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Preface		v
Part I THE MOLECULAR DESIGN OF LIFE		1
CHAPTER 1 Biochemistry: An Evolving Science		1
1.1 Biochemical Unity Underlies Biological Diversity		1
1.2 DNA Illustrates the Interplay Between Form and Function		4
	DNA is constructed from four building blocks	4
	Two single strands of DNA combine to form a double helix	5
	DNA structure explains heredity and the storage of information	5
1.3 Concepts from Chemistry Explain the Properties of Biological Molecules		6
	The formation of the DNA double helix as a key example	6
	The double helix can form from its component strands	6
	Covalent and noncovalent bonds are important for the structure and stability of biological molecules	6
	The double helix is an expression of the rules of chemistry	9
	The laws of thermodynamics govern the behavior of biochemical systems	10
	Heat is released in the formation of the double helix	12
	Acid–base reactions are central in many biochemical processes	13
	Acid–base reactions can disrupt the double helix	14
	Buffers regulate pH in organisms and in the laboratory	15
1.4 The Genomic Revolution Is Transforming Biochemistry, Medicine, and Other Fields		17
	Genome sequencing has transformed biochemistry and other fields	17
	Environmental factors influence human biochemistry	20
	Genome sequences encode proteins and patterns of expression	21
APPENDIX: Visualizing Molecular Structures I: Small Molecules		22
CHAPTER 2 Protein Composition and Structure		27
2.1 Proteins Are Built from a Repertoire of 20 Amino Acids		29
2.2 Primary Structure: Amino Acids Are Linked by Peptide Bonds to Form Polypeptide Chains		35
	Proteins have unique amino acid sequences specified by genes	37
	Polypeptide chains are flexible yet conformationally restricted	38
2.3 Secondary Structure: Polypeptide Chains Can Fold into Regular Structures Such As the Alpha Helix, the Beta Sheet, and Turns and Loops		40
	The alpha helix is a coiled structure stabilized by intrachain hydrogen bonds	40
	Beta sheets are stabilized by hydrogen bonding between polypeptide strands	42
	Polypeptide chains can change direction by making reverse turns and loops	44
	Fibrous proteins provide structural support for cells and tissues	44
2.4 Tertiary Structure: Water-Soluble Proteins Fold into Compact Structures with Nonpolar Cores		46
2.5 Quaternary Structure: Polypeptide Chains Can Assemble into Multisubunit Structures		48
2.6 The Amino Acid Sequence of a Protein Determines Its Three-Dimensional Structure		49
	Amino acids have different propensities for forming α helices, β sheets, and turns	51
	Protein folding is a highly cooperative process	52
	Proteins fold by progressive stabilization of intermediates rather than by random search	53
	Prediction of three-dimensional structure from sequence remains a great challenge	54
	Some proteins are inherently unstructured and can exist in multiple conformations	55
	Protein misfolding and aggregation are associated with some neurological diseases	56
	Protein modification and cleavage confer new capabilities	57
APPENDIX: Visualizing Molecular Structures II: Proteins		61
CHAPTER 3 Exploring Proteins and Proteomes		65
	The proteome is the functional representation of the genome	66
3.1 The Purification of Proteins Is an Essential First Step in Understanding Their Function		66
	The assay: How do we recognize the protein that we are looking for?	67
	Proteins must be released from the cell to be purified	67
	Proteins can be purified according to solubility, size, charge, and binding affinity	68
	Proteins can be separated by gel electrophoresis and displayed	71
	A protein purification scheme can be quantitatively evaluated	75
	Ultracentrifugation is valuable for separating biomolecules and determining their masses	76
	Protein purification can be made easier with the use of recombinant DNA technology	78
3.2 Immunology Provides Important Techniques with Which to Investigate Proteins		79
	Antibodies to specific proteins can be generated	79
	Monoclonal antibodies with virtually any desired specificity can be readily prepared	80
	Proteins can be detected and quantified by using an enzyme-linked immunosorbent assay	82
	Western blotting permits the detection of proteins separated by gel electrophoresis	83
	Fluorescent markers make the visualization of proteins in the cell possible	84
3.3 Mass Spectrometry Is a Powerful Technique for the Identification of Peptides and Proteins		85
	Peptides can be sequenced by mass spectrometry	87
	Proteins can be specifically cleaved into small peptides to facilitate analysis	88
	Genomic and proteomic methods are complementary	89
	The amino acid sequence of a protein provides valuable information	90
	Individual proteins can be identified by mass spectrometry	91
3.4 Peptides Can Be Synthesized by Automated Solid-Phase Methods		92
3.5 Three-Dimensional Protein Structure Can Be Determined by X-ray Crystallography and NMR Spectroscopy		95
	X-ray crystallography reveals three-dimensional structure in atomic detail	95
	Nuclear magnetic resonance spectroscopy can reveal the structures of proteins in solution	97
CHAPTER 4 DNA, RNA, and the Flow of Genetic Information		105
4.1 A Nucleic Acid Consists of Four Kinds of Bases Linked to a Sugar–Phosphate Backbone		106
	RNA and DNA differ in the sugar component and one of the bases	106
	Nucleotides are the monomeric units of nucleic acids	107
	DNA molecules are very long and have directionality	108
4.2 A Pair of Nucleic Acid Strands with Complementary Sequences Can Form a Double-Helical Structure		109
	The double helix is stabilized by hydrogen bonds and van der Waals interactions	109
	DNA can assume a variety of structural forms	111
	Z-DNA is a left-handed double helix in which backbone phosphates zigzag	112
	Some DNA molecules are circular and supercoiled	113
	Single-stranded nucleic acids can adopt elaborate structures	113
4.3 The Double Helix Facilitates the Accurate Transmission of Hereditary Information		114
	Differences in DNA density established the validity of the semiconservative replication hypothesis	115
	The double helix can be reversibly melted	116
4.4 DNA Is Replicated by Polymerases That Take Instructions from Templates		117
	DNA polymerase catalyzes phosphodiester bridge formation	117
	The genes of some viruses are made of RNA	118
4.5 Gene Expression Is the Transformation of DNA Information into Functional Molecules		119
	Several kinds of RNA play key roles in gene expression	119
	All cellular RNA is synthesized by RNA polymerases	120
	RNA polymerases take instructions from DNA templates	121
	Transcription begins near promoter sites and ends at terminator sites	122
	Transfer RNAs are the adaptor molecules in protein synthesis	123
4.6 Amino Acids Are Encoded by Groups of Three Bases Starting from a Fixed Point		124
	Major features of the genetic code	125
	Messenger RNA contains start and stop signals for protein synthesis	126
	The genetic code is nearly universal	126
4.7 Most Eukaryotic Genes Are Mosaics of Introns and Exons		127
	RNA processing generates mature RNA	127
	Many exons encode protein domains	128
CHAPTER 5 Exploring Genes and Genomes		135
5.1 The Exploration of Genes Relies on Key Tools		136
	Restriction enzymes split DNA into specific fragments	137
	Restriction fragments can be separated by gel electrophoresis and visualized	137
	DNA can be sequenced by controlled termination of replication	138
	DNA probes and genes can be synthesized by automated solid-phase methods	139
