitalis Specifically Inhibits the Na + -K + Pump by Blocking Its Dephosphorylation
                                • 13.5.1. Patch-Clamp Conductance Measurements Reveal the Activities of Single Channels
                                • 13.5.2. Ion-Channel Proteins Are Built of Similar Units
                                • 13.5.3. Action Potentials Are Mediated by Transient Changes in Na + and K + Permeability
                                • 13.5.4. The Sodium Channel Is an Example of a Voltage-Gated Channel
                                • 13.5.5. Potassium Channels Are Homologous to the Sodium Channel
                                • 13.5.6. The Structure of a Potassium Channel Reveals the Basis of Rapid Ion Flow with Specificity
                                • 13.5.7. The Structure of the Potassium Channel Explains Its Rapid Rates of Transport
                                • 13.5.8. A Channel Can Be Inactivated by Occlusion of the Pore: The Ball-and-Chain Model
                                • The Transport of Molecules Across a Membrane May Be Active or Passive
                                • A Family of Membrane Proteins Uses ATP Hydrolysis to Pump Ions Across Membranes
                                • Multidrug Resistance and Cystic Fibrosis Highlight a Family of Membrane Proteins with ATP-Binding Cassette Domains
                                • Secondary Transporters Use One Concentration Gradient to Power the Formation of Another
                                • Specific Channels Can Rapidly Transport Ions Across Membranes
                                • Gap Junctions Allow Ions and Small Molecules to Flow Between Communicating Cells
                                • Key Terms
                                • Chapter Integration Problem
                                • Mechanism Problem
                                • Data Interpretation Problem
                                • Media Problem
                                • Where to start
                                • Books
                                • Voltage-gated ion channels
                                • Ligand-gated ion channels
                                • ATP-driven ion pumps
                                • ATP-binding cassette (ABC) proteins
                                • Symporters and antiporters
                                • Gap junctions
                                • Chapter 14. Metabolism: Basic Concepts and Design
                                  • 14.1. Metabolism Is Composed of Many Coupled, Interconnecting Reactions
                                    • 14.1.1. A Thermodynamically Unfavorable Reaction Can Be Driven by a Favorable Reaction
                                    • 14.1.2. ATP Is the Universal Currency of Free Energy in Biological Systems
                                    • 14.1.3. ATP Hydrolysis Drives Metabolism by Shifting the Equilibrium of Coupled Reactions
                                    • 14.1.4. Structural Basis of the High Phosphoryl Transfer Potential of ATP
                                    • 14.1.5. Phosphoryl Transfer Potential Is an Important Form of Cellular Energy Transformation
                                    • 14.2.1. High Phosphoryl Transfer Potential Compounds Can Couple Carbon Oxidation to ATP Synthesis
                                    • 14.2.2. Ion Gradients Across Membranes Provide an Important Form of Cellular Energy That Can Be Coupled to ATP Synthesis
                                    • 14.2.3. Stages in the Extraction of Energy from Foodstuffs
                                    • 14.3.1. Activated Carriers Exemplify the Modular Design and Economy of Metabolism
                                    • 14.3.2. Key Reactions Are Reiterated Throughout Metabolism
                                    • 14.3.3. Metabolic Processes Are Regulated in Three Principal Ways
                                    • 14.3.4. Evolution of Metabolic Pathways
                                    • Metabolism Is Composed of Many Coupled, Interconnecting Reactions
                                    • The Oxidation of Carbon Fuels Is an Important Source of Cellular Energy
                                    • Metabolic Pathways Contain Many Recurring Motifs
                                    • Key Terms
                                    • Chapter Integration Problem
                                    • Data Interpretation
                                    • Media Problem
                                    • Where to start
                                    • Books
                                    • Thermodynamics
                                    • Bioenergetics and metabolism
                                    • Regulation of metabolism
                                    • Historical aspects
                                    • 15.1. Seven-Transmembrane-Helix Receptors Change Conformation in Response to Ligand Binding and Activate G Proteins
                                      • 15.1.1. Ligand Binding to 7TM Receptors Leads to the Activation of G Proteins
                                      • 15.1.2. G Proteins Cycle Between GDP- and GTP-Bound Forms
                                      • 15.1.3. Activated G Proteins Transmit Signals by Binding to Other Proteins
                                      • 15.1.4. G Proteins Spontaneously Reset Themselves Through GTP Hydrolysis
                                      • 15.1.5. Cyclic AMP Stimulates the Phosphorylation of Many Target Proteins by Activating Protein Kinase A
                                      • 15.2.1. Inositol 1,4,5-trisphosphate Opens Channels to Release Calcium Ions from Intracellular Stores
                                      • 15.2.2. Diacylglycerol Activates Protein Kinase C, Which Phosphorylates Many Target Proteins
                                      • 15.3.1. Ionophores Allow the Visualization of Changes in Calcium Concentration
                                      • 15.3.2. Calcium Activates the Regulatory Protein Calmodulin, Which Stimulates Many Enzymes and Transporters
                                      • 15.4.1. Some Receptors Contain Tyrosine Kinase Domains Within Their Covalent Structures
                                      • 15.4.2. Ras, Another Class of Signaling G Protein
                                      • 15.5.1. Protein Kinase Inhibitors May Be Effective Anticancer Drugs
                                      • 15.5.2. Cholera and Whooping Cough Are Due to Altered G-Protein Activity
                                      • Seven-Transmembrane-Helix Receptors Change Conformation in Response to Ligand Binding and Activate G Proteins
                                      • The Hydrolysis of Phosphatidyl Inositol Bisphosphate by Phospholipase C Generates Two Messengers
                                      • Calcium Ion Is a Ubiquitous Cytosolic Messenger
                                      • Some Receptors Dimerize in Response to Ligand Binding and Signal by Cross-Phosphorylation
                                      • Defects in Signaling Pathways Can Lead to Cancer and Other Diseases
                                      • Recurring Features of Signal-Transduction Pathways Reveal Evolutionary Relationships
                                      • Key Terms
                                      • Chapter Integration Problem
                                      • Mechanism Problem
                                      • Data Interpretation Problems
                                      • Media Problem
                                      • Where to start
                                      • G proteins and 7TM receptors
                                      • cAMP cascade
                                      • Phosphoinositide cascade
                                      • Calcium
                                      • Protein kinases, including receptor tyrosine kinases
                                      • Ras
                                      • Cancer
                                      • 16.1. Glycolysis Is an Energy-Conversion Pathway in Many Organisms
                                        • 16.1.1. Hexokinase Traps Glucose in the Cell and Begins Glycolysis
                                        • 16.1.2. The Formation of Fructose 1,6-bisphosphate from Glucose 6-phosphate
                                        • 16.1.3. The Six-Carbon Sugar Is Cleaved into Two Three-Carbon Fragments by Aldolase
                                        • 16.1.4. Triose phosphate isomerase Salvages a Three-Carbon Fragment
                                        • 16.1.5. Energy Transformation: Phosphorylation Is Coupled to the Oxidation of Glyceraldehyde 3-phosphate by a Thioester Intermediate
                                        • 16.1.6. The Formation of ATP from 1,3-Bisphosphoglycerate
                                        • 16.1.7. The Generation of Additional ATP and the Formation of Pyruvate
                                        • 16.1.8. Energy Yield in the Conversion of Glucose into Pyruvate
                                        • 16.1.9. Maintaining Redox Balance: The Diverse Fates of Pyruvate
                                        • 16.1.10. The Binding Site for NAD + Is Similar in Many Dehydrogenases
                                        • 16.1.11. The Entry of Fructose and Galactose into Glycolysis
                                        • 16.1.12. Many Adults Are Intolerant of Milk Because They Are Deficient in Lactase
                                        • 16.1.13. Galactose Is Highly Toxic If the Transferase Is Missing
                                        • 16.2.1. Phosphofructokinase Is the Key Enzyme in the Control of Glycolysis
                                        • 16.2.2. A Regulated Bifunctional Enzyme Synthesizes and Degrades Fructose 2,6 -bisphosphate
                                        • 16.2.3. Hexokinase and Pyruvate kinase Also Set the Pace of Glycolysis
                                        • 16.2.4. A Family of Transporters Enables Glucose to Enter and Leave Animal Cells
                                        • 16.2.5. Cancer and Glycolysis
                                        • 16.3.1. Gluconeogenesis Is Not a Reversal of Glycolysis
                                        • 16.3.2. The Conversion of Pyruvate into Phosphoenolpyruvate Begins with the Formation of Oxaloacetate
                                        • 16.3.3. Oxaloacetate Is Shuttled into the Cytosol and Converted into Phosphoenolpyruvate
                                        • 16.3.4. The Conversion of Fructose 1,6-bisphosphate into Fructose 6-phosphate and Orthophosphate Is an Irreversible Step
                                        • 16.3.5. The Generation of Free Glucose Is an Important Control Point
                                        • 16.3.6. Six High Transfer Potential Phosphoryl Groups Are Spent in Synthesizing Glucose from Pyruvate
                                        • 16.4.1. Substrate Cycles Amplify Metabolic Signals and Produce Heat
                                        • 16.4.2. Lactate and Alanine Formed by Contracting Muscle Are Used by Other Organs
                                        • 16.4.3. Glycolysis and Gluconeogenesis Are Evolutionarily Intertwined
                                        • Glycolysis Is an Energy-Conversion Pathway in Many Organisms
                                        • The Glycolytic Pathway Is Tightly Controlled
                                        • Glucose Can Be Synthesized from Noncarbohydrate Precursors
                                        • Gluconeogenesis and Glycolysis Are Reciprocally Regulated
                                        • Key Terms
                                        • Mechanism Problem
                                        • Chapter Integration Problem
                                        • Data Interpretation Problem
                                        • Media Problems
                                        • Where to start
                                        • Books
                                        • Structure of glycolytic and gluconeogenic enzymes
                                        • Catalytic mechanisms
                                        • Regulation
                                        • Sugar transporters
                                        • Genetic diseases
                                        • Evolution
                                        • Historical aspects
                                        • 17.1. The Citric Acid Cycle Oxidizes Two-Carbon Units
                                          • 17.1.1. The Formation of Acetyl Coenzyme A from Pyruvate
                                          • 17.1.2. Flexible Linkages Allow Lipoamide to Move Between Different Active Sites
                                          • 17.1.3. Citrate Synthase Forms Citrate from Oxaloacetate and Acetyl Coenzyme A
                                          • 17.1.4. Citrate Is Isomerized into Isocitrate
                                          • 17.1.5. Isocitrate Is Oxidized and Decarboxylated to α-Ketoglutarate
                                          • 17.1.6. Succinyl Coenzyme A Is Formed by the Oxidative Decarboxylation of α-Ketoglutarate
                                          • 17.1.7. A High Phosphoryl-Transfer Potential Compound Is Generated from Succinyl Coenzyme A
                                          • 17.1.8. Oxaloacetate Is Regenerated by the Oxidation of Succinate
                                          • 17.1.9. Stoichiometry of the Citric Acid Cycle
                                          • 17.2.1. The Pyruvate Dehydrogenase Complex Is Regulated Allosterically and by Reversible Phosphorylation
                                          • 17.2.2. The Citric Acid Cycle Is Controlled at Several Points
                                          • 17.3.1. The Citric Acid Cycle Must Be Capable of Being Rapidly Replenished
                                          • 17.3.2. The Disruption of Pyruvate Metabolism Is the Cause of Beriberi and Poisoning by Mercury and Arsenic
                                          • 17.3.3. Speculations on the Evolutionary History of the Citric Acid Cycle
                                          • The Citric Acid Cycle Oxidizes Two-Carbon Units
                                          • Entry to the Citric Acid Cycle and Metabolism Through It Are Controlled
                                          • The Citric Acid Cycle Is a Source of Biosynthetic Precursors
                                          • The Glyoxylate Cycle Enables Plants and Bacteria to Grow on Acetate
                                          • Key Terms
                                          • Chapter Integration Problem
                                          • Mechanism Problems
                                          • Data Interpretation
                                          • Where to start
                                          • Pyruvate dehydrogenase complex
                                          • Structure of citric acid cycle enzymes
                                          • Organization of the citric acid cycle
                                          • Regulation
                                          • Evolutionary aspects
                                          • Discovery of the citric acid cycle
                                          • 18.1. Oxidative Phosphorylation in Eukaryotes Takes Place in Mitochondria
                                            • 18.1.1. Mitochondria Are Bounded by a Double Membrane
                                            • 18.1.2. Mitochondria Are the Result of an Endosymbiotic Event
                                            • 18.2.1. High-Energy Electrons: Redox Potentials and Free-Energy Changes
                                            • 18.2.2. A 1.14-Volt Potential Difference Between NADH and O2 Drives Electron Transport Through the Chain and Favors the Formation of a Proton Gradient
                                            • 18.2.3. Electrons Can Be Transferred Between Groups That Are Not in Contact
                                            • 18.3.1. The High-Potential Electrons of NADH Enter the Respiratory Chain at NADH-Q Oxidoreductase
                                            • 18.3.2. Ubiquinol Is the Entry Point for Electrons from FADH2 of Flavoproteins
                                            • 18.3.3. Electrons Flow from Ubiquinol to Cytochrome c Through Q-Cytochrome c Oxidoreductase
                                            • 18.3.4. Transmembrane Proton Transport: The Q Cycle
                                            • 18.3.5. Cytochrome c Oxidase Catalyzes the Reduction of Molecular Oxygen to Water
                                            • 18.3.6. Toxic Derivatives of Molecular Oxygen Such as Superoxide Radical Are Scavenged by Protective Enzymes
                                            • 18.3.7. The Conformation of Cytochrome c Has Remained Essentially Constant for More Than a Billion Years
                                            • 18.4.1. ATP Synthase Is Composed of a Proton-Conducting Unit and a Catalytic Unit
                                            • 18.4.2. Proton Flow Through ATP Synthase Leads to the Release of Tightly Bound ATP: The Binding-Change Mechanism
                                            • 18.4.3. The World's Smallest Molecular Motor: Rotational Catalysis
                                            • 18.4.4. Proton Flow Around the c Ring Powers ATP Synthesis
                                            • 18.4.5. ATP Synthase and G Proteins Have Several Common Features
                                            • 18.5.1. Electrons from Cytosolic NADH Enter Mitochondria by Shuttles
                                            • 18.5.2. The Entry of ADP into Mitochondria Is Coupled to the Exit of ATP by ATP-ADP Translocase
                                            • 18.5.3. Mitochondrial Transporters for Metabolites Have a Common Tripartite Motif
                                            • 18.6.1. The Complete Oxidation of Glucose Yields About 30 Molecules of ATP
                                            • 18.6.2. The Rate of Oxidative Phosphorylation Is Determined by the Need for ATP
                                            • 18.6.3. Oxidative Phosphorylation Can Be Inhibited at Many Stages
                                            • 18.6.4. Regulated Uncoupling Leads to the Generation of Heat
                                            • 18.6.5. Mitochondrial Diseases Are Being Discovered
                                            • 18.6.6. Mitochondria Play a Key Role in Apoptosis
                                            • 18.6.7. Power Transmission by Proton Gradients: A Central Motif of Bioenergetics