	Selected DNA sequences can be greatly amplified by the polymerase chain reaction	141
	PCR is a powerful technique in medical diagnostics, forensics, and studies of molecular evolution	142
	The tools for recombinant DNA technology have been used to identify disease-causing mutations	143
5.2 Recombinant DNA Technology Has Revolutionized All Aspects of Biology		143
	Restriction enzymes and DNA ligase are key tools in forming recombinant DNA molecules	143
	Plasmids and λ phage are choice vectors for DNA cloning in bacteria	144
	Bacterial and yeast artificial chromosomes	147
	Specific genes can be cloned from digests of genomic DNA	147
	Complementary DNA prepared from mRNA can be expressed in host cells	149
	Proteins with new functions can be created through directed changes in DNA	150
	Recombinant methods enable the exploration of the functional effects of disease-causing mutations	152
5.3 Complete Genomes Have Been Sequenced and Analyzed		152
	The genomes of organisms ranging from bacteria to multicellular eukaryotes have been sequenced	153
	The sequence of the human genome has been completed	154
	Next-generation sequencing methods enable the rapid determination of a complete genome sequence	155
	Comparative genomics has become a powerful research tool	156
5.4 Eukaryotic Genes Can Be Quantitated and Manipulated with Considerable Precision		157
	Gene-expression levels can be comprehensively examined	157
	New genes inserted into eukaryotic cells can be efficiently expressed	159
	Transgenic animals harbor and express genes introduced into their germ lines	160
	Gene disruption and genome editing provide clues to gene function and opportunities for new therapies	160
	RNA interference provides an additional tool for disrupting gene expression	162
	Tumor-inducing plasmids can be used to introduce new genes into plant cells	163
	Human gene therapy holds great promise for medicine	164
CHAPTER 6 Exploring Evolution and Bioinformatics		169
6.1 Homologs Are Descended from a Common Ancestor		170
6.2 Statistical Analysis of Sequence Alignments Can Detect Homology		171
	The statistical significance of alignments can be estimated by shuffling	173
	Distant evolutionary relationships can be detected through the use of substitution matrices	174
	Databases can be searched to identify homologous sequences	177
6.3 Examination of Three-Dimensional Structure Enhances Our Understanding of Evolutionary Relationships		177
	Tertiary structure is more conserved than primary structure	178
	Knowledge of three-dimensional structures can aid in the evaluation of sequence alignments	179
	Repeated motifs can be detected by aligning sequences with themselves	180
	Convergent evolution illustrates common solutions to biochemical challenges	181
	Comparison of RNA sequences can be a source of insight into RNA secondary structures	182
6.4 Evolutionary Trees Can Be Constructed on the Basis of Sequence Information		183
	Horizontal gene transfer events may explain unexpected branches of the evolutionary tree	184
6.5 Modern Techniques Make the Experimental Exploration of Evolution Possible		185
	Ancient DNA can sometimes be amplified and sequenced	185
	Molecular evolution can be examined experimentally	185
CHAPTER 7 Hemoglobin: Portrait of a Protein in Action		191
7.1 Myoglobin and Hemoglobin Bind Oxygen at Iron Atoms in Heme		192
	Changes in heme electronic structure upon oxygen binding are the basis for functional imaging studies	193
	The structure of myoglobin prevents the release of reactive oxygen species	194
	Human hemoglobin is an assembly of four myoglobin like subunits	195
7.2 Hemoglobin Binds Oxygen Cooperatively		195
	Oxygen binding markedly changes the quaternary structure of hemoglobin	197
	Hemoglobin cooperativity can be potentially explained by several models	198
	Structural changes at the heme groups are transmitted to the α₁β₁–α₂β₂ interface	200
	2,3-Bisphosphoglycerate in red cells is crucial in determining the oxygen affinity of hemoglobin	200
	Carbon monoxide can disrupt oxygen transport by hemoglobin	201
7.3 Hydrogen Ions and Carbon Dioxide Promote the Release of Oxygen: The Bohr Effect		202
7.4 Mutations in Genes Encoding Hemoglobin Subunits Can Result in Disease		204
	Sickle-cell anemia results from the aggregation of mutated deoxyhemoglobin molecules	205
	Thalassemia is caused by an imbalanced production of hemoglobin chains	207
	The accumulation of free alpha-hemoglobin chains is prevented	207
	Additional globins are encoded in the human genome	208
APPENDIX: Binding Models Can Be Formulated in Quantitative Terms: The Hill Plot and the Concerted Model		210
CHAPTER 8 Enzymes: Basic Concepts and Kinetics		215
8.1 Enzymes are Powerful and Highly Specific Catalysts		216
	Many enzymes require cofactors for activity	217
	Enzymes can transform energy from one form into another	217
8.2 Gibbs Free Energy Is a Useful Thermodynamic Function for Understanding Enzymes		218
	The free-energy change provides information about the spontaneity but not the rate of a reaction	218
	The standard free-energy change of a reaction is related to the equilibrium constant	219
	Enzymes alter only the reaction rate and not the reaction equilibrium	220
8.3 Enzymes Accelerate Reactions by Facilitating the Formation of the Transition State		221
	The formation of an enzyme–substrate complex is the first step in enzymatic catalysis	222
	The active sites of enzymes have some common features	223
	The binding energy between enzyme and substrate is important for catalysis	225
8.4 The Michaelis–Menten Model Accounts for the Kinetic Properties of Many Enzymes		225
	Kinetics is the study of reaction rates	225
	The steady-state assumption facilitates a description of enzyme kinetics	226
	Variations in K_M can have physiological consequences	228
	K_M and V_max values can be determined by several means	228
	K_M and V_max values are important enzyme characteristics	229
	k_cat/K_M is a measure of catalytic efficiency	230
	Most biochemical reactions include multiple substrates	231
	Allosteric enzymes do not obey Michaelis–Menten kinetics	233
8.5 Enzymes Can Be Inhibited by Specific Molecules		234
	The different types of reversible inhibitors are kinetically distinguishable	235
	Irreversible inhibitors can be used to map the active site	237
	Penicillin irreversibly inactivates a key enzyme in bacterial cell-wall synthesis	239
	Transition-state analogs are potent inhibitors of enzymes	240
	Catalytic antibodies demonstrate the importance of selective binding of the transition state to enzymatic activity	241
8.6 Enzymes Can Be Studied One Molecule at a Time		242
APPENDIX: Enzymes are Classified on the Basis of the Types of Reactions That They Catalyze		245
CHAPTER 9 Catalytic Strategies		251
	A few basic catalytic principles are used by many enzymes	252
9.1 Proteases Facilitate a Fundamentally Difficult Reaction		253
	Chymotrypsin possesses a highly reactive serine residue	253
	Chymotrypsin action proceeds in two steps linked by a covalently bound intermediate	254
	Serine is part of a catalytic triad that also includes histidine and aspartate	255
	Catalytic triads are found in other hydrolytic enzymes	258
	The catalytic triad has been dissected by site-directed mutagenesis	260
	Cysteine, aspartyl, and metalloproteases are other major classes of peptide-cleaving enzymes	260
	Protease inhibitors are important drugs	263
9.2 Carbonic Anhydrases Make a Fast Reaction Faster		264
	Carbonic anhydrase contains a bound zinc ion essential for catalytic activity	265
	Catalysis entails zinc activation of a water molecule	265
	A proton shuttle facilitates rapid regeneration of the active form of the enzyme	267
9.3 Restriction Enzymes Catalyze Highly Specific DNA-Cleavage Reactions		269
	Cleavage is by in-line displacement of 3′-oxygen from phosphorus by magnesium-activated water	269
	Restriction enzymes require magnesium for catalytic activity	271
	The complete catalytic apparatus is assembled only within complexes of cognate DNA molecules, ensuring specificity	272
	Host-cell DNA is protected by the addition of methyl groups to specific bases	274
	Type II restriction enzymes have a catalytic core in common and are probably related by horizontal gene transfer	275
9.4 Myosins Harness Changes in Enzyme Conformation to Couple ATP Hydrolysis to Mechanical Work		275
	ATP hydrolysis proceeds by the attack of water on the gamma-phosphoryl group	276
	Formation of the transition state for ATP hydrolysis is associated with a substantial conformational change	277
	The altered conformation of myosin persists for a substantial period of time	278
	Scientists can watch single molecules of myosin move	279
	Myosins are a family of enzymes containing P-loop structures	280
CHAPTER 10 Regulatory Strategies		285
10.1 Aspartate Transcarbamoylase Is Allosterically Inhibited by the End Product of Its Pathway		286
	Allosterically regulated enzymes do not follow Michaelis–Menten kinetics	287
	ATCase consists of separable catalytic and regulatory subunits	287
	Allosteric interactions in ATCase are mediated by large changes in quaternary structure	288
	Allosteric regulators modulate the T-to-R equilibrium	291
10.2 Isozymes Provide a Means of Regulation Specific to Distinct Tissues and Developmental Stages		292
10.3 Covalent Modification Is a Means of Regulating Enzyme Activity		293
	Kinases and phosphatases control the extent of protein phosphorylation	294
	Phosphorylation is a highly effective means of regulating the activities of target proteins	296
	Cyclic AMP activates protein kinase A by altering the quaternary structure	297
	ATP and the target protein bind to a deep cleft in the catalytic subunit of protein kinase A	298
10.4 Many Enzymes Are Activated by Specific Proteolytic Cleavage		299
	Chymotrypsinogen is activated by specific cleavage of a single peptide bond	299
	Proteolytic activation of chymotrypsinogen leads to the formation of a substrate-binding site	300
	The generation of trypsin from trypsinogen leads to the activation of other zymogens	301
	Some proteolytic enzymes have specific inhibitors	302
	Blood clotting is accomplished by a cascade of zymogen activations	303
	Prothrombin requires a vitamin K-dependent modification for activation	304
	Fibrinogen is converted by thrombin into a fibrin clot	304
	Vitamin K is required for the formation of γ-carboxyglutamate	306
	The clotting process must be precisely regulated	307
	Hemophilia revealed an early step in clotting	308
CHAPTER 11 Carbohydrates		315
11.1 Monosaccharides Are the Simplest Carbohydrates		316
	Many common sugars exist in cyclic forms	318
	Pyranose and furanose rings can assume different conformations	320
	Glucose is a reducing sugar	321
	Monosaccharides are joined to alcohols and amines through glycosidic bonds	322
	Phosphorylated sugars are key intermediates in energy generation and biosyntheses	322
11.2 Monosaccharides Are Linked to Form Complex Carbohydrates		323
	Sucrose, lactose, and maltose are the common disaccharides	323
	Glycogen and starch are storage forms of glucose	324
	Cellulose, a structural component of plants, is made of chains of glucose	324
11.3 Carbohydrates Can Be Linked to Proteins to Form Glycoproteins		325
	Carbohydrates can be linked to proteins through asparagine (N-linked) or through serine or threonine (O-linked) residues	326
	The glycoprotein erythropoietin is a vital hormone	327
	Glycosylation functions in nutrient sensing	327
	Proteoglycans, composed of polysaccharides and protein, have important structural roles	327
	Proteoglycans are important components of cartilage	328
	Mucins are glycoprotein components of mucus	329
	Protein glycosylation takes place in the lumen of the endoplasmic reticulum and in the Golgi complex	330
	Specific enzymes are responsible for oligosaccharide assembly	331
	Blood groups are based on protein glycosylation patterns	331
	Errors in glycosylation can result in pathological conditions	332
	Oligosaccharides can be “sequenced”	332
11.4 Lectins Are Specific Carbohydrate-Binding Proteins		333
	Lectins promote interactions between cells	334
	Lectins are organized into different classes	334
	Influenza virus binds to sialic acid residues	335
CHAPTER 12 Lipids and Cell Membranes		341
	Many common features underlie the diversity of biological membranes	342
12.1 Fatty Acids Are Key Constituents of Lipids		342
	Fatty acid names are based on their parent hydrocarbons	342
	Fatty acids vary in chain length and degree of unsaturation	343
12.2 There Are Three Common Types of Membrane Lipids		344
	Phospholipids are the major class of membrane lipids	344
	Membrane lipids can include carbohydrate moieties	345
	Cholesterol is a lipid based on a steroid nucleus	346
	Archaeal membranes are built from ether lipids with branched chains	346
	A membrane lipid is an amphipathic molecule containing a hydrophilic and a hydrophobic moiety	347
12.3 Phospholipids and Glycolipids Readily Form Bimolecular Sheets in Aqueous Media		348
	Lipid vesicles can be formed from phospholipids	348
	Lipid bilayers are highly impermeable to ions and most polar molecules	349
12.4 Proteins Carry Out Most Membrane Processes		350
	Proteins associate with the lipid bilayer in a variety of ways	351
	Proteins interact with membranes in a variety of ways	351
	Some proteins associate with membranes through covalently attached hydrophobic groups	354
	Transmembrane helices can be accurately predicted from amino acid sequences	354
12.5 Lipids and Many Membrane Proteins Diffuse Rapidly in the Plane of the Membrane		356
	The fluid mosaic model allows lateral movement but not rotation through the membrane	357
	Membrane fluidity is controlled by fatty acid composition and cholesterol content	357
	Lipid rafts are highly dynamic complexes formed between cholesterol and specific lipids	358
	All biological membranes are asymmetric	358
12.6 Eukaryotic Cells Contain Compartments Bounded by Internal Membranes		359
CHAPTER 13 Membrane Channels and Pumps		367
	The expression of transporters largely defines the metabolic activities of a given cell type	368
13.1 The Transport of Molecules Across a Membrane May Be Active or Passive		368
	Many molecules require protein transporters to cross membranes	368
	Free energy stored in concentration gradients can be quantified	369
13.2 Two Families of Membrane Proteins Use ATP Hydrolysis to Pump Ions and Molecules Across Membranes		370
	P-type ATPases couple phosphorylation and conformational changes to pump calcium ions across membranes	370
	Digitalis specifically inhibits the Na⁺–K⁺ pump by blocking its dephosphorylation	373
	P-type ATPases are evolutionarily conserved and play a wide range of roles	374
	Multidrug resistance highlights a family of membrane pumps with ATP-binding cassette domains	374
13.3 Lactose Permease Is an Archetype of Secondary Transporters That Use One Concentration Gradient to Power the Formation of Another		376