                                            • Oxidative Phosphorylation in Eukaryotes Takes Place in Mitochondria
                                            • Oxidative Phosphorylation Depends on Electron Transfer
                                            • The Respiratory Chain Consists of Four Complexes: Three Proton Pumps and a Physical Link to the Citric Acid Cycle
                                            • A Proton Gradient Powers the Synthesis of ATP
                                            • Many Shuttles Allow Movement Across the Mitochondrial Membranes
                                            • The Regulation of Oxidative Phosphorylation Is Governed Primarily by the Need for ATP
                                            • Key Terms
                                            • Chapter Integration Problem
                                            • Data Interpretation Problem
                                            • Mechanism Problem
                                            • Media Problem
                                            • Where to start
                                            • Books
                                            • Electron-transport chain
                                            • ATP synthase
                                            • Translocators
                                            • Superoxide dismutase and catalase
                                            • Mitochondrial diseases
                                            • Apoptosis
                                            • Historical aspects
                                            • 19.1. Photosynthesis Takes Place in Chloroplasts
                                              • 19.1.1. The Primary Events of Photosynthesis Take Place in Thylakoid Membranes
                                              • 19.1.2. The Evolution of Chloroplasts
                                              • 19.2.1. Photosynthetic Bacteria and the Photosynthetic Reaction Centers of Green Plants Have a Common Core
                                              • 19.2.2. A Special Pair of Chlorophylls Initiates Charge Separation
                                              • 19.3.1. Photosystem II Transfers Electrons from Water to Plastoquinone and Generates a Proton Gradient
                                              • 19.3.2. Cytochrome bf Links Photosystem II to Photosystem I
                                              • 19.3.3. Photosystem I Uses Light Energy to Generate Reduced Ferredoxin, a Powerful Reductant
                                              • 19.3.4. Ferredoxin-NADP + Reductase Converts NADP + into NADPH
                                              • 19.4.1. The ATP Synthase of Chloroplasts Closely Resembles Those of Mitochondria and Prokaryotes
                                              • 19.4.2. Cyclic Electron Flow Through Photosystem I Leads to the Production of ATP Instead of NADPH
                                              • 19.4.3. The Absorption of Eight Photons Yields One O2, Two NADPH, and Three ATP Molecules
                                              • 19.5.1. Resonance Energy Transfer Allows Energy to Move from the Site of Initial Absorbance to the Reaction Center
                                              • 19.5.2. Light-Harvesting Complexes Contain Additional Chlorophylls and Carotinoids
                                              • 19.5.3. Phycobilisomes Serve as Molecular Light Pipes in Cyanobacteria and Red Algae
                                              • 19.5.4. Components of Photosynthesis Are Highly Organized
                                              • 19.5.5. Many Herbicides Inhibit the Light Reactions of Photosynthesis
                                              • Photosynthesis Takes Place in Chloroplasts
                                              • Light Absorption by Chlorophyll Induces Electron Transfer
                                              • Two Photosystems Generate a Proton Gradient and NADPH in Oxygenic Photosynthesis
                                              • A Proton Gradient Across the Thylakoid Membrane Drives ATP Synthesis
                                              • Accessory Pigments Funnel Energy into Reaction Centers
                                              • The Ability to Convert Light into Chemical Energy Is Ancient
                                              • Key Terms
                                              • Mechanism Problem
                                              • Data Interpretation and Chapter Integration Problem
                                              • Where to start
                                              • Books and general reviews
                                              • Electron-transfer mechanisms
                                              • Photosystem II
                                              • Oxygen evolution
                                              • Photosystem I and cytochrome bf
                                              • ATP synthase
                                              • Light-harvesting assemblies
                                              • Evolution
                                              • 20.1. The Calvin Cycle Synthesizes Hexoses from Carbon Dioxide and Water
                                                • 20.1.1. Carbon Dioxide Reacts with Ribulose 1,5-bisphosphate to Form Two Molecules of 3-Phosphoglycerate
                                                • 20.1.2. Catalytic Imperfection: Rubisco Also Catalyzes a Wasteful Oxygenase Reaction
                                                • 20.1.3. Hexose Phosphates Are Made from Phosphoglycerate, and Ribulose 1,5-bisphosphate Is Regenerated
                                                • 20.1.4. Three Molecules of ATP and Two Molecules of NADPH Are Used to Bring Carbon Dioxide to the Level of a Hexose
                                                • 20.1.5. Starch and Sucrose Are the Major Carbohydrate Stores in Plants
                                                • 20.2.1. Rubisco Is Activated by Light-Driven Changes in Proton and Magnesium Ion Concentrations
                                                • 20.2.2. Thioredoxin Plays a Key Role in Regulating the Calvin Cycle
                                                • 20.2.3. The C4 Pathway of Tropical Plants Accelerates Photosynthesis by Concentrating Carbon Dioxide
                                                • 20.2.4. Crassulacean Acid Metabolism Permits Growth in Arid Ecosystems
                                                • 20.3.1. Two Molecules of NADPH Are Generated in the Conversion of Glucose 6-phosphate into Ribulose 5-phosphate
                                                • 20.3.2. The Pentose Phosphate Pathway and Glycolysis Are Linked by Transketolase and Transaldolase
                                                • 20.3.3. Transketolase and Transaldolase Stabilize Carbanionic Intermediates by Different Mechanisms
                                                • 20.4.1. The Rate of the Pentose Phosphate Pathway Is Controlled by the Level of NADP +
                                                • 20.4.2. The Flow of Glucose 6-phosphate Depends on the Need for NADPH, Ribose 5-phosphate, and ATP
                                                • 20.4.3. Through the Looking Glass: The Calvin Cycle and the Pentose Phosphate Pathway
                                                • 20.5.1. Glucose 6-phosphate Dehydrogenase Deficiency Causes a Drug-Induced Hemolytic Anemia
                                                • 20.5.2. A Deficiency of Glucose 6-phosphate Dehydrogenase Confers an Evolutionary Advantage in Some Circumstances
                                                • The Calvin Cycle Synthesizes Hexoses from Carbon Dioxide and Water
                                                • The Activity of the Calvin Cycle Depends on Environmental Conditions
                                                • The Pentose Phosphate Pathway Generates NADPH and Synthesizes Five-Carbon Sugars
                                                • The Metabolism of Glucose 6-phosphate by the Pentose Phosphate Pathway Is Coordinated with Glycolysis
                                                • Glucose 6-phosphate Dehydrogenase Plays a Key Role in Protection Against Reactive Oxygen Species
                                                • Key Terms
                                                • Mechanism Problems
                                                • Chapter Integration Problems
                                                • Date Interpretation Problem
                                                • Where to start
                                                • Books and general reviews
                                                • Enzymes and reaction mechanisms
                                                • Carbon dioxide fixation and rubisco
                                                • Regulation
                                                • Glucose 6-phosphate dehydrogenase
                                                • Evolution
                                                • 21.1. Glycogen Breakdown Requires the Interplay of Several Enzymes
                                                  • 21.1.1. Phosphorylase Catalyzes the Phosphorolytic Cleavage of Glycogen to Release Glucose 1-phosphate
                                                  • 21.1.2. A Debranching Enzyme Also Is Needed for the Breakdown of Glycogen
                                                  • 21.1.3. Phosphoglucomutase Converts Glucose 1-phosphate into Glucose 6-phosphate
                                                  • 21.1.4. Liver Contains Glucose 6-phosphatase, a Hydrolytic Enzyme Absent from Muscle
                                                  • 21.1.5. Pyridoxal Phosphate Participates in the Phosphorolytic Cleavage of Glycogen
                                                  • 21.2.1. Muscle Phosphorylase Is Regulated by the Intracellular Energy Charge
                                                  • 21.2.2. Liver Phosphorylase Produces Glucose for Use by Other Tissues
                                                  • 21.2.3. Phosphorylase Kinase Is Activated by Phosphorylation and Calcium Ions
                                                  • 21.3.1. G Proteins Transmit the Signal for the Initiation of Glycogen Breakdown
                                                  • 21.3.2. Glycogen Breakdown Must Be Capable of Being Rapidly Turned Off
                                                  • 21.3.3. The Regulation of Glycogen Phosphorylase Became More Sophisticated as the Enzyme Evolved
                                                  • 21.4.1. UDP-Glucose Is an Activated Form of Glucose
                                                  • 21.4.2. Glycogen Synthase Catalyzes the Transfer of Glucose from UDP-Glucose to a Growing Chain
                                                  • 21.4.3. A Branching Enzyme Forms α-1,6 Linkages
                                                  • 21.4.4. Glycogen Synthase Is the Key Regulatory Enzyme in Glycogen Synthesis
                                                  • 21.4.5. Glycogen Is an Efficient Storage Form of Glucose
                                                  • 21.5.1. Protein Phosphatase 1 Reverses the Regulatory Effects of Kinases on Glycogen Metabolism
                                                  • 21.5.2. Insulin Stimulates Glycogen Synthesis by Activating Protein Phosphatase 1
                                                  • 21.5.3. Glycogen Metabolism in the Liver Regulates the Blood-Glucose Level
                                                  • 21.5.4. A Biochemical Understanding of Glycogen-Storage Diseases Is Possible
                                                  • Glycogen Breakdown Requires the Interplay of Several Enzymes
                                                  • Phosphorylase Is Regulated by Allosteric Interactions and Reversible Phosphorylation
                                                  • Epinephrine and Glucagon Signal the Need for Glycogen Breakdown
                                                  • Glycogen Is Synthesized and Degraded by Different Pathways
                                                  • Glycogen Breakdown and Synthesis Are Reciprocally Regulated
                                                  • Key Terms
                                                  • Mechanism Problem
                                                  • Chapter Integration and Data Interpretation Problems
                                                  • Media Problem
                                                  • Where to start
                                                  • Books and general reviews
                                                  • X-ray crystallographic studies
                                                  • Priming of glycogen synthesis
                                                  • Catalytic mechanisms
                                                  • Regulation of glycogen metabolism
                                                  • Genetic diseases
                                                  • Evolution
                                                  • 22.1. Triacylglycerols Are Highly Concentrated Energy Stores
                                                    • 22.1.1. Dietary Lipids Are Digested by Pancreatic Lipases
                                                    • 22.1.2. Dietary Lipids Are Transported in Chylomicrons
                                                    • 22.2.1. Triacylglycerols Are Hydrolyzed by Cyclic AMP-Regulated Lipases
                                                    • 22.2.2. Fatty Acids Are Linked to Coenzyme A Before They Are Oxidized
                                                    • 22.2.3. Carnitine Carries Long-Chain Activated Fatty Acids into the Mitochondrial Matrix
                                                    • 22.2.4. Acetyl CoA, NADH, and FADH2 Are Generated in Each Round of Fatty Acid Oxidation
                                                    • 22.2.5. The Complete Oxidation of Palmitate Yields 106 Molecules of ATP
                                                    • 22.3.1. An Isomerase and a Reductase Are Required for the Oxidation of Unsaturated Fatty Acids
                                                    • 22.3.2. Odd-Chain Fatty Acids Yield Propionyl Coenzyme A in the Final Thiolysis Step
                                                    • 22.3.3. Propionyl CoA Is Converted into Succinyl CoA in a Reaction That Requires Vitamin B12
                                                    • 22.3.4. Fatty Acids Are Also Oxidized in Peroxisomes
                                                    • 22.3.5. Ketone Bodies Are Formed from Acetyl Coenzyme A When Fat Breakdown Predominates
                                                    • 22.3.6. Ketone Bodies Are a Major Fuel in Some Tissues
                                                    • 22.3.7. Animals Cannot Convert Fatty Acids into Glucose
                                                    • 22.4.1. The Formation of Malonyl Coenzyme A Is the Committed Step in Fatty Acid Synthesis
                                                    • 22.4.2. Intermediates in Fatty Acid Synthesis Are Attached to an Acyl Carrier Protein
                                                    • 22.4.3. The Elongation Cycle in Fatty Acid Synthesis
                                                    • 22.4.4. Fatty Acids Are Synthesized by a Multifunctional Enzyme Complex in Eukaryotes
                                                    • 22.4.5. The Flexible Phosphopantetheinyl Unit of ACP Carries Substrate from One Active Site to Another
                                                    • 22.4.6. The Stoichiometry of Fatty Acid Synthesis
                                                    • 22.4.7. Citrate Carries Acetyl Groups from Mitochondria to the Cytosol for Fatty Acid Synthesis
                                                    • 22.4.8. Sources of NADPH for Fatty Acid Synthesis
                                                    • 22.4.9. Fatty Acid Synthase Inhibitors May Be Useful Drugs
                                                    • 22.4.10. Variations on a Theme: Polyketide and Nonribosomal Peptide Synthetases Resemble Fatty Acid Synthase
                                                    • Global Regulation
                                                    • Local Regulation
                                                    • Response to Diet
                                                    • 22.6.1. Membrane-Bound Enzymes Generate Unsaturated Fatty Acids
                                                    • 22.6.2. Eicosanoid Hormones Are Derived from Polyunsaturated Fatty Acids
                                                    • Triacylglycerols Are Highly Concentrated Energy Stores
                                                    • The Utilization of Fatty Acids as Fuel Requires Three Stages of Processing
                                                    • Certain Fatty Acids Require Additional Steps for Degradation
                                                    • Fatty Acids Are Synthesized and Degraded by Different Pathways
                                                    • Acetyl Coenzyme A Carboxylase Plays a Key Role in Controlling Fatty Acid Metabolism
                                                    • Elongation and Unsaturation of Fatty Acids Are Accomplished by Accessory Enzyme Systems
                                                    • Key Terms
                                                    • Mechanism Problems
                                                    • Chapter Integration Problems
                                                    • Data Interpretation Problem
                                                    • Media Problem
                                                    • Where to start
                                                    • Books
                                                    • Fatty acid oxidation
                                                    • Fatty acid synthesis
                                                    • Acetyl CoA carboxylase
                                                    • Eicosanoids
                                                    • Genetic diseases
                                                    • 23.1. Proteins Are Degraded to Amino Acids
                                                      • 23.1.1. The Digestion and Absorption of Dietary Proteins
                                                      • 23.1.2. Cellular Proteins Are Degraded at Different Rates
                                                      • 23.2.1. Ubiquitin Tags Proteins for Destruction
                                                      • 23.2.2. The Proteasome Digests the Ubiquitin-Tagged Proteins
                                                      • 23.2.3. Protein Degradation Can Be Used to Regulate Biological Function
                                                      • 23.2.4. The Ubiquitin Pathway and the Proteasome Have Prokaryotic Counterparts
                                                      • 23.3.1. Alpha-Amino Groups Are Converted into Ammonium Ions by the Oxidative Deamination of Glutamate
                                                      • 23.3.2. Pyridoxal Phosphate Forms Schiff-Base Intermediates in Aminotransferases
                                                      • 23.3.3. Aspartate Aminotransferase Is a Member of a Large and Versatile Family of Pyridoxal-Dependent Enzymes
                                                      • 23.3.4. Serine and Threonine Can Be Directly Deaminated
                                                      • 23.3.5. Peripheral Tissues Transport Nitrogen to the Liver
                                                      • 23.4.1. The Urea Cycle Begins with the Formation of Carbamoyl Phosphate
                                                      • 23.4.2. The Urea Cycle Is Linked to the Citric Acid Cycle
                                                      • 23.4.3. The Evolution of the Urea Cycle
                                                      • 23.4.4. Inherited Defects of the Urea Cycle Cause Hyperammonemia and Can Lead to Brain Damage
                                                      • 23.4.5. Urea Is Not the Only Means of Disposing of Excess Nitrogen
                                                      • 23.5.1. Pyruvate as an Entry Point into Metabolism
                                                      • 23.5.2. Oxaloacetate as an Entry Point into Metabolism
                                                      • 23.5.3. Alpha-Ketoglutarate as an Entry Point into Metabolism
                                                      • 23.5.4. Succinyl Coenzyme A Is a Point of Entry for Several Nonpolar Amino Acids
                                                      • 23.5.5. Methionine Degradation Requires the Formation of a Key Methyl Donor, S-Adenosylmethionine
                                                      • 23.5.6. The Branched-Chain Amino Acids Yield Acetyl CoA, Acetoacetate, or Propionyl CoA
                                                      • 23.5.7. Oxygenases Are Required for the Degradation of Aromatic Amino Acids
                                                      • Proteins Are Degraded to Amino Acids
                                                      • Protein Turnover Is Tightly Regulated
                                                      • The First Step in Amino Acid Degradation Is the Removal of Nitrogen
                                                      • Ammonium Ion Is Converted into Urea in Most Terrestrial Vertebrates
                                                      • Carbon Atoms of Degraded Amino Acids Emerge as Major Metabolic Intermediates
                                                      • Inborn Errors of Metabolism Can Disrupt Amino Acid Degradation
                                                      • Key Terms
                                                      • Mechanism Problems
                                                      • Chapter Integration Problems
                                                      • Data Interpretation Problem
                                                      • Where to start
                                                      • Books
                                                      • Ubiquitin and the proteasome
                                                      • Pyridoxal phosphate-dependent enzymes
                                                      • Urea-cycle enzymes
                                                      • Amino acid degradation
                                                      • Genetic diseases
                                                      • Historical aspects and the process of discovery
                                                      • Chapter 24. The Biosynthesis of Amino Acids
                                                        • 24.1. Nitrogen Fixation: Microorganisms Use ATP and a Powerful Reductant to Reduce Atmospheric Nitrogen to Ammonia
                                                          • 24.1.1. The Iron-Molybdenum Cofactor of Nitrogenase Binds and Reduces Atmospheric Nitrogen
                                                          • 24.1.2. Ammonium Ion Is Assimilated into an Amino Acid Through Glutamate and Glutamine
                                                          • 24.2.1. Human Beings Can Synthesize Some Amino Acids but Must Obtain Others from the Diet
                                                          • 24.2.2. A Common Step Determines the Chirality of All Amino Acids
                                                          • 24.2.3. An Adenylated Intermediate Is Required to Form Asparagine from Aspartate
                                                          • 24.2.4. Glutamate Is the Precursor of Glutamine, Proline, and Arginine
                                                          • 24.2.5. Serine, Cysteine, and Glycine Are Formed from 3-Phosphoglycerate
                                                          • 24.2.6. Tetrahydrofolate Carries Activated One-Carbon Units at Several Oxidation Levels
                                                          • 24.2.7. S-Adenosylmethionine Is the Major Donor of Methyl Groups
                                                          • 24.2.8. Cysteine Is Synthesized from Serine and Homocysteine
                                                          • 24.2.9. High Homocysteine Levels Are Associated with Vascular Disease
                                                          • 24.2.10. Shikimate and Chorismate Are Intermediates in the Biosynthesis of Aromatic Amino Acids
                                                          • 24.2.11. Tryptophan Synthetase Illustrates Substrate Channeling in Enzymatic Catalysis
                                                          • 24.3.1. Branched Pathways Require Sophisticated Regulation
                                                          • 24.3.2. The Activity of Glutamine Synthetase Is Modulated by an Enzymatic Cascade
                                                          • 24.4.1. Glutathione, a Gamma-Glutamyl Peptide, Serves as a Sulfhydryl Buffer and an Antioxidant
                                                          • 24.4.2. Nitric Oxide, a Short-Lived Signal Molecule, Is Formed from Arginine
                                                          • 24.4.3. Mammalian Porphyrins Are Synthesized from Glycine and Succinyl Coenzyme A
                                                          • 24.4.4. Porphyrins Accumulate in Some Inherited Disorders of Porphyrin Metabolism
                                                          • Nitrogen Fixation: Microorganisms Use ATP and a Powerful Reductant to Reduce Atmospheric Nitrogen to Ammonia
                                                          • Amino Acids Are Made from Intermediates of the Citric Acid Cycle and Other Major Pathways
                                                          • Amino Acid Biosynthesis Is Regulated by Feedback Inhibition
                                                          • Amino Acids Are Precursors of Many Biomolecules
                                                          • Key Terms
                                                          • Mechanism Problems
                                                          • Chapter Integration Problems
                                                          • Chapter Integration and Data Interpretation Problem
                                                          • Where to start
                                                          • Books
                                                          • Nitrogen fixation
                                                          • Regulation of amino acid biosynthesis
                                                          • Aromatic amino acid biosynthesis
                                                          • Glutathione
                                                          • Ethylene and nitric oxide
                                                          • Biosynthesis of porphyrins
                                                          • 25.1. In de Novo Synthesis, the Pyrimidine Ring Is Assembled from Bicarbonate, Aspartate, and Glutamine
                                                            • 25.1.1. Bicarbonate and Other Oxygenated Carbon Compounds Are Activated by Phosphorylation
                                                            • 25.1.2. The Side Chain of Glutamine Can Be Hydrolyzed to Generate Ammonia
                                                            • 25.1.3. Intermediates Can Move Between Active Sites by Channeling
                                                            • 25.1.4. Orotate Acquires a Ribose Ring from PRPP to Form a Pyrimidine Nucleotide and Is Converted into Uridylate
                                                            • 25.1.5. Nucleotide Mono-, Di-, and Triphosphates Are Interconvertible
                                                            • 25.1.6. CTP Is Formed by Amination of UTP
                                                            • 25.2.1. Salvage Pathways Economize Intracellular Energy Expenditure
                                                            • 25.2.2. The Purine Ring System Is Assembled on Ribose Phosphate
                                                            • 25.2.3. The Purine Ring Is Assembled by Successive Steps of Activation by Phosphorylation Followed by Displacement
                                                            • 25.2.4. AMP and GMP Are Formed from IMP
                                                            • 25.3.1. Thymidylate Is Formed by the Methylation of Deoxyuridylate
                                                            • 25.3.2. Dihydrofolate Reductase Catalyzes the Regeneration of Tetrahydrofolate, a One-Carbon Carrier
                                                            • 25.3.3. Several Valuable Anticancer Drugs Block the Synthesis of Thymidylate
                                                            • 25.6.1. Purines Are Degraded to Urate in Human Beings
                                                            • 25.6.2. Lesch-Nyhan Syndrome Is a Dramatic Consequence of Mutations in a Salvage-Pathway Enzyme
                                                            • In de Novo Synthesis, the Pyrimidine Ring Is Assembled from Bicarbonate, Aspartate, and Glutamine
                                                            • Purines Bases Can Be Synthesized de Novo or Recycled by Salvage Pathways
                                                            • Deoxyribonucleotides Are Synthesized by the Reduction of Ribonucleotides Through a Radical Mechanism
                                                            • Key Steps in Nucleotide Biosynthesis Are Regulated by Feedback Inhibition
                                                            • NAD + , FAD, and Coenzyme A Are Formed from ATP
                                                            • Disruptions in Nucleotide Metabolism Can Cause Pathological Conditions
                                                            • Key Terms
                                                            • Mechanism Problems
                                                            • Chapter Integration Problems
                                                            • Where to start
                                                            • Pyrimidine biosynthesis
                                                            • Purine biosynthesis
                                                            • Ribonucleotide reductases
                                                            • Thymidylate synthase and dihydrofolate reductase
                                                            • Genetic diseases
                                                            • 26.1. Phosphatidate Is a Common Intermediate in the Synthesis of Phospholipids and Triacylglycerols
                                                              • 26.1.1. The Synthesis of Phospholipids Requires an Activated Intermediate
                                                              • 26.1.2. Plasmalogens and Other Ether Phospholipids Are Synthesized from Dihydroxyacetone Phosphate
                                                              • 26.1.3. Sphingolipids Are Synthesized from Ceramide
                                                              • 26.1.4. Gangliosides Are Carbohydrate-Rich Sphingolipids That Contain Acidic Sugars
                                                              • 26.1.5. Sphingolipids Confer Diversity on Lipid Structure and Function
                                                              • 26.1.6. Respiratory Distress Syndrome and Tay-Sachs Disease Result from the Disruption of Lipid Metabolism
                                                              • 26.2.1. The Synthesis of Mevalonate, Which Is Activated as Isopentenyl Pyrophosphate, Initiates the Synthesis of Cholesterol
                                                              • 26.2.2. Squalene (C30) Is Synthesized from Six Molecules of Isopentenyl Pyrophosphate (C5)
                                                              • 26.2.3. Squalene Cyclizes to Form Cholesterol
                                                              • 26.3.1. Lipoproteins Transport Cholesterol and Triacylglycerols Throughout the Organism
                                                              • 26.3.2. The Blood Levels of Certain Lipoproteins Can Serve Diagnostic Purposes
                                                              • 26.3.3. Low-Density Lipoproteins Play a Central Role in Cholesterol Metabolism
                                                              • 26.3.4. The LDL Receptor Is a Transmembrane Protein Having Five Different Functional Regions
                                                              • 26.3.5. The Absence of the LDL Receptor Leads to Hypercholesteremia and Atherosclerosis
                                                              • 26.3.6. The Clinical Management of Cholesterol Levels Can Be Understood at a Biochemical Level
                                                              • Bile Salts
                                                              • Steroid Hormones
                                                              • 26.4.1. The Nomenclature of Steroid Hormones
                                                              • 26.4.2. Steroids Are Hydroxylated by Cytochrome P450 Monooxygenases That Utilize NADPH and O2
                                                              • 26.4.3. The Cytochrome P450 System Is Widespread and Performs a Protective Function
                                                              • 26.4.4. Pregnenolone, a Precursor for Many Other Steroids, Is Formed from Cholesterol by Cleavage of Its Side Chain
                                                              • 26.4.5. The Synthesis of Progesterone and Corticosteroids from Pregnenolone
                                                              • 26.4.6. The Synthesis of Androgens and Estrogens from Pregnenolone
                                                              • 26.4.7. Vitamin D Is Derived from Cholesterol by the Ring-Splitting Activity of Light
                                                              • 26.4.8. Isopentenyl Pyrophosphate Is a Precursor for a Wide Variety of Biomolecules
                                                              • Phosphatidate Is a Common Intermediate in the Synthesis of Phospholipids and Triacylglycerols
                                                              • Cholesterol Is Synthesized from Acetyl Coenzyme A in Three Stages
                                                              • The Complex Regulation of Cholesterol Biosynthesis Takes Place at Several Levels
                                                              • Important Derivatives of Cholesterol Include Bile Salts and Steroid Hormones
                                                              • Key Terms
                                                              • Mechanism Problem
                                                              • Data Interpretation and Chapter Integration Problems
                                                              • Where to start
                                                              • Books
                                                              • Phospholipids and sphingolipids
                                                              • Biosynthesis of cholesterol and steroids
                                                              • Lipoproteins and their receptors
                                                              • Oxygen activation and P450 catalysis
                                                              • 27.1. DNA Can Assume a Variety of Structural Forms
                                                                • 27.1.1. A-DNA Is a Double Helix with Different Characteristics from Those of the More Common B-DNA
                                                                • 27.1.2. The Major and Minor Grooves Are Lined by Sequence-Specific Hydrogen-Bonding Groups
                                                                • 27.1.3. The Results of Studies of Single Crystals of DNA Revealed Local Variations in DNA Structure
                                                                • 27.1.4. Z-DNA Is a Left-Handed Double Helix in Which Backbone Phosphates Zigzag
                                                                • 27.2.1. All DNA Polymerases Have Structural Features in Common
                                                                • 27.2.2. Two Bound Metal Ions Participate in the Polymerase Reaction
                                                                • 27.2.3. The Specificity of Replication Is Dictated by Hydrogen Bonding and the Complementarity of Shape Between Bases