13.4 Specific Channels Can Rapidly Transport Ions Across Membranes		378
	Action potentials are mediated by transient changes in Na⁺ and K⁺ permeability	378
	Patch-clamp conductance measurements reveal the activities of single channels	379
	The structure of a potassium ion channel is an archetype for many ion-channel structures	379
	The structure of the potassium ion channel reveals the basis of ion specificity	380
	The structure of the potassium ion channel explains its rapid rate of transport	383
	Voltage gating requires substantial conformational changes in specific ion-channel domains	383
	A channel can be inactivated by occlusion of the pore: the ball-and-chain model	384
	The acetylcholine receptor is an archetype for ligand-gated ion channels	385
	Action potentials integrate the activities of several ion channels working in concert	387
	Disruption of ion channels by mutations or chemicals can be potentially life-threatening	388
13.5 Gap Junctions Allow Ions and Small Molecules to Flow Between Communicating Cells		389
13.6 Specific Channels Increase the Permeability of Some Membranes to Water		390
CHAPTER 14 Signal-Transduction Pathways		397
	Signal transduction depends on molecular circuits	398
14.1 Heterotrimeric G Proteins Transmit Signals and Reset Themselves		399
	Ligand binding to 7TM receptors leads to the activation of heterotrimeric G proteins	400
	Activated G proteins transmit signals by binding to other proteins	402
	Cyclic AMP stimulates the phosphorylation of many target proteins by activating protein kinase A	403
	G proteins spontaneously reset themselves through GTP hydrolysis	403
	Some 7TM receptors activate the phosphoinositide cascade	404
	Calcium ion is a widely used second messenger	405
	Calcium ion often activates the regulatory protein calmodulin	407
14.2 Insulin Signaling: Phosphorylation Cascades Are Central to Many Signal-Transduction Processes		407
	The insulin receptor is a dimer that closes around a bound insulin molecule	408
	Insulin binding results in the cross-phosphorylation and activation of the insulin receptor	408
	The activated insulin-receptor kinase initiates a kinase cascade	409
	Insulin signaling is terminated by the action of phosphatases	411
14.3 EGF Signaling: Signal-Transduction Pathways Are Poised to Respond		411
	EGF binding results in the dimerization of the EGF receptor	411
	The EGF receptor undergoes phosphorylation of its carboxyl-terminal tail	413
	EGF signaling leads to the activation of Ras, a small G protein	413
	Activated Ras initiates a protein kinase cascade	414
	EGF signaling is terminated by protein phosphatases and the intrinsic GTPase activity of Ras	414
14.4 Many Elements Recur with Variation in Different Signal-Transduction Pathways		415
14.5 Defects in Signal-Transduction Pathways Can Lead to Cancer and Other Diseases		416
	Monoclonal antibodies can be used to inhibit signal-transduction pathways activated in tumors	416
	Protein kinase inhibitors can be effective anticancer drugs	417
	Cholera and whooping cough are the result of altered G-protein activity	417
Part II TRANSDUCING AND STORING ENERGY
CHAPTER 15 Metabolism: Basic Concepts and Design		423
15.1 Metabolism Is Composed of Many Coupled, Interconnecting Reactions		424
	Metabolism consists of energy-yielding and energy-requiring reactions	424
	A thermodynamically unfavorable reaction can be driven by a favorable reaction	425
15.2 ATP Is the Universal Currency of Free Energy in Biological Systems		426
	ATP hydrolysis is exergonic	426
	ATP hydrolysis drives metabolism by shifting the equilibrium of coupled reactions	427
	The high phosphoryl potential of ATP results from structural differences between ATP and its hydrolysis products	429
	Phosphoryl-transfer potential is an important form of cellular energy transformation	430
15.3 The Oxidation of Carbon Fuels Is an Important Source of Cellular Energy		432
	Compounds with high phosphoryl-transfer potential can couple carbon oxidation to ATP synthesis	432
	Ion gradients across membranes provide an important form of cellular energy that can be coupled to ATP synthesis	433
	Phosphates play a prominent role in biochemical processes	434
	Energy from foodstuffs is extracted in three stages	434
15.4 Metabolic Pathways Contain Many Recurring Motifs		435
	Activated carriers exemplify the modular design and economy of metabolism	435
	Many activated carriers are derived from vitamins	438
	Key reactions are reiterated throughout metabolism	440
	Metabolic processes are regulated in three principal ways	442
	Aspects of metabolism may have evolved from an RNA world	444
CHAPTER 16 Glycolysis and Gluconeogenesis		449
	Glucose is generated from dietary carbohydrates	450
	Glucose is an important fuel for most organisms	451
16.1 Glycolysis Is an Energy-Conversion Pathway in Many Organisms		451
	Hexokinase traps glucose in the cell and begins glycolysis	451
	Fructose 1,6-bisphosphate is generated from glucose 6-phosphate	453
	The six-carbon sugar is cleaved into two three-carbon fragments	454
	Mechanism: Triose phosphate isomerase salvages a three-carbon fragment	455
	The oxidation of an aldehyde to an acid powers the formation of a compound with high phosphoryl-transfer potential	457
	Mechanism: Phosphorylation is coupled to the oxidation of glyceraldehyde 3-phosphate by a thioester intermediate	458
	ATP is formed by phosphoryl transfer from 1,3-bisphosphoglycerate	459
	Additional ATP is generated with the formation of pyruvate	460
	Two ATP molecules are formed in the conversion of glucose into pyruvate	461
	NAD⁺ is regenerated from the metabolism of pyruvate	462
	Fermentations provide usable energy in the absence of oxygen	464
	The binding site for NAD⁺ is similar in many dehydrogenases	465
	Fructose is converted into glycolytic intermediates by fructokinase	465
	Excessive fructose consumption can lead to pathological conditions	466
	Galactose is converted into glucose 6-phosphate	466
	Many adults are intolerant of milk because they are deficient in lactase	467
	Galactose is highly toxic if the transferase is missing	468
16.2 The Glycolytic Pathway Is Tightly Controlled		469
	Glycolysis in muscle is regulated to meet the need for ATP	469
	The regulation of glycolysis in the liver illustrates the biochemical versatility of the liver	472
	A family of transporters enables glucose to enter and leave animal cells	473
	Aerobic glycolysis is a property of rapidly growing cells	474
	Cancer and endurance training affect glycolysis in a similar fashion	476
16.3 Glucose Can Be Synthesized from Noncarbohydrate Precursors		476
	Gluconeogenesis is not a reversal of glycolysis	478
	The conversion of pyruvate into phosphoenolpyruvate begins with the formation of oxaloacetate	478
	Oxaloacetate is shuttled into the cytoplasm and converted into phosphoenolpyruvate	480
	The conversion of fructose 1,6-bisphosphate into fructose 6-phosphate and orthophosphate is an irreversible step	480
	The generation of free glucose is an important control point	481
	Six high-transfer-potential phosphoryl groups are spent in synthesizing glucose from pyruvate	481
16.4 Gluconeogenesis and Glycolysis Are Reciprocally Regulated		482
	Energy charge determines whether glycolysis or gluconeogenesis will be most active	482
	The balance between glycolysis and gluconeogenesis in the liver is sensitive to blood-glucose concentration	483
	Substrate cycles amplify metabolic signals and produce heat	485