                                                                • 27.2.4. Many Polymerases Proofread the Newly Added Bases and Excise Errors
                                                                • 27.2.5. The Separation of DNA Strands Requires Specific Helicases and ATP Hydrolysis
                                                                • 27.3.1. The Linking Number of DNA, a Topological Property, Determines the Degree of Supercoiling
                                                                • 27.3.2. Helical Twist and Superhelical Writhe Are Correlated with Each Other Through the Linking Number
                                                                • 27.3.3. Type I Topoisomerases Relax Supercoiled Structures
                                                                • 27.3.4. Type II Topoisomerases Can Introduce Negative Supercoils Through Coupling to ATP Hydrolysis
                                                                • 27.4.1. An RNA Primer Synthesized by Primase Enables DNA Synthesis to Begin
                                                                • 27.4.2. One Strand of DNA Is Made Continuously, Whereas the Other Strand Is Synthesized in Fragments
                                                                • 27.4.3. DNA Ligase Joins Ends of DNA in Duplex Regions
                                                                • 27.4.4. DNA Replication Requires Highly Processive Polymerases
                                                                • 27.4.5. The Leading and Lagging Strands Are Synthesized in a Coordinated Fashion
                                                                • 27.4.6. DNA Synthesis Is More Complex in Eukaryotes Than in Prokaryotes
                                                                • 27.4.7. Telomeres Are Unique Structures at the Ends of Linear Chromosomes
                                                                • 27.4.8. Telomeres Are Replicated by Telomerase, a Specialized Polymerase That Carries Its Own RNA Template
                                                                • 27.5.1. Recombination Reactions Proceed Through Holliday Junction Intermediates
                                                                • 27.5.2. Recombinases Are Evolutionarily Related to Topoisomerases
                                                                • 27.6.1. Some Chemical Mutagens Are Quite Specific
                                                                • 27.6.2. Ultraviolet Light Produces Pyrimidine Dimers
                                                                • 27.6.3. A Variety of DNA-Repair Pathways Are Utilized
                                                                • 27.6.4. The Presence of Thymine Instead of Uracil in DNA Permits the Repair of Deaminated Cytosine
                                                                • 27.6.5. Many Cancers Are Caused by Defective Repair of DNA
                                                                • 27.6.6. Some Genetic Diseases Are Caused by the Expansion of Repeats of Three Nucleotides
                                                                • 27.6.7. Many Potential Carcinogens Can Be Detected by Their Mutagenic Action on Bacteria
                                                                • DNA Can Assume a Variety of Structural Forms
                                                                • DNA Polymerases Require a Template and a Primer
                                                                • Double-Stranded DNA Can Wrap Around Itself to Form Supercoiled Structures
                                                                • DNA Replication of Both Strands Proceeds Rapidly from Specific Start Sites
                                                                • Double-Stranded DNA Molecules with Similar Sequences Sometimes Recombine
                                                                • Mutations Are Produced by Several Types of Changes in the Base Sequence of DNA
                                                                • Key Terms
                                                                • Mechanism Problems
                                                                • Data Interpretation and Chapter Integration Problems
                                                                • Media Problem
                                                                • Where to begin
                                                                • Books
                                                                • DNA structure
                                                                • DNA topology and topoisomerases
                                                                • Mechanism of replication
                                                                • DNA polymerases and other enzymes of replication
                                                                • Recombinases
                                                                • Mutations and DNA repair
                                                                • Defective DNA repair and cancer
                                                                • 28.1. Transcription Is Catalyzed by RNA Polymerase
                                                                  • 28.1.1. Transcription Is Initiated at Promoter Sites on the DNA Template
                                                                  • 28.1.2. Sigma Subunits of RNA Polymerase Recognize Promoter Sites
                                                                  • 28.1.3. RNA Polymerase Must Unwind the Template Double Helix for Transcription to Take Place
                                                                  • 28.1.4. RNA Chains Are Formed de Novo and Grow in the 5′-to-3′ Direction
                                                                  • 28.1.5. Elongation Takes Place at Transcription Bubbles That Move Along the DNA Template
                                                                  • 28.1.6. An RNA Hairpin Followed by Several Uracil Residues Terminates the Transcription of Some Genes
                                                                  • 28.1.7. The Rho Protein Helps Terminate the Transcription of Some Genes
                                                                  • 28.1.8. Precursors of Transfer and Ribosomal RNA Are Cleaved and Chemically Modified After Transcription
                                                                  • 28.1.9. Antibiotic Inhibitors of Transcription
                                                                  • 28.2.1. RNA in Eukaryotic Cells Is Synthesized by Three Types of RNA Polymerase
                                                                  • 28.2.2. Cis- And Trans-Acting Elements: Locks and Keys of Transcription
                                                                  • 28.2.3. Most Promoters for RNA Polymerase II Contain a TATA Box Near the Transcription Start Site
                                                                  • 28.2.4. The TATA-Box-Binding Protein Initiates the Assembly of the Active Transcription Complex
                                                                  • 28.2.5. Multiple Transcription Factors Interact with Eukaryotic Promoters
                                                                  • 28.2.6. Enhancer Sequences Can Stimulate Transcription at Start Sites Thousands of Bases Away
                                                                  • 28.3.1. The Ends of the Pre-mRNA Transcript Acquire a 5′ Cap and a 3′ Poly(A) Tail
                                                                  • 28.3.2. RNA Editing Changes the Proteins Encoded by mRNA
                                                                  • 28.3.3. Splice Sites in mRNA Precursors Are Specified by Sequences at the Ends of Introns
                                                                  • 28.3.4. Splicing Consists of Two Transesterification Reactions
                                                                  • 28.3.5. Small Nuclear RNAs in Spliceosomes Catalyze the Splicing of mRNA Precursors
                                                                  • 28.3.6. Some Pre-mRNA Molecules Can Be Spliced in Alternative Ways to Yield Different mRNAs
                                                                  • Transcription Is Catalyzed by RNA Polymerase
                                                                  • Eukaryotic Transcription and Translation Are Separated in Space and Time
                                                                  • The Transcription Products of All Three Eukaryotic Polymerases Are Processed
                                                                  • The Discovery of Catalytic RNA Was Revealing with Regard to Both Mechanism And Evolution
                                                                  • Key Terms
                                                                  • Mechanism Problem
                                                                  • Chapter Integration Problems
                                                                  • Data Interpretation Problems
                                                                  • Where to begin
                                                                  • Books
                                                                  • RNA polymerases
                                                                  • Initiation and elongation
                                                                  • Promoters, enhancers, and transcription factors
                                                                  • Termination
                                                                  • 5′-Cap formation and polyadenylation
                                                                  • RNA editing
                                                                  • Splicing of mRNA precursors
                                                                  • Self-splicing and RNA catalysis
                                                                  • 29.1. Protein Synthesis Requires the Translation of Nucleotide Sequences Into Amino Acid Sequences
                                                                    • 29.1.1. The Synthesis of Long Proteins Requires a Low Error Frequency
                                                                    • 29.1.2. Transfer RNA Molecules Have a Common Design
                                                                    • 29.1.3. The Activated Amino Acid and the Anticodon of tRNA Are at Opposite Ends of the L-Shaped Molecule
                                                                    • 29.2.1. Amino Acids Are First Activated by Adenylation
                                                                    • 29.2.2. Aminoacyl-tRNA Synthetases Have Highly Discriminating Amino Acid Activation Sites
                                                                    • 29.2.3. Proofreading by Aminoacyl-tRNA Synthetases Increases the Fidelity of Protein Synthesis
                                                                    • 29.2.4. Synthetases Recognize the Anticodon Loops and Acceptor Stems of Transfer RNA Molecules
                                                                    • 29.2.5. Aminoacyl-tRNA Synthetases Can Be Divided into Two Classes
                                                                    • 29.3.1. Ribosomal RNAs (5S, 16S, and 23S rRNA) Play a Central Role in Protein Synthesis
                                                                    • 29.3.2. Proteins Are Synthesized in the Amino-to-Carboxyl Direction
                                                                    • 29.3.3. Messenger RNA Is Translated in the 5′-to-3′ Direction
                                                                    • 29.3.4. The Start Signal Is AUG (or GUG) Preceded by Several Bases That Pair with 16S rRNA
                                                                    • 29.3.5. Bacterial Protein Synthesis Is Initiated by Formylmethionyl Transfer RNA
                                                                    • 29.3.6. Ribosomes Have Three tRNA-Binding Sites That Bridge the 30S and 50S Subunits
                                                                    • 29.3.7. The Growing Polypeptide Chain Is Transferred Between tRNAs on Peptide-Bond Formation
                                                                    • 29.3.8. Only the Codon-Anticodon Interactions Determine the Amino Acid That Is Incorporated
                                                                    • 29.3.9. Some Transfer RNA Molecules Recognize More Than One Codon Because of Wobble in Base-Pairing
                                                                    • 29.4.1. Formylmethionyl-tRNAf Is Placed in the P Site of the Ribosome During Formation of the 70S Initiation Complex
                                                                    • 29.4.2. Elongation Factors Deliver Aminoacyl-tRNA to the Ribosome
                                                                    • 29.4.3. The Formation of a Peptide Bond Is Followed by the GTP-Driven Translocation of tRNAs and mRNA
                                                                    • 29.4.4. Protein Synthesis Is Terminated by Release Factors That Read Stop Codons
                                                                    • 29.5.1. Many Antibiotics Work by Inhibiting Protein Synthesis
                                                                    • 29.5.2. Diphtheria Toxin Blocks Protein Synthesis in Eukaryotes by Inhibiting Translocation
                                                                    • Protein Synthesis Requires the Translation of Nucleotide Sequences into Amino Acid Sequences
                                                                    • Aminoacyl-Transfer-RNA Synthetases Read the Genetic Code
                                                                    • A Ribosome Is a Ribonucleoprotein Particle (70S) Made of a Small (30S) and a Large (50S) Subunit
                                                                    • Protein Factors Play Key Roles in Protein Synthesis
                                                                    • Eukaryotic Protein Synthesis Differs from Prokaryotic Protein Synthesis Primarily in Translation Initiation
                                                                    • Key Terms
                                                                    • Mechanism Problems
                                                                    • Chapter Integration Problems
                                                                    • Data Interpretation Problem
                                                                    • Media Problem
                                                                    • Where to start
                                                                    • Books
                                                                    • Aminoacyl-tRNA synthetases
                                                                    • Transfer RNA
                                                                    • Ribosomes and ribosomal RNAs
                                                                    • Initiation factors
                                                                    • Elongation factors
                                                                    • Peptide-bond formation and translocation
                                                                    • Termination
                                                                    • Fidelity and proofreading
                                                                    • Eukaryotic protein synthesis
                                                                    • Antibiotics and toxins
                                                                    • 30.1. Metabolism Consist of Highly Interconnected Pathways
                                                                      • 30.1.1. Recurring Motifs in Metabolic Regulation
                                                                      • 30.1.2. Major Metabolic Pathways and Control Sites
                                                                      • 30.1.3. Key Junctions: Glucose 6-phosphate, Pyruvate, and Acetyl CoA
                                                                      • 30.3.1. Metabolic Adaptations in Prolonged Starvation Minimize Protein Degradation
                                                                      • 30.3.2. Metabolic Derangements in Diabetes Result from Relative Insulin Insufficiency and Glucagon Excess
                                                                      • 30.3.3. Caloric Homeostasis: A Means of Regulating Body Weight
                                                                      • Metabolism Consists of Highly Interconnected Pathways
                                                                      • Each Organ Has a Unique Metabolic Profile
                                                                      • Food Intake and Starvation Induce Metabolic Changes
                                                                      • Fuel Choice During Exercise Is Determined by Intensity and Duration of Activity
                                                                      • Ethanol Alters Energy Metabolism in the Liver
                                                                      • Key Terms
                                                                      • Where to start
                                                                      • Books
                                                                      • Fuel metabolism
                                                                      • Metabolic adaptations in starvation
                                                                      • Diabetes mellitus
                                                                      • Exercise metabolism
                                                                      • Ethanol metabolism
                                                                      • 31.1. Prokaryotic DNA-Binding Proteins Bind Specifically to Regulatory Sites in Operons
                                                                        • 31.1.1. An Operon Consists of Regulatory Elements and Protein-Encoding Genes
                                                                        • 31.1.2. The lac Operator Has a Symmetric Base Sequence
                                                                        • 31.1.3. The lac Repressor Protein in the Absence of Lactose Binds to the Operator and Blocks Transcription
                                                                        • 31.1.4. Ligand Binding Can Induce Structural Changes in Regulatory Proteins
                                                                        • 31.1.5. The Operon Is a Common Regulatory Unit in Prokaryotes
                                                                        • 31.1.6. Transcription Can Be Stimulated by Proteins That Contact RNA Polymerase
                                                                        • 31.1.7. The Helix-Turn-Helix Motif Is Common to Many Prokaryotic DNA-Binding Proteins
                                                                        • 31.2.1. Nucleosomes Are Complexes of DNA and Histones
                                                                        • 31.2.2. Eukaryotic DNA Is Wrapped Around Histones to Form Nucleosomes
                                                                        • 31.2.3. The Control of Gene Expression Requires Chromatin Remodeling
                                                                        • 31.2.4. Enhancers Can Stimulate Transcription by Perturbing Chromatin Structure
                                                                        • 31.2.5. The Modification of DNA Can Alter Patterns of Gene Expression
                                                                        • 31.3.1. Steroids and Related Hydrophobic Molecules Pass Through Membranes and Bind to DNA-Binding Receptors
                                                                        • 31.3.2. Nuclear Hormone Receptors Regulate Transcription by Recruiting Coactivators and Corepressors to the Transcription Complex
                                                                        • 31.3.3. Steroid-Hormone Receptors Are Targets for Drugs
                                                                        • 31.3.4. Chromatin Structure Is Modulated Through Covalent Modifications of Histone Tails
                                                                        • 31.3.5. Histone Deacetylases Contribute to Transcriptional Repression
                                                                        • 31.3.6. Ligand Binding to Membrane Receptors Can Regulate Transcription Through Phosphorylation Cascades
                                                                        • 31.3.7. Chromatin Structure Effectively Decreases the Size of the Genome
                                                                        • 31.4.1. Attenuation Is a Prokaryotic Mechanism for Regulating Transcription Through Modulation of Nascent RNA Secondary Structure
                                                                        • 31.4.2. Genes Associated with Iron Metabolism Are Translationally Regulated in Animals
                                                                        • Prokaryotic DNA-Binding Proteins Bind Specifically to Regulatory Sites in Operons
                                                                        • The Greater Complexity of Eukaryotic Genomes Requires Elaborate Mechanisms for Gene Regulation
                                                                        • Transcriptional Activation and Repression Are Mediated by Protein-Protein Interactions
                                                                        • Gene Expression Can Be Controlled at Posttranscriptional Levels
                                                                        • Key Terms
                                                                        • Mechanism Problem
                                                                        • Chapter Integration Problem
                                                                        • Data Interpretation Problem
                                                                        • Where to start
                                                                        • Books
                                                                        • Prokaryotic gene regulation
                                                                        • Nucleosomes and histones
                                                                        • Nuclear hormone receptors
                                                                        • Chromatin and chromatin remodeling
                                                                        • Posttranscriptional regulation
                                                                        • Historical aspects
                                                                        • Chapter 32. Sensory Systems
                                                                          • 32.1. A Wide Variety of Organic Compounds Are Detected by Olfaction
                                                                            • 32.1.1. Olfaction Is Mediated by an Enormous Family of Seven-Transmembrane-Helix Receptors
                                                                            • 32.1.2. Odorants Are Decoded by a Combinatorial Mechanism
                                                                            • 32.1.3. Functional Magnetic Resonance Imaging Reveals Regions of the Brain Processing Sensory Information
                                                                            • 32.2.1. Sequencing the Human Genome Led to the Discovery of a Large Family of 7TM Bitter Receptors
                                                                            • 32.2.2. A Family of 7TM Receptors Almost Certainly Respond to Sweet Compounds
                                                                            • 32.2.3. Salty Tastes Are Detected Primarily by the Passage of Sodium Ions Through Channels
                                                                            • 32.2.4. Sour Tastes Arise from the Effects of Hydrogen Ions (Acids) on Channels
                                                                            • 32.2.5. Umami, the Taste of Glutamate, Is Detected by a Specialized Form of Glutamate Receptor
                                                                            • 32.3.1. Rhodopsin, a Specialized 7TM Receptor, Absorbs Visible Light
                                                                            • 32.3.2. Light Absorption Induces a Specific Isomerization of Bound 11-cis-Retinal
                                                                            • 32.3.3. Light-Induced Lowering of the Calcium Level Coordinates Recovery
                                                                            • 32.3.4. Color Vision Is Mediated by Three Cone Receptors That Are Homologs of Rhodopsin
                                                                            • 32.3.5. Rearrangements in the Genes for the Green and Red Pigments Lead to 𠇌olor Blindness”
                                                                            • 32.4.1. Hair Cells Use a Connected Bundle of Stereocilia to Detect Tiny Motions
                                                                            • 32.4.2. Mechanosensory Channels Have Been Identified in Drosophila and Bacteria
                                                                            • 32.5.1. Studies of Capsaicin, the Active Ingredient in “Hot” Peppers, Reveal a Receptor for Sensing High Temperatures and Other Painful Stimuli
                                                                            • 32.5.2. Subtle Sensory Systems Detect Other Environmental Factors Such as Earth's Magnetic Field
                                                                            • Smell, Taste, Vision, Hearing, and Touch Are Based on Signal-Transduction Pathways Activated by Signals from the Environment
                                                                            • A Wide Variety of Organic Compounds Are Detected by Olfaction
                                                                            • Taste Is a Combination of Senses That Function by Different Mechanisms
                                                                            • Photoreceptor Molecules in the Eye Detect Visible Light
                                                                            • Hearing Depends on the Speedy Detection of Mechanical Stimuli
                                                                            • Touch Includes the Sensing of Pressure, Temperature, and Other Factors
                                                                            • Key Terms
                                                                            • Chapter Integration Problem
                                                                            • Mechanism Problem
                                                                            • Media Problems
                                                                            • Where to start
                                                                            • Olfaction
                                                                            • Taste
                                                                            • Vision
                                                                            • Hearing
                                                                            • Touch and pain reception
                                                                            • Other sensory systems
                                                                            • 33.1. Antibodies Possess Distinct Antigen-Binding and Effector Units
                                                                            • 33.2. The Immunoglobulin Fold Consists of a Beta-Sandwich Framework with Hypervariable Loops
                                                                            • 33.3. Antibodies Bind Specific Molecules Through Their Hypervariable Loops
                                                                              • 33.3.1. X-Ray Analyses Have Revealed How Antibodies Bind Antigens
                                                                              • 33.3.2. Large Antigens Bind Antibodies with Numerous Interactions
                                                                              • 33.4.1. J (Joining) Genes and D (Diversity) Genes Increase Antibody Diversity
                                                                              • 33.4.2. More Than 10 8 Antibodies Can Be Formed by Combinatorial Association and Somatic Mutation
                                                                              • 33.4.3. The Oligomerization of Antibodies Expressed on the Surface of Immature B Cells Triggers Antibody Secretion
                                                                              • 33.4.4. Different Classes of Antibodies Are Formed by the Hopping of VH Genes
                                                                              • 33.5.1. Peptides Presented by MHC Proteins Occupy a Deep Groove Flanked by Alpha Helices
                                                                              • 33.5.2. T-Cell Receptors Are Antibody-like Proteins Containing Variable and Constant Regions
                                                                              • 33.5.3. CD8 on Cytotoxic T Cells Acts in Concert with T-Cell Receptors
                                                                              • 33.5.4. Helper T Cells Stimulate Cells That Display Foreign Peptides Bound to Class II MHC Proteins
                                                                              • 33.5.5. Helper T Cells Rely on the T-Cell Receptor and CD4 to Recognize Foreign Peptides on Antigen-Presenting Cells
                                                                              • 33.5.6. MHC Proteins Are Highly Diverse
                                                                              • 33.5.7. Human Immunodeficiency Viruses Subvert the Immune System by Destroying Helper T Cells
                                                                              • 33.6.1. T Cells Are Subject to Positive and Negative Selection in the Thymus
                                                                              • 33.6.2. Autoimmune Diseases Result from the Generation of Immune Responses Against Self-Antigens
                                                                              • 33.6.3. The Immune System Plays a Role in Cancer Prevention
                                                                              • Antibodies Possess Distinct Antigen-Binding and Effector Units
                                                                              • The Immunoglobulin Fold Consists of a Beta-Sandwich Framework with Hypervariable Loops
                                                                              • Antibodies Bind Specific Molecules Through Their Hypervariable Loops
                                                                              • Diversity Is Generated by Gene Rearrangements
                                                                              • Major-Histocompatibility-Complex Proteins Present Peptide Antigens on Cell Surfaces for Recognition by T-Cell Receptors
                                                                              • Immune Responses Against Self-Antigens Are Suppressed
                                                                              • Key Terms
                                                                              • Mechanism Problem
                                                                              • Chapter Integration Problem
                                                                              • Data Interpretation Problem
                                                                              • Where to start
                                                                              • Books
                                                                              • Structure of antibodies and antibody-antigen complexes
                                                                              • Generation of diversity
                                                                              • MHC proteins and antigen processing
                                                                              • T-cell receptors and signaling complexes
                                                                              • HIV and AIDS
                                                                              • Discovery of major concepts
                                                                              • 34.1. Most Molecular-Motor Proteins Are Members of the P-Loop NTPase Superfamily
                                                                                • 34.1.1. A Motor Protein Consists of an ATPase Core and an Extended Structure
                                                                                • 34.1.2. ATP Binding and Hydrolysis Induce Changes in the Conformation and Binding Affinity of Motor Proteins
                                                                                • 34.2.1. Muscle Is a Complex of Myosin and Actin
                                                                                • 34.2.2. Actin Is a Polar, Self-Assembling, Dynamic Polymer
                                                                                • 34.2.3. Motions of Single Motor Proteins Can Be Directly Observed
                                                                                • 34.2.4. Phosphate Release Triggers the Myosin Power Stroke
                                                                                • 34.2.5. The Length of the Lever Arm Determines Motor Velocity
                                                                                • 34.3.1. Microtubules Are Hollow Cylindrical Polymers
                                                                                • 34.3.2. Kinesin Motion Is Highly Processive
                                                                                • 34.3.3. Small Structural Changes Can Reverse Motor Polarity
                                                                                • 34.4.1. Bacteria Swim by Rotating Their Flagella
                                                                                • 34.4.2. Proton Flow Drives Bacterial Flagellar Rotation
                                                                                • 34.4.3. Bacterial Chemotaxis Depends on Reversal of the Direction of Flagellar Rotation
                                                                                • Most Molecular-Motor Proteins Are Members of the P-Loop NTPase Superfamily
                                                                                • Myosins Move Along Actin Filaments
                                                                                • Kinesin and Dynein Move Along Microtubules
                                                                                • A Rotary Motor Drives Bacterial Motion
                                                                                • Key Terms
                                                                                • Mechanism Problem
                                                                                • Chapter Integration Problem
                                                                                • Data Interpretation Problem
                                                                                • Where to start
                                                                                • Books
                                                                                • Myosin and actin
                                                                                • Kinesin, dynein, and microtubules
                                                                                • Bacterial motion and chemotaxis
                                                                                • Historical aspects
                                                                                • Appendix A: Physical Constants and Conversion of Units
                                                                                • Appendix B: Acidity Constants
                                                                                • Appendix C: Standard Bond Lengths