	Lactate and alanine formed by contracting muscle are used by other organs	485
	Glycolysis and gluconeogenesis are evolutionarily intertwined	487
CHAPTER 17 The Citric Acid Cycle		495
	The citric acid cycle harvests high-energy electrons	496
17.1 The Pyruvate Dehydrogenase Complex Links Glycolysis to the Citric Acid Cycle		497
	Mechanism: The synthesis of acetyl coenzyme A from pyruvate requires three enzymes and five coenzymes	498
	Flexible linkages allow lipoamide to move between different active sites	500
17.2 The Citric Acid Cycle Oxidizes Two-Carbon Units		501
	Citrate synthase forms citrate from oxaloacetate and acetyl coenzyme A	502
	Mechanism: The mechanism of citrate synthase prevents undesirable reactions	502
	Citrate is isomerized into isocitrate	504
	Isocitrate is oxidized and decarboxylated to alpha-ketoglutarate	504
	Succinyl coenzyme A is formed by the oxidative decarboxylation of alpha-ketoglutarate	505
	A compound with high phosphoryl-transfer potential is generated from succinyl coenzyme A	505
	Mechanism: Succinyl coenzyme A synthetase transforms types of biochemical energy	506
	Oxaloacetate is regenerated by the oxidation of succinate	507
	The citric acid cycle produces high-transfer-potential electrons, ATP, and CO₂	508
17.3 Entry to the Citric Acid Cycle and Metabolism Through It Are Controlled		510
	The pyruvate dehydrogenase complex is regulated allosterically and by reversible phosphorylation	511
	The citric acid cycle is controlled at several points	512
	Defects in the citric acid cycle contribute to the development of cancer	513
17.4 The Citric Acid Cycle Is a Source of Biosynthetic Precursors		514
	The citric acid cycle must be capable of being rapidly replenished	514
	The disruption of pyruvate metabolism is the cause of beriberi and poisoning by mercury and arsenic	515
	The citric acid cycle may have evolved from preexisting pathways	516
17.5 The Glyoxylate Cycle Enables Plants and Bacteria to Grow on Acetate		516
CHAPTER 18 Oxidative Phosphorylation		523
18.1 Eukaryotic Oxidative Phosphorylation Takes Place in Mitochondria		524
	Mitochondria are bounded by a double membrane	524
	Mitochondria are the result of an endosymbiotic event	525
18.2 Oxidative Phosphorylation Depends on Electron Transfer		526
	The electron-transfer potential of an electron is measured as redox potential	526
	A 1.14-volt potential difference between NADH and molecular oxygen drives electron transport through the chain and favors the formation of a proton gradient	528
18.3 The Respiratory Chain Consists of Four Complexes: Three Proton Pumps and a Physical Link to the Citric Acid Cycle		529
	Iron–sulfur clusters are common components of the electron transport chain	531
	The high-potential electrons of NADH enter the respiratory chain at NADH-Q oxidoreductase	532
	Ubiquinol is the entry point for electrons from FADH₂ of flavoproteins	533
	Electrons flow from ubiquinol to cytochrome c through Q-cytochrome c oxidoreductase	533
	The Q cycle funnels electrons from a two-electron carrier to a one-electron carrier and pumps protons	535
	Cytochrome c oxidase catalyzes the reduction of molecular oxygen to water	535
	Toxic derivatives of molecular oxygen such as superoxide radicals are scavenged by protective enzymes	538
	Electrons can be transferred between groups that are not in contact	540
	The conformation of cytochrome c has remained essentially constant for more than a billion years	541
18.4 A Proton Gradient Powers the Synthesis of ATP		541
	ATP synthase is composed of a proton-conducting unit and a catalytic unit	543
	Proton flow through ATP synthase leads to the release of tightly bound ATP: The binding-change mechanism	544
	Rotational catalysis is the world’s smallest molecular motor	546
	Proton flow around the c ring powers ATP synthesis	546
	ATP synthase and G proteins have several common features	548
18.5 Many Shuttles Allow Movement Across Mitochondrial Membranes		549
	Electrons from cytoplasmic NADH enter mitochondria by shuttles	549
	The entry of ADP into mitochondria is coupled to the exit of ATP by ATP-ADP translocase	550
	Mitochondrial transporters for metabolites have a common tripartite structure	551
18.6 The Regulation of Cellular Respiration Is Governed Primarily by the Need for ATP		552
	The complete oxidation of glucose yields about 30 molecules of ATP	552
	The rate of oxidative phosphorylation is determined by the need for ATP	553
	ATP synthase can be regulated	554
	Regulated uncoupling leads to the generation of heat	554
	Oxidative phosphorylation can be inhibited at many stages	556
	Mitochondrial diseases are being discovered	557
	Mitochondria play a key role in apoptosis	557
	Power transmission by proton gradients is a central motif of bioenergetics	558
CHAPTER 19 The Light Reactions of Photosynthesis		565
	Photosynthesis converts light energy into chemical energy	566
19.1 Photosynthesis Takes Place in Chloroplasts		567
	The primary events of photosynthesis take place in thylakoid membranes	567
	Chloroplasts arose from an endosymbiotic event	568
19.2 Light Absorption by Chlorophyll Induces Electron Transfer		568
	A special pair of chlorophylls initiate charge separation	569
	Cyclic electron flow reduces the cytochrome of the reaction center	572
19.3 Two Photosystems Generate a Proton Gradient and NADPH in Oxygenic Photosynthesis		572
	Photosystem II transfers electrons from water to plastoquinone and generates a proton gradient	572
	Cytochrome bf links photosystem II to photosystem I	575
	Photosystem I uses light energy to generate reduced ferredoxin, a powerful reductant	575
	Ferredoxin–NADP⁺ reductase converts NADP⁺ into NADPH	576
19.4 A Proton Gradient across the Thylakoid Membrane Drives ATP Synthesis		578
	The ATP synthase of chloroplasts closely resembles those of mitochondria and prokaryotes	578
	The activity of chloroplast ATP synthase is regulated	579
	Cyclic electron flow through photosystem I leads to the production of ATP instead of NADPH	580
	The absorption of eight photons yields one O₂, two NADPH, and three ATP molecules	581
19.5 Accessory Pigments Funnel Energy into Reaction Centers		581
	Resonance energy transfer allows energy to move from the site of initial absorbance to the reaction center	582
	The components of photosynthesis are highly organized	583
	Many herbicides inhibit the light reactions of photosynthesis	584
19.6 The Ability to Convert Light into Chemical Energy Is Ancient		584
	Artificial photosynthetic systems may provide clean, renewable energy	585
CHAPTER 20 The Calvin Cycle and the Pentose Phosphate Pathway		589
20.1 The Calvin Cycle Synthesizes Hexoses from Carbon Dioxide and Water		590
	Carbon dioxide reacts with ribulose 1,5-bisphosphate to form two molecules of 3-phosphoglycerate	591
	Rubisco activity depends on magnesium and carbamate	592
	Rubisco activase is essential for rubisco activity	593
	Rubisco also catalyzes a wasteful oxygenase reaction: Catalytic imperfection	593
	Hexose phosphates are made from phosphoglycerate, and ribulose 1,5-bisphosphate is regenerated	594
	Three ATP and two NADPH molecules are used to bring carbon dioxide to the level of a hexose	597
	Starch and sucrose are the major carbohydrate stores in plants	597
20.2 The Activity of the Calvin Cycle Depends on Environmental Conditions		598
	Rubisco is activated by light-driven changes in proton and magnesium ion concentrations	598
	Thioredoxin plays a key role in regulating the Calvin cycle	599