                                                                                By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

                                                                                Competition can have consequences beyond the typical predator-and-prey interactions that keep populations in check. When a species loses food and habitat, it can become endangered or extinct. Hunting and urbanization has played a role in species loss.

                                                                                For example, passenger pigeons once numbered in the billions from New York to California before they were hunted and forced out of their native nesting areas.

                                                                                According to the American Museum of Natural History, the growing population of humans on the planet poses the biggest threat to other species. Humans exploit thousands of species and deplete limited natural resources to maintain comfortable lifestyles. Human over-consumption leaves fewer resources for other species that cannot compete with human activity.

                                                                                Ongoing threats to the ecosystem include global warming, pollution, deforestation, over-fishing and introduction of invasive species.

                                                                                The spreading front of invasive species in favorable habitat or unfavorable habitat ☆

                                                                                Spatial heterogeneity and habitat characteristic are shown to determine the asymptotic profile of the solution to a reaction–diffusion model with free boundary, which describes the moving front of the invasive species. A threshold value R 0 Fr ( D , t ) is introduced to determine the spreading and vanishing of the invasive species. We prove that if R 0 Fr ( D , t 0 ) ⩾ 1 for some t 0 ⩾ 0 , the spreading must happen while if R 0 Fr ( D , 0 ) < 1 , the spreading is also possible. Our results show that the species in the favorable habitat can establish itself if the diffusion is slow or the occupying habitat is large. In an unfavorable habitat, the species dies out if the initial value of the species is small. However, big initial number of the species is benefit for the species to survive. When the species spreads in the whole habitat, the asymptotic spreading speed is given. Some implications of these theoretical results are also discussed.

                                                                                6.2 Metabolism

                                                                                Metabolism (from Greek: μεταβολή metabolē, “change”) is the set of life-sustaining chemical reactions in organisms. The three main purposes of metabolism are: the conversion of food to energy to run cellular processes the conversion of food/fuel to building blocks for proteins, lipids, nucleic acids, and some carbohydrates and the elimination of nitrogenous wastes. These enzyme-catalyzed reactions allow organisms to grow and reproduce, maintain their structures, and respond to their environments. (The word metabolism can also refer to the sum of all chemical reactions that occur in living organisms, including digestion and the transport of substances into and between different cells, in which case the above described set of reactions within the cells is called intermediary metabolism or intermediate metabolism).

                                                                                Metabolic reactions may be categorized as catabolic – the breaking down of compounds (for example, the breaking down of glucose to pyruvate by cellular respiration) or anabolic – the building up (synthesis) of compounds (such as proteins, carbohydrates, lipids, and nucleic acids). Usually, catabolism releases energy, and anabolism consumes energy.

                                                                                The chemical reactions of metabolism are organized into metabolic pathways, in which one chemical is transformed through a series of steps into another chemical, each step being facilitated by a specific enzyme. Enzymes are crucial to metabolism because they allow organisms to drive desirable reactions that require energy that will not occur by themselves, by coupling them to spontaneous reactions that release energy. Enzymes act as catalysts – they allow a reaction to proceed more rapidly – and they also allow the regulation of the rate of a metabolic reaction, for example in response to changes in the cell’s environment or to signals from other cells.

                                                                                The metabolic system of a particular organism determines which substances it will find nutritious and which poisonous. For example, some prokaryotes use hydrogen sulfide as a nutrient, yet this gas is poisonous to animals. The basal metabolic rate of an organism is the measure of the amount of energy consumed by all of these chemical reactions.

                                                                                A striking feature of metabolism is the similarity of the basic metabolic pathways among vastly different species. For example, the set of carboxylic acids that are best known as the intermediates in the citric acid cycle are present in all known organisms, being found in species as diverse as the unicellular bacterium Escherichia coli and huge multicellular organisms like elephants. These similarities in metabolic pathways are likely due to their early appearance in evolutionary history, and their retention because of their efficacy. The metabolism of cancer cells is also different from the metabolism of normal cells and these differences can be used to find targets for therapeutic intervention in cancer.

                                                                                Most of the structures that make up animals, plants and microbes are made from four basic classes of molecule: amino acids, carbohydrates , nucleic acid and lipids (often called fats). As these molecules are vital for life, metabolic reactions either focus on making these molecules during the construction of cells and tissues, or by breaking them down and using them as a source of energy, by their digestion. These biochemicals can be joined together to make polymers such as DNA and proteins, essential macromolecules of life.

                                                                                Table 6.1: The three essential polymeric macromolecules of life
                                                                                Type of molecule Name of monomer forms Name of polymer forms Examples of polymer forms
                                                                                Amino acids Amino acids Proteins (made of polypeptides) Fibrous proteins and globular proteins
                                                                                Carbohydrates Monosaccharides Polysaccharides Starch, glycogen and cellulose
                                                                                Nucleic acids Nucleotides Polynucleotides DNA and RNA

                                                                                The history of the scientific study of metabolism spans several centuries and has moved from examining whole animals in early studies, to examining individual metabolic reactions in modern biochemistry. The first controlled experiments in human metabolism were published by Santorio Santorio in 1614 in his book Ars de statica medicina. He described how he weighed himself before and after eating, sleep, working, sex, fasting, drinking, and excreting. He found that most of the food he took in was lost through what he called “insensible perspiration”.

                                                                                In these early studies, the mechanisms of these metabolic processes had not been identified and a vital force was thought to animate living tissue. In the 19th century, when studying the fermentation of sugar to alcohol by yeast, Louis Pasteur concluded that fermentation was catalyzed by substances within the yeast cells he called “ferments”. He wrote that “alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells.” This discovery, along with the publication by Friedrich Wöhler in 1828 of a paper on the chemical synthesis of urea, and is notable for being the first organic compound prepared from wholly inorganic precursors. This proved that the organic compounds and chemical reactions found in cells were no different in principle than any other part of chemistry.

                                                                                It was the discovery of enzymes at the beginning of the 20th century by Eduard Buchner that separated the study of the chemical reactions of metabolism from the biological study of cells, and marked the beginnings of biochemistry. The mass of biochemical knowledge grew rapidly throughout the early 20th century. One of the most prolific of these modern biochemists was Hans Krebs who made huge contributions to the study of metabolism. He discovered the urea cycle and later, working with Hans Kornberg, the citric acid cycle and the glyoxylate cycle. Modern biochemical research has been greatly aided by the development of new techniques such as chromatography, X-ray diffraction, NMR spectroscopy, radioisotopic labelling, electron microscopy and molecular dynamics simulations. These techniques have allowed the discovery and detailed analysis of the many molecules and metabolic pathways in cells.

                                                                                6.2.1 Catabolism

                                                                                Catabolism is the set of metabolic processes that break down large molecules. These include breaking down and oxidizing food molecules. The purpose of the catabolic reactions is to provide the energy and components needed by anabolic reactions which build molecules. The exact nature of these catabolic reactions differ from organism to organism, and organisms can be classified based on their sources of energy and carbon (their primary nutritional groups), as shown in the table below. Organic molecules are used as a source of energy by organotrophs, while lithotrophs use inorganic substrates, and phototrophs capture sunlight as chemical energy. However, all these different forms of metabolism depend on redox reactions that involve the transfer of electrons from reduced donor molecules such as organic molecules, water, ammonia, hydrogen sulfide or ferrous ions to acceptor molecules such as oxygen, nitrate or sulfate. In animals, these reactions involve complex organic molecules that are broken down to simpler molecules, such as carbon dioxide and water. In photosynthetic organisms, such as plants and cyanobacteria, these electron-transfer reactions do not release energy but are used as a way of storing energy absorbed from sunlight.

                                                                                The most common set of catabolic reactions in animals can be separated into three main stages. In the first stage, large organic molecules, such as proteins, polysaccharides or lipids, are digested into their smaller components outside cells. Next, these smaller molecules are taken up by cells and converted to smaller molecules, usually acetyl coenzyme A (acetyl-CoA), which releases some energy. Finally, the acetyl group on the CoA is oxidised to water and carbon dioxide in the citric acid cycle and electron transport chain, releasing the energy that is stored by reducing the coenzyme nicotinamide adenine dinucleotide (NAD + ) into NADH.

                                                                                6.2.2 Digestion

                                                                                Macromolecules cannot be directly processed by cells. Macromolecules must be broken into smaller units before they can be used in cell metabolism. Different classes of enzymes were being used to digest these polymers. These digestive enzymes include proteases that digest proteins into amino acids, as well as glycoside hydrolases that digest polysaccharides into simple sugars known as monosaccharides

                                                                                Microbes simply secrete digestive enzymes into their surroundings, while animals only secrete these enzymes from specialized cells in their guts, including the stomach and pancreas, and salivary glands. The amino acids or sugars released by these extracellular enzymes are then pumped into cells by active transport proteins.

                                                                                6.2.3 Energy From Organic Compounds

                                                                                Carbohydrate catabolism is the breakdown of carbohydrates into smaller units. Carbohydrates are usually taken into cells once they have been digested into monosaccharides. Once inside, the major route of breakdown is glycolysis, where sugars such as glucose and fructose are converted into pyruvate and some ATP is generated. Pyruvate is an intermediate in several metabolic pathways, but the majority is converted to acetyl-CoA through aerobic (with oxygen) glycolysis and fed into the citric acid cycle. Although some more ATP is generated in the citric acid cycle, the most important product is NADH, which is made from NAD + as the acetyl-CoA is oxidized. This oxidation releases carbon dioxide as a waste product. In anaerobic conditions, glycolysis produces lactate, through the enzyme lactate dehydrogenase re-oxidizing NADH to NAD + for re-use in glycolysis. An alternative route for glucose breakdown is the pentose phosphate pathway, which reduces the coenzyme NADPH and produces pentose sugars such as ribose, the sugar component of nucleic acids.

                                                                                Fats are catabolised by hydrolysis to free fatty acids and glycerol. The glycerol enters glycolysis and the fatty acids are broken down by beta oxidation to release acetyl-CoA, which then is fed into the citric acid cycle. Fatty acids release more energy upon oxidation than carbohydrates because carbohydrates contain more oxygen in their structures. Steroids are also broken down by some bacteria in a process similar to beta oxidation, and this breakdown process involves the release of significant amounts of acetyl-CoA, propionyl-CoA, and pyruvate, which can all be used by the cell for energy. M. tuberculosis can also grow on the lipid cholesterol as a sole source of carbon, and genes involved in the cholesterol use pathway(s) have been validated as important during various stages of the infection lifecycle of M. tuberculosis.