	The C₄ pathway of tropical plants accelerates photosynthesis by concentrating carbon dioxide	599
	Crassulacean acid metabolism permits growth in arid ecosystems	601
20.3 The Pentose Phosphate Pathway Generates NADPH and Synthesizes Five-Carbon Sugars		601
	Two molecules of NADPH are generated in the conversion of glucose 6-phosphate into ribulose 5-phosphate	602
	The pentose phosphate pathway and glycolysis are linked by transketolase and transaldolase	602
	Mechanism: Transketolase and transaldolase stabilize carbanionic intermediates by different mechanisms	605
20.4 The Metabolism of Glucose 6-Phosphate by the Pentose Phosphate Pathway Is Coordinated with Glycolysis		607
	The rate of the pentose phosphate pathway is controlled by the level of NADP⁺	607
	The flow of glucose 6-phosphate depends on the need for NADPH, ribose 5-phosphate, and ATP	608
	The pentose phosphate pathway is required for rapid cell growth	610
	Through the looking-glass: The Calvin cycle and the pentose phosphate pathway are mirror images	610
20.5 Glucose 6-Phosphate Dehydrogenase Plays a Key Role in Protection Against Reactive Oxygen Species		610
	Glucose 6-phosphate dehydrogenase deficiency causes a drug-induced hemolytic anemia	610
	A deficiency of glucose 6-phosphate dehydrogenase confers an evolutionary advantage in some circumstances	612
CHAPTER 21 Glycogen Metabolism		617
	Glycogen metabolism is the regulated release and storage of glucose	618
21.1 Glycogen Breakdown Requires the Interplay of Several Enzymes		619
	Phosphorylase catalyzes the phosphorolytic cleavage of glycogen to release glucose 1-phosphate	619
	Mechanism: Pyridoxal phosphate participates in the phosphorolytic cleavage of glycogen	620
	A debranching enzyme also is needed for the breakdown of glycogen	621
	Phosphoglucomutase converts glucose 1-phosphate into glucose 6-phosphate	622
	The liver contains glucose 6-phosphatase, a hydrolytic enzyme absent from muscle	622
21.2 Phosphorylase Is Regulated by Allosteric Interactions and Reversible Phosphorylation		623
	Liver phosphorylase produces glucose for use by other tissues	623
	Muscle phosphorylase is regulated by the intracellular energy charge	625
	Biochemical characteristics of muscle fiber types differ	625
	Phosphorylation promotes the conversion of phosphorylase b to phosphorylase a	626
	Phosphorylase kinase is activated by phosphorylation and calcium ions	626
21.3 Epinephrine and Glucagon Signal the Need for Glycogen Breakdown		627
	G proteins transmit the signal for the initiation of glycogen breakdown	627
	Glycogen breakdown must be rapidly turned off when necessary	629
	The regulation of glycogen phosphorylase became more sophisticated as the enzyme evolved	629
21.4 Glycogen Is Synthesized and Degraded by Different Pathways		630
	UDP-glucose is an activated form of glucose	630
	Glycogen synthase catalyzes the transfer of glucose from UDP-glucose to a growing chain	630
	A branching enzyme forms α-1,6 linkages	631
	Glycogen synthase is the key regulatory enzyme in glycogen synthesis	632
	Glycogen is an efficient storage form of glucose	632
21.5 Glycogen Breakdown and Synthesis Are Reciprocally Regulated		632
	Protein phosphatase 1 reverses the regulatory effects of kinases on glycogen metabolism	633
	Insulin stimulates glycogen synthesis by inactivating glycogen synthase kinase	635
	Glycogen metabolism in the liver regulates the blood-glucose level	635
	A biochemical understanding of glycogen-storage diseases is possible	637
CHAPTER 22 Fatty Acid Metabolism		643
	Fatty acid degradation and synthesis mirror each other in their chemical reactions	644
22.1 Triacylglycerols Are Highly Concentrated Energy Stores		645
	Dietary lipids are digested by pancreatic lipases	645
	Dietary lipids are transported in chylomicrons	646
22.2 The Use of Fatty Acids as Fuel Requires Three Stages of Processing		647
	Triacylglycerols are hydrolyzed by hormone-stimulated lipases	647
	Free fatty acids and glycerol are released into the blood	648
	Fatty acids are linked to coenzyme A before they are oxidized	648
	Carnitine carries long-chain activated fatty acids into the mitochondrial matrix	649
	Acetyl CoA, NADH, and FADH₂ are generated in each round of fatty acid oxidation	650
	The complete oxidation of palmitate yields 106 molecules of ATP	652
22.3 Unsaturated and Odd-Chain Fatty Acids Require Additional Steps for Degradation		652
	An isomerase and a reductase are required for the oxidation of unsaturated fatty acids	652
	Odd-chain fatty acids yield propionyl CoA in the final thiolysis step	654
	Vitamin B₁₂ contains a corrin ring and a cobalt atom	654
	Mechanism: Methylmalonyl CoA mutase catalyzes a rearrangement to form succinyl CoA	655
	Fatty acids are also oxidized in peroxisomes	656
	Ketone bodies are formed from acetyl CoA when fat breakdown predominates	657
	Ketone bodies are a major fuel in some tissues	658
	Animals cannot convert fatty acids into glucose	660
	Some fatty acids may contribute to the development of pathological conditions	661
	An isomerase and a reductase are required for the oxidation of unsaturated fatty acids	652
22.4 Fatty Acids Are Synthesized by Fatty Acid Synthase		661
	Fatty acids are synthesized and degraded by different pathways	661
	The formation of malonyl CoA is the committed step in fatty acid synthesis	662
	Intermediates in fatty acid synthesis are attached to an acyl carrier protein	662
	Fatty acid synthesis consists of a series of condensation, reduction, dehydration, and reduction reactions	662
	Fatty acids are synthesized by a multifunctional enzyme complex in animals	664
	The synthesis of palmitate requires 8 molecules of acetyl CoA, 14 molecules of NADPH, and 7 molecules of ATP	666
	Citrate carries acetyl groups from mitochondria to the cytoplasm for fatty acid synthesis	666
	Several sources supply NADPH for fatty acid synthesis	667
	Fatty acid metabolism is altered in tumor cells	667
22.5 The Elongation and Unsaturation of Fatty Acids are Accomplished by Accessory Enzyme Systems		668
	Membrane-bound enzymes generate unsaturated fatty acids	668
	Eicosanoid hormones are derived from polyunsaturated fatty acids	669
	Variations on a theme: Polyketide and nonribosomal peptide synthetases resemble fatty acid synthase	670
22.6 Acetyl CoA Carboxylase Plays a Key Role in Controlling Fatty Acid Metabolism		670
	Acetyl CoA carboxylase is regulated by conditions in the cell	671
	Acetyl CoA carboxylase is regulated by a variety of hormones	671
CHAPTER 23 Protein Turnover and Amino Acid Catabolism		681
23.1 Proteins are Degraded to Amino Acids		682
	The digestion of dietary proteins begins in the stomach and is completed in the intestine	682
	Cellular proteins are degraded at different rates	682
23.2 Protein Turnover Is Tightly Regulated		683
	Ubiquitin tags proteins for destruction	683
	The proteasome digests the ubiquitin-tagged proteins	685
	The ubiquitin pathway and the proteasome have prokaryotic counterparts	686
	Protein degradation can be used to regulate biological function	687
23.3 The First Step in Amino Acid Degradation Is the Removal of Nitrogen		687
	Alpha-amino groups are converted into ammonium ions by the oxidative deamination of glutamate	687
	Mechanism: Pyridoxal phosphate forms Schiff-base intermediates in aminotransferases	689
	Aspartate aminotransferase is an archetypal pyridoxal-dependent transaminase	690
	Blood levels of aminotransferases serve a diagnostic function	691
	Pyridoxal phosphate enzymes catalyze a wide array of reactions	691