                                                                                Amino acids are either used to synthesize proteins and other biomolecules, or oxidized to urea and carbon dioxide as a source of energy. The oxidation pathway starts with the removal of the amino group by a transaminase. The amino group is fed into the urea cycle, leaving a deaminated carbon skeleton in the form of a keto acid. Several of these keto acids are intermediates in the citric acid cycle, for example the deamination of glutamate forms α-ketoglutarate. The glucogenic amino acids can also be converted into glucose, through gluconeogenesis (discussed below).

                                                                                2 Answers 2

                                                                                The enzymes don't need physical interactions to couple reactions. Some enzymes do share subunits which are physically associated, but this is a special case. The following review gives a sort of general example during glycolysis,

                                                                                For example, in the biochemical pathway that breaks down glucose for energy, two enzymes work one after the other to create a high-energy ATP molecule:

                                                                                We can also look at the peptidyltransferase reaction during the elongation step in translation. Earlier, an aminoacyl tRNA synthetase catalyzed the covalent addition of an amino acid to it's associated tRNA. The energy from breaking this bond in the ribosome provides energy for the peptidyltransferase to link the two amino acids together. This isn't assuming the ATP/GTP needed by elongation factors, etc.

                                                                                What are Spontaneous Reactions

                                                                                Spontaneous reactions refer to the chemical reactions that occur without being driven by an outside force. The two driving forces of a chemical reaction are enthalpy and entropy. Enthalpy is a thermodynamic property of a system that is the sum of the internal energy added to the product of the pressure and the volume of the system. Entropy is the other thermodynamic property that accounts for the system’s thermal energy per unit temperature. It describes the randomness and disorder of molecules. When the occurrence of a chemical reaction decreases the enthalpy and increases the entropy of the system, it is considered as a favourable reaction. As spontaneous reactions fulfil the above two conditions, they occur without inside intervention.

                                                                                Figure 1: Wood Combustion

                                                                                Combustion is an example of spontaneous reactions. The products of the fire partly consist of the two gases: carbon dioxide and water vapour. Combustion generates heat. Thus, it is an exergonic reaction. Heat increases the entropy of the system. But, the entropy of the products of the combustion has a reduced entropy.

                                                                                The Limits of Organic Life in Planetary Systems (2007)

                                                                                To search for additional constraints on the limits of life, the committee considered topics related to the origin of life. There is a clear distinction between environments that are habitable and environments that might support the emergence of animate matter from inanimate matter. Indeed, many observers believe that although the surface of modern Earth is a habitable environment, life could not emerge here now. According to that thinking, the dioxygen that is present in today&rsquos terran atmosphere would be toxic to any primitive life form that might emerge spontaneously.

                                                                                It is conceivable that if we understood the processes by which life arises, we might constrain the existence of life to a small number of locales, to a similar array of organic species, or to a smaller number of liquid phases than the more general thermodynamic-structure-solvent trichotomy, discussed above, would tolerate. That would, in turn, be considered alongside emerging models of planetary formation to provide better direction for the targets of National Aeronautics and Space Administration (NASA) missions to the solar system.

                                                                                Fifty years&rsquo worth of effort has shown that it is difficult to model how life might have originated in any specific environment. The committee recognized that it is still more difficult to consider how life might have arisen in a generic environment. The details of an environment almost certainly determine how life might emerge.

                                                                                The environment on early Earth is not well defined. The committee recommends that more information be obtained from missions, especially to comets, and that models of planetary formation continue to be developed. It is not certain even that terran life originated on Earth. On the basis of various considerations&mdashincluding the abundance of water, the paucity of some minerals, and the nature of the atmosphere modeled for early Earth&mdashvarious authors have suggested that life on Earth originated elsewhere, including locales as nearby as Mars and as distant as galactic nebulas. The geological record is considered to be intact for 4.5 Ga on Mars and Ceres, so there may still be mineralogical and isotopic signatures indicating past life. However, the detection of signs of past life would not be evidence that Mars or Ceres had an origin of life separate from Earth&rsquos origin, nor would it provide evidence that panspermia occurred. In the absence of firm information concerning the requirements for the origin of life as we know it and the mechanisms of its formation, such speculation seems premature. Our knowledge of the environments in those remote locales several billion years ago is even less complete than our understanding of early Earth.

                                                                                It is also not clear that terran life originated on Earth in the chemical form that we know now. Respectable hypotheses suggest, for example, that the three-biopolymer (DNA-RNA-proteins) system that characterizes all life that we know on Earth, a system in which nucleic acids serve roles predominantly in genetics and information transfer and proteins serve roles predominantly in catalysis, may not have been characteristic of life as it first originated. Only one of these complex chemical entities may have been represented in primitive life, or perhaps none at all.

                                                                                Several hypotheses argue that RNA was the only genetically encoded component of biological catalysis during an earlier episode of life on Earth. Some others view that statement as true for the very first form of life on Earth (the RNA-first hypothesis). Others have argued that the first form of life on Earth was supported by genetic molecules that had structures quite different from the structure of DNA or RNA.

                                                                                Some have even argued that the original genetic material was mineral, not organic. 1 , 2 They suggest that a truly primitive replicator might have been a layered inorganic mineral, crystallizing from solution and in the process amplifying some particular permutation of stacking: either identical layers stacked on top of each other in different orientations or stacks of two or more chemically different layers. The &ldquoinformation&rdquo would be the particular stacking sequence of a crystal displayed like a bar code on its edges and maintained and extended through crystal growth with ions, or small molecular units, adding only to the edges. The stacking sequences would also specify particular phenotypic properties that would allow Darwinian competition.

                                                                                As is evident in Section 5.7, a case can be made that the earliest forms of life on Earth contained no macromolecules at all and that heredity was carried by monomers 3 &mdashstill another route for future exploration.

                                                                                5.1LABORATORY SYNTHESIS OF ORGANIC MONOMERS

                                                                                It has been more than 50 years since Stanley Miller first explored electrically induced chemical reactions that might convert simple gases into small organic molecules. 4 The production of amino acids was especially easily demonstrated. More recently, the highly reducing atmosphere used by Miller has fallen out of favor as representative of the likely atmosphere on early Earth (although Kasting has shown that the impact of a large asteroid with iron causes a transient reducing atmosphere 5 ). Even with more contemporary models of early planetary atmospheres, however, electrical discharge, ultraviolet radiation, and other sources of energy are suitable for creating organic species. For example, Box 5.1 lists compounds, called &ldquotholins,&rdquo produced from relatively oxidizing environments under these conditions.

                                                                                Organic Compounds Identified in Tholin Mixtures

                                                                                SOURCE: Derived from Sagan, C., Khare, N.B., Bandurski, L.E., and Batholomew, N., 1978, Ultraviolet-photoproduced organic solids synthesized under simulated Jovian conditions: Molecular analysis, Science 199:1199-1201 Sagan, C., and Khare, N.B., 1979, Tholins: Organic chemistry of interstellar grains and gas, Nature 277:102-107 and Pietrogrande, M.C., Coll, P., Sternberg, R., Szopa, C., Navarro-Gonzalez, R., Vidal-Madjar, C., and Dondi, F., 2001, Analysis of complex mixtures recovered from space missions: Statistical approach to the study of Titan atmosphere analogues tholins, J. Chromatogr. A. 939:69-77.

                                                                                TABLE 5.1 Carbon in the Murchison Meteorite

                                                                                Carbon as interstellar grains

                                                                                SOURCE: Modified after J.R. Cronin, &ldquoClues from the Origin of the Solar System: Meteorites,&rdquo pp. 119-146 in The Molecular Origins of Life: Assembling Pieces of the Puzzle, A. Brack A. (ed.), Cambridge University Press, Cambridge, U.K., 1998.

                                                                                Similar experiments have generated nonbiological routes for the synthesis of other organic molecules, including some molecules that are used in our own biochemistry. For example, the Oró-Orgel synthesis exploits the reactivity of HCN to make adenine (C5H5N5), one of the five nucleobases used to store information in DNA and RNA. Analogous synthesis generates adenine from formamide.

                                                                                The complexity of the products of adding energy to simple organic mixtures, including the complexity of tholins, has a disadvantage. The diversity of products is so great in such experiments in prebiotic chemistry that they do not greatly limit the inventory of organic species that might have been present on early Earth.

                                                                                5.2NATURAL AVAILABILITY OF BIOLOGICAL-LIKE MOLECULES

                                                                                5.2.1Biological-like Molecules from the Cosmos

                                                                                There is little doubt that natural processes generate organic molecules analogous to those generated by the laboratory experiments described above. Amino acids are found in natural specimens, including meteorites, that are almost certainly not influenced by biological processes. They include many amino acids that are not part of the human-like standard collection of encoded amino acids.

                                                                                Some chemical fragments of DNA and RNA can also be found in meteorites (Tables 5.1 and 5.2). For example, some meteorites have been reported to contain small amounts of adenine, one of the nucleobases found in RNA and DNA. The current view is that the Murchison meteorite contained adenine, guanine, their hydrolysis products hypoxanthine and xanthine, and uracil. The reported concentration of all those substances, however, is low, about 1.3 ppm. The Murchison and other meteorites may also contain ribitol and ribonic acid, the reduced and oxidized forms of ribose, respectively, but ribose itself has not been found. 6

                                                                                TABLE 5.2 Organic Compounds in the Murchison Meteorite

                                                                                SOURCE: Data from Cronin, J.R., and Pizzarello, S. 1986. Amino acids of the Murchison meteorite. III. Seven carbon acyclic primary alpha-amino alkanoic acids. Geochim. Cosmochim. Acta 50:2419-2427.

                                                                                TABLE 5.3 The Organic Content of the Tagish Lake Meteorite

                                                                                Pyridine carboxylic acids

                                                                                SOURCE: Data from Pizzarello, S., Huang, Y.S., Becker, L., Poreda, R.J., Nieman, R.A., Cooper, G., and Williams, M. 2001. The organic content of the Tagish Lake meteorite. Science 293:2236.

                                                                                We do not know the extent to which the Murchison organics reflect what was available on early Earth before life emerged. The rich inventory of amino acids does not appear to be universal in carbonaceous chondrites (although the number that have been examined in detail is very small). For example, only a few amino acids (glycine, alanine, &alpha-aminoisobutyric acid, &alpha-amino-n-butyric acid, &gamma-aminobutyric acid) are found in the meteorite that fell in 2000 on Tagish Lake, Canada (Table 5.3). 7 The near absence of complex amino acids is significant, inasmuch as the meteorite was captured in a pristine condition soon after it fell.

                                                                                It is also significant that no discovery of a dipeptide in meteorites has yet been reported. Joining two amino acids is the first step toward the synthesis of proteins, such as those found in contemporary terran life. If the meteorite organics analyzed to date are representative of planetary processing of primitive organic compounds, the process of assembling amino acids into polypeptides (short strings) may have been carried out first within living cells.

                                                                                5.2.2Biological-like Molecules from Planetary Processes

                                                                                Current research is showing the interactions between organic molecules and a wide array of minerals. These include the formation of carboxylic acids in thermal vent chemistry and the formation of reduced chemical species through photochemistry involving semiconducting minerals. 8

                                                                                5.2.3The Origin of Phosphorus

                                                                                Phosphorus is an important component of terran life, but its synthesis in stars is not simple. It is produced as phosphorus-31 in stars with 15 protons and 16 neutrons and hence is an &ldquoodd-Z&rdquo element. Odd-Z elements are more difficult to produce than &ldquoeven-Z&rdquo elements having an equal number of protons and neutrons these can be produced from other even-Z elements via an &ldquoalpha chain&rdquo from helium. Odd-Z elements like P-31 are generally produced in abundance only when there is an excess of neutrons to protons. This excess emerges only as the universe ages, implying that life based on phosphorus cannot have emerged early in the life of the universe. Odd-Z elements are also less abundant in the Sun than common elements, such as carbon and oxygen, by factors in excess of 100, although current models with sophisticated stellar nucleosynthesis account rather well for the observed phosphorus abundance in the Sun. 9

                                                                                Phosphorus is abundant on Earth, both as an element (the 11th-most abundant atom in Earth&rsquos crust) and as phosphate. Meteorites hold a variety of phosphate-containing minerals and some phosphide minerals. 10 Scientists at the University of Arizona have recently suggested that Fe3P, the mineral schreibersite, leads to the formation of phosphate and phosphite when corroded in water. Although phosphorylation of alcohols was not demonstrated, mechanistic considerations suggest that it should be possible. It is noteworthy that a clear prebiotic pathway for the chemical incorporation of phosphate into RNA or DNA has not been found. No nucleosides (nucleobases joined to sugars) have been reported from meteorites. Nor has evidence been found in any meteorite of the presence of nucleosides or nucleotides (nucleosides attached to phosphates). That suggests that nucleic acids were first formed as products of metabolism.