	Serine and threonine can be directly deaminated	692
	Peripheral tissues transport nitrogen to the liver	692
23.4 Ammonium Ion Is Converted into Urea in Most Terrestrial Vertebrates		693
	The urea cycle begins with the formation of carbamoyl phosphate	693
	Carbamoyl phosphate synthetase is the key regulatory enzyme for urea synthesis	694
	Carbamoyl phosphate reacts with ornithine to begin the urea cycle	694
	The urea cycle is linked to gluconeogenesis	696
	Urea-cycle enzymes are evolutionarily related to enzymes in other metabolic pathways	696
	Inherited defects of the urea cycle cause hyperammonemia and can lead to brain damage	697
	Urea is not the only means of disposing of excess nitrogen	698
23.5 Carbon Atoms of Degraded Amino Acids Emerge as Major Metabolic Intermediates		698
	Pyruvate is an entry point into metabolism for a number of amino acids	699
	Oxaloacetate is an entry point into metabolism for aspartate and asparagine	700
	Alpha-ketoglutarate is an entry point into metabolism for five-carbon amino acids	700
	Succinyl coenzyme A is a point of entry for several nonpolar amino acids	701
	Methionine degradation requires the formation of a key methyl donor, S-adenosylmethionine	701
	The branched-chain amino acids yield acetyl CoA, acetoacetate, or propionyl CoA	701
	Oxygenases are required for the degradation of aromatic amino acids	703
23.6 Inborn Errors of Metabolism Can Disrupt Amino Acid Degradation		705
	Phenylketonuria is one of the most common metabolic disorders	706
	Determining the basis of the neurological symptoms of phenylketonuria is an active area of research	706
Part III SYNTHESIZING THE MOLECULES OF LIFE
CHAPTER 24 The Biosynthesis of Amino Acids		713
	Amino acid synthesis requires solutions to three key biochemical problems	714
24.1 Nitrogen Fixation: Microorganisms Use ATP and a Powerful Reductant to Reduce Atmospheric Nitrogen to Ammonia		714
	The iron–molybdenum cofactor of nitrogenase binds and reduces atmospheric nitrogen	715
	Ammonium ion is assimilated into an amino acid through glutamate and glutamine	717
24.2 Amino Acids Are Made from Intermediates of the Citric Acid Cycle and Other Major Pathways		719
	Human beings can synthesize some amino acids but must obtain others from their diet	719
	Aspartate, alanine, and glutamate are formed by the addition of an amino group to an alpha-ketoacid	720
	A common step determines the chirality of all amino acids	721
	The formation of asparagine from aspartate requires an adenylated intermediate	721
	Glutamate is the precursor of glutamine, proline, and arginine	722
	3-Phosphoglycerate is the precursor of serine, cysteine, and glycine	722
	Tetrahydrofolate carries activated one-carbon units at several oxidation levels	723
	S-Adenosylmethionine is the major donor of methyl groups	724
	Cysteine is synthesized from serine and homocysteine	726
	High homocysteine levels correlate with vascular disease	726
	Shikimate and chorismate are intermediates in the biosynthesis of aromatic amino acids	727
	Tryptophan synthase illustrates substrate channeling in enzymatic catalysis	729
24.3 Feedback Inhibition Regulates Amino Acid Biosynthesis		730
	Branched pathways require sophisticated regulation	731
	The sensitivity of glutamine synthetase to allosteric regulation is altered by covalent modification	732
24.4 Amino Acids Are Precursors of Many Biomolecules		734
	Glutathione, a gamma-glutamyl peptide, serves as a sulfhydryl buffer and an antioxidant	734
	Nitric oxide, a short-lived signal molecule, is formed from arginine	735
	Porphyrins are synthesized from glycine and succinyl coenzyme A	736
	Porphyrins accumulate in some inherited disorders of porphyrin metabolism	737
CHAPTER 25 Nucleotide Biosynthesis		743
	Nucleotides can be synthesized by de novo or salvage pathways	744
25.1 The Pyrimidine Ring Is Assembled de Novo or Recovered by Salvage Pathways		744
	Bicarbonate and other oxygenated carbon compounds are activated by phosphorylation	745
	The side chain of glutamine can be hydrolyzed to generate ammonia	745
	Intermediates can move between active sites by channeling	745
	Orotate acquires a ribose ring from PRPP to form a pyrimidine nucleotide and is converted into uridylate	746
	Nucleotide mono-, di-, and triphosphates are interconvertible	747
	CTP is formed by amination of UTP	747
	Salvage pathways recycle pyrimidine bases	748
25.2 Purine Bases Can Be Synthesized de Novo or Recycled by Salvage Pathways		748
	The purine ring system is assembled on ribose phosphate	749
	The purine ring is assembled by successive steps of activation by phosphorylation followed by displacement	749
	AMP and GMP are formed from IMP	751
	Enzymes of the purine synthesis pathway associate with one another in vivo	752
	Salvage pathways economize intracellular energy expenditure	752
25.3 Deoxyribonucleotides Are Synthesized by the Reduction of Ribonucleotides Through a Radical Mechanism		753
	Mechanism: A tyrosyl radical is critical to the action of ribonucleotide reductase	753
	Stable radicals other than tyrosyl radical are employed by other ribonucleotide reductases	755
	Thymidylate is formed by the methylation of deoxyuridylate	755
	Dihydrofolate reductase catalyzes the regeneration of tetrahydrofolate, a one-carbon carrier	756
	Several valuable anticancer drugs block the synthesis of thymidylate	757
25.4 Key Steps in Nucleotide Biosynthesis Are Regulated by Feedback Inhibition		758
	Pyrimidine biosynthesis is regulated by aspartate transcarbamoylase	758
	The synthesis of purine nucleotides is controlled by feedback inhibition at several sites	758
	The synthesis of deoxyribonucleotides is controlled by the regulation of ribonucleotide reductase	759
25.5 Disruptions in Nucleotide Metabolism Can Cause Pathological Conditions		760
	The loss of adenosine deaminase activity results in severe combined immunodeficiency	760
	Gout is induced by high serum levels of urate	761
	Lesch–Nyhan syndrome is a dramatic consequence of mutations in a salvage-pathway enzyme	761
	Folic acid deficiency promotes birth defects such as spina bifida	762
CHAPTER 26 The Biosynthesis of Membrane Lipids and Steroids		767
26.1 Phosphatidate Is a Common Intermediate in the Synthesis of Phospholipids and Triacylglycerols		768
	The synthesis of phospholipids requires an activated intermediate	769
	Some phospholipids are synthesized from an activated alcohol	770
	Phosphatidylcholine is an abundant phospholipid	770
	Excess choline is implicated in the development of heart disease	771
	Base-exchange reactions can generate phospholipids	771
	Sphingolipids are synthesized from ceramide	772
	Gangliosides are carbohydrate-rich sphingolipids that contain acidic sugars	772
	Sphingolipids confer diversity on lipid structure and function	773
	Respiratory distress syndrome and Tay–Sachs disease result from the disruption of lipid metabolism	774
	Ceramide metabolism stimulates tumor growth	774
	Phosphatidic acid phosphatase is a key regulatory enzyme in lipid metabolism	775
26.2 Cholesterol Is Synthesized from Acetyl Coenzyme A in Three Stages		776
	The synthesis of mevalonate, which is activated as isopentenyl pyrophosphate, initiates the synthesis of cholesterol	776
	Squalene (C₃₀) is synthesized from six molecules of isopentenyl pyrophosphate (C₅)	777
	Squalene cyclizes to form cholesterol	778
26.3 The Complex Regulation of Cholesterol Biosynthesis Takes Place at Several Levels		779