                                                                                5.2.4The Origin of Metabolism

                                                                                Considerations of the emergence of life on Earth have often focused on the spontaneous abiotic formation of RNA, which is both a genetic polymer and a catalytic polymer. The chemical complexity of this molecule suggests that the probability of such an event, although not zero, is extremely small, given the absence on present-day Earth of conditions that would favor its formation. 11

                                                                                Catalysts may have played an important role in establishing the early metabolism that ultimately led to the biosynthesis of RNA. An intriguing possibility is that modern metabolic pathways emerged by a stepwise process of recruitment of ever more effective catalysts to catalyze steps in a primordial chemical-reaction network. Transitionmetal sulfides and mineral surfaces are known to be able to catalyze the formation of simple organic compounds. Later, small molecules&mdashsuch as amino acids, short peptides, and cofactors&mdashmay have catalyzed reactions required to produce more complicated organic compounds. Although their catalytic abilities are known to be limited in both acceleration and specificity compared with later macromolecular RNA or protein catalysts, some small molecules are remarkably effective catalysts. For example, pyridoxal phosphate catalyzes the rate of decarboxylation of amino acids by 10 orders of magnitude. 12 That cofactor has been retained at the active site of many modern enzymes. Iron-sulfur clusters are also found in many modern enzymes and may be relics of a time in which they catalyzed similar reactions but without the context of the protein. A stage in which RNA provided the best function, either alone or in combination with peptides that helped to stabilize folded RNA structures, may have come next. 13 What is clear is that of the synthesis of polypeptides by the translation of encoded RNA eventually became a focus of natural selection, in which the fitness of organisms depended critically on the catalytic abilities of enzymes involved in metabolic processes. In that transformation, protein enzymes replaced most RNA enzymes. An alternative possibility is that RNA catalysis never exceeded the extent to which it is present in modern biochemistry and that short peptides and cofactors carried the catalytic burden until the development of translation.

                                                                                That diversity of possibilities creates ample opportunities for Earth-based experimental work in the origin of life, and the committee recommends enhanced efforts to exploit them. Such Earth-based research is critical for informing the design of planetary missions whose payloads can detect the conditions for the emergence of life and also detect primitive life, especially life that has not yet evolved to the point where it synthesizes peptides by translation.

                                                                                5.3THERMODYNAMIC EQUILIBRIA

                                                                                Given a source of organic precursors, the question remains, Which reactions might have occurred with and between the precursors on early Earth, and in what quantities would they have been found? To address that question, the committee looked at the thermodynamic properties of molecules.

                                                                                First, it considered the concept of the reduction-oxidation (redox) state, which is often used to describe organic and other molecules. The rules used to calculate an oxidation state are different between inorganic species and organic species. For example, Fe++ and Fe+++ have different redox states the second lacks an electron that the first has. For organic molecules, however, the redox state is generally described with the ratio of the number of hydrogen atoms in a molecule to the number of heteroatoms.

                                                                                Because its carbon is bonded to two oxygen atoms and no hydrogen atoms, carbon dioxide is as oxidized as a carbon atom can be. Methane, in which carbon is bonded only to hydrogen, is as reduced as a carbon atom can be. Formaldehyde is at the same oxidation level as elemental carbon (because it has an equal number of bonds to hydrogen and oxygen). Viewed alternatively,the ratio of hydrogen atoms (2) to oxygen atoms (1) is the same in formaldehyde as in water. Thus, compounds of the formula Cn(H2O)n can be converted to elemental carbon by heating, which extrudes water without a net change in the redox state of the carbons.

                                                                                At one level, understanding the thermodynamics of carbon-containing molecules with respect to oxidation or reduction is as simple as asking whether hydrogen or oxygen is more abundant in the environment. In the modern terran atmosphere, which contains abundant dioxygen, essentially all compounds that contain reduced carbon are thermodynamically unstable with respect to oxidation to carbon dioxide. From a thermodynamic perspective, virtually all organic matter placed in today&rsquos atmosphere will eventually &ldquoburn&rdquo and yield carbon dioxide

                                                                                and water. The rate of the burning, however, can be very low at 20-40°C and at today&rsquos atmospheric oxygen partial pressure.

                                                                                In the absence of oxygen and in the presence of H2, reduced carbon is thermodynamically preferred. That is certainly true deep in the ocean, for example, near hydrothermal vents, where the synthesis of reduced organic compounds is thermodynamically favored. Shock, Cody, and others have exploited that fact to propose net synthesis of organic molecules in anoxic environments. 14 , 15

                                                                                A reaction that is thermodynamically &ldquouphill&rdquo (not energetically favored) in one direction can become &ldquodownhill&rdquo in the same direction if the environmental conditions are changed. If (A + B) (C + D), the reaction can be pulled to the right if D is removed, converting all (A + B) to C. Conversely, if excess D is added, C will be driven to (A + B). That behavior of equilibria often appears in textbooks as Le Chatelier&rsquos principle.

                                                                                It is important to note that no biological compound can ever be said to be universally &ldquohigh in energy.&rdquo Each reaction has a free energy, or &DeltaG 0 , which is measured at a standard, arbitrarily defined, concentration. &DeltaG 0 does not determine whether the corresponding chemical reaction runs in the forward or reverse direction, however. This is determined as well by the concentrations of the reactants and the products, and the direction in which the state is out of equilibrium. This is captured by &DeltaG, which reflects both &DeltaG 0 as well as the concentration of the reactants and products.

                                                                                For this reason, it is not useful to speak of the &ldquoenergy&rdquo of any particular compound. Rather, the free energy &DeltaG of a system, which makes a statement about whether it can do work, is determined by the degree to which the system is out of equilibrium. This, in turn, is defined by the equation &DeltaG = &DeltaG 0 + RT ln [product]/[reactant].

                                                                                In that context, adenosine triphosphate (ATP), the currency of energy in all cells, is viewed as &ldquohigh energy&rdquo only because at equilibrium the reaction ATP + water ADP + inorganic phosphate contains more ADP and inorganic phosphate than ATP. If, however, the initial state contains ADP + inorganic phosphate and no ATP, the process spontaneously proceeds in the direction of the synthesis of ATP from ADP and inorganic phosphate. In that case, ADP and inorganic phosphate are the &ldquohigh-energy&rdquo compounds.

                                                                                Other generalizations concerning reactivity are based on the principles of thermodynamics. For example, organic molecules contain hydrogen atoms, which, given an appropriate catalyst or source of energy (ultraviolet light, for example), might generate H2. Because H2 molecules have a lower mass than other molecules, they move faster on average and therefore preferentially escape from planetary bodies, especially those with low mass and, consequentially, weak gravitational attraction. Although both the formation and the loss of H2 may be slow, cosmic processes have time. A collection of organic molecules slowly becomes more oxidized through loss of H2.

                                                                                That is presumably what is occurring today on the surface of Mars. Above Mars, water is dissociated by ultraviolet radiation to yield H· and ·OH, the hydrogen radical and the hydroxyl radical. Two H· units can combine to give H2. The H2 then escapes from Mars, leaving behind HOOH, hydrogen peroxide. Under typical conditions on Earth, hydrogen peroxide might be viewed as a high-energy compoundon Mars, escape of H2 leads to its formation over time. On an aqueous body, such as Europa, the hydrogen peroxide formed by radiation will decompose into water and oxygen. The oxygen would then be available for the biological oxidation of other organic compounds formed by radiation or water-rock reactions, such as methane and formaldehyde. The concentrations of formaldehyde and oxygen from radiation were considered sufficient to support a microbial ecosystem on Europa. 16

                                                                                Carbon is likely to congeal to high-molecular-weight polymers as H2 distills off. In extraterrestrial environments, we expect lower hydrocarbons eventually to transform into pure carbon, either diamond (in which all the carbons are singly bonded to other carbons), fullerenes and graphite (in which each interaction between a pair of carbons is the approximate equivalent of 1.5 bonds), or carbon bonded to other elements that cannot be converted to a volatile form.

                                                                                Polycyclic aromatic hydrocarbons can be viewed as &ldquocarbon on the way to forming graphite.&rdquo They are common in extraterrestrial environments. Their central structures are fragments of graphite with bonding to hydrogen atoms at the edges. They become larger and larger, and more and more like graphite, as more hydrogen distills away.

                                                                                5.4PROBLEMS IN ORIGINS

                                                                                Chemists&rsquo objection to the notion that life is a natural consequence of organic reactivity is simple and comes from broadly based empirical experience in organic-chemistry laboratories. Addition of energy to mixtures of

                                                                                organic species makes the mixtures more complex and less likely to support life. Shapiro has provided a thoughtful and detailed discussion of the difficulties. 17 - 22 Briefly summarized, it suggests that existing prebiotic chemistry experiments do not offer plausible hypotheses for routes to complex biomolecules. In the complex chemical mixtures generated under prebiotic conditions, one may be able to find trace amounts of amino acids and perhaps nucleobases. Some might indeed catalyze reactions that have some utility. But other compounds may well inhibit catalysis or catalyze undesired reactions. For example, Joyce and Orgel pointed out that the clay-catalyzed condensation of nucleotides to yield small chains performed best, under the conditions that they considered, if only one enantiomer of the starting material was present. If both were present, the desired reaction with the desired enantiomer might be inhibited by the other enantiomer. 23 Furthermore, the combination of any bifunctional molecule into an information-bearing polymer would be expected to be terminated at an early stage by the presence of an excess of molecules that bear only one functionality. 24

                                                                                Even crystallization, a well-documented method of obtaining order through self-organization, is not a particularly powerful way to separate mixtures of organic chemicals into their constituents. Normally, an organic compound must be relatively pure before crystallization occurs. That salts crystallize better may explain why crystals are more common in the mineral world than in the organic world. Even organic salts can have problems in crystallizing from an impure mixture.

                                                                                Those facts generate the central problem in prebiotic chemistry. Spontaneous self-organization is not known to be an intrinsic property of most organic matter, at least as observed in the laboratory. It can be driven only by an external source of free energy that is coupled to the organic system.

                                                                                5.4.1Nucleophilic and Electrophilic Reactions Can Destroy as Well as Create

                                                                                As described above, formidable chemical obstacles oppose the abiotic synthesis of such biopolymers as RNA, DNA, and protein despite their prominence in life today. Numerous degradative processes would also hinder any event of that kind. The same inherent reactivities that generate organic molecules can convert them into complex mixtures. An example can be seen in the processes that might have generated the sugar ribose, a key component of RNA and DNA, under prebiotic conditions. A reaction called the formose reaction is known to produce ribose by converting formaldehyde in the presence of calcium hydroxide into several sugars, including ribose. 25 - 27

                                                                                The formose reaction exploits the natural electrophilicity of formaldehyde and the natural nucleophilicity of the enediolate of glycolaldehyde, a carbohydrate that has been detected in interstellar clouds. 28 That species reacts as a nucleophile with formaldehyde (acting as an electrophile) to yield glyceraldehyde. Reaction of glyceraldehyde with a second equivalent of the enediolate generates a pentose sugar (ribose, arabinose, xylose, or lyxose, depending on stereochemistry). A curved-arrow mechanism describes this process in Figure 5.1.

                                                                                Despite the reactivity inherent in glycolaldehyde and formaldehyde, the formose reaction does not offer a compelling source of prebiotic ribose. Under typical formose reaction conditions, ribose not only forms but also decomposes. In the presence of calcium hydroxide, ribose is rapidly converted to a mixture of organic species this mixture has never been thoroughly characterized, but it does not appear to contain much ribose, and it is not an auspicious precursor of life. The further reaction of ribose in the presence of calcium hydroxide occurs because ribose itself has both electrophilic and nucleophilic sites, respectively, at the aldehyde carbon and at the carbon directly bonded to the aldehyde (after enolization&mdashsee Figure 5.1). Molecules having both reactivities tend, as expected, to polymerize as the nucleophilic sites and electrophilic sites react with each other, with more formaldehyde, with water, or with other electrophiles in the increasingly complex mixture. Those reactivities undoubtedly cause the rapid destruction of the ribose formed under formose conditions. On the basis of those reactivities, Larralde, Robertson, and Miller concluded that &ldquoribose and other sugars were not components of the first genetic material.&rdquo 29

                                                                                A solution to the instability of ribose has been offered by Eschenmoser, Arrhenius, and others. It has focused on the generation of sugar phosphates, which have long been known to be more stable to degradation under alkaline conditions. A possible mechanism for forming them is shown in Figure 5.2.

                                                                                For those reasons, some have suggested that life may have begun with an alternative organic compound as a genetic material, not RNA, but have been based on molecules that are less fragile. 30 They are commonly suggested to be molecules that do not have carbohydrates in their backbones. Underlying that concept is the notion

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