	Lipoproteins transport cholesterol and triacylglycerols throughout the organism	782
	Low-density lipoproteins play a central role in cholesterol metabolism	784
	The absence of the LDL receptor leads to hypercholesterolemia and atherosclerosis	784
	Mutations in the LDL receptor prevent LDL release and result in receptor destruction	785
	Cycling of the LDL receptor is regulated	787
	HDL appears to protect against atherosclerosis	787
	The clinical management of cholesterol levels can be understood at a biochemical level	788
26.4 Important Derivatives of Cholesterol Include Bile Salts and Steroid Hormones		788
	Letters identify the steroid rings and numbers identify the carbon atoms	790
	Steroids are hydroxylated by cytochrome P450 monooxygenases that use NADPH and O₂	790
	The cytochrome P450 system is widespread and performs a protective function	791
	Pregnenolone, a precursor of many other steroids, is formed from cholesterol by cleavage of its side chain	792
	Progesterone and corticosteroids are synthesized from pregnenolone	792
	Androgens and estrogens are synthesized from pregnenolone	792
	Vitamin D is derived from cholesterol by the ring-splitting activity of light	794
CHAPTER 27 The Integration of Metabolism		801
27.1 Caloric Homeostasis Is a Means of Regulating Body Weight		802
27.2 The Brain Plays a Key Role in Caloric Homeostasis		804
	Signals from the gastrointestinal tract induce feelings of satiety	804
	Leptin and insulin regulate long-term control over caloric homeostasis	805
	Leptin is one of several hormones secreted by adipose tissue	806
	Leptin resistance may be a contributing factor to obesity	806
	Dieting is used to combat obesity	807
27.3 Diabetes Is a Common Metabolic Disease Often Resulting from Obesity		807
	Insulin initiates a complex signal-transduction pathway in muscle	808
	Metabolic syndrome often precedes type 2 diabetes	809
	Excess fatty acids in muscle modify metabolism	810
	Insulin resistance in muscle facilitates pancreatic failure	810
	Metabolic derangements in type 1 diabetes result from insulin insufficiency and glucagon excess	812
27.4 Exercise Beneficially Alters the Biochemistry of Cells		813
	Mitochondrial biogenesis is stimulated by muscular activity	813
	Fuel choice during exercise is determined by the intensity and duration of activity	813
27.5 Food Intake and Starvation Induce Metabolic Changes		816
	The starved–fed cycle is the physiological response to a fast	816
	Metabolic adaptations in prolonged starvation minimize protein degradation	818
27.6 Ethanol Alters Energy Metabolism in the Liver		819
	Ethanol metabolism leads to an excess of NADH	820
	Excess ethanol consumption disrupts vitamin metabolism	821
CHAPTER 28 DNA Replication, Repair, and Recombination		827
28.1 DNA Replication Proceeds by the Polymerization of Deoxyribonucleoside Triphosphates Along a Template		828
	DNA polymerases require a template and a primer	829
	All DNA polymerases have structural features in common	829
	Two bound metal ions participate in the polymerase reaction	829
	The specificity of replication is dictated by complementarity of shape between bases	830
	An RNA primer synthesized by primase enables DNA synthesis to begin	831
	One strand of DNA is made continuously, whereas the other strand is synthesized in fragments	831
	DNA ligase joins ends of DNA in duplex regions	832
	The separation of DNA strands requires specific helicases and ATP hydrolysis	832
28.2 DNA Unwinding and Supercoiling Are Controlled by Topoisomerases		833
	The linking number of DNA, a topological property, determines the degree of supercoiling	835
	Topoisomerases prepare the double helix for unwinding	836
	Type I topoisomerases relax supercoiled structures	836
	Type II topoisomerases can introduce negative supercoils through coupling to ATP hydrolysis	837
28.3 DNA Replication Is Highly Coordinated		839
	DNA replication requires highly processive polymerases	839
	The leading and lagging strands are synthesized in a coordinated fashion	840
	DNA replication in Escherichia coli begins at a unique site	842
	DNA synthesis in eukaryotes is initiated at multiple sites	843
	Telomeres are unique structures at the ends of linear chromosomes	844
	Telomeres are replicated by telomerase, a specialized polymerase that carries its own RNA template	845
28.4 Many Types of DNA Damage Can Be Repaired		845
	Errors can arise in DNA replication	846
	Bases can be damaged by oxidizing agents, alkylating agents, and light	846
	DNA damage can be detected and repaired by a variety of systems	847
	The presence of thymine instead of uracil in DNA permits the repair of deaminated cytosine	849
	Some genetic diseases are caused by the expansion of repeats of three nucleotides	850
	Many cancers are caused by the defective repair of DNA	850
	Many potential carcinogens can be detected by their mutagenic action on bacteria	852
28.5 DNA Recombination Plays Important Roles in Replication, Repair, and Other Processes		852
	RecA can initiate recombination by promoting strand invasion	853
	Some recombination reactions proceed through Holliday-junction intermediates	854
CHAPTER 29 RNA Synthesis and Processing		859
	RNA synthesis comprises three stages: Initiation, elongation, and termination	860
29.1 RNA Polymerases Catalyze Transcription		861
	RNA chains are formed de novo and grow in the 5′-to-3′ direction	862
	RNA polymerases backtrack and correct errors	863
	RNA polymerase binds to promoter sites on the DNA template to initiate transcription	864
	Sigma subunits of RNA polymerase recognize promoter sites	865
	RNA polymerases must unwind the template double helix for transcription to take place	865
	Elongation takes place at transcription bubbles that move along the DNA template	866
	Sequences within the newly transcribed RNA signal termination	866
	Some messenger RNAs directly sense metabolite concentrations	867
	The rho protein helps to terminate the transcription of some genes	868
	Some antibiotics inhibit transcription	869
	Precursors of transfer and ribosomal RNA are cleaved and chemically modified after transcription in prokaryotes	870
29.2 Transcription in Eukaryotes Is Highly Regulated		871
	Three types of RNA polymerase synthesize RNA in eukaryotic cells	872
	Three common elements can be found in the RNA polymerase II promoter region	874
	The TFIID protein complex initiates the assembly of the active transcription complex	874
	Multiple transcription factors interact with eukaryotic promoters	875
	Enhancer sequences can stimulate transcription at start sites thousands of bases away	876
29.3 The Transcription Products of Eukaryotic Polymerases Are Processed		876
	RNA polymerase I produces three ribosomal RNAs	877
	RNA polymerase III produces transfer RNA	877
	The product of RNA polymerase II, the pre-mRNA transcript, acquires a 5′ cap and a 3′ poly(A) tail	878
	Small regulatory RNAs are cleaved from larger precursors	879
	RNA editing changes the proteins encoded by mRNA	879
	Sequences at the ends of introns specify splice sites in mRNA precursors	880
	Splicing consists of two sequential transesterification reactions	881
	Small nuclear RNAs in spliceosomes catalyze the splicing of mRNA precursors	882
	Transcription and processing of mRNA are coupled	883
	Mutations that affect pre-mRNA splicing cause disease	884
	Most human pre-mRNAS can be spliced in alternative ways to yield different proteins	885
29.4 The Discovery of Catalytic RNA was Revealing in Regard to Both Mechanism and Evolution		886
CHAPTER 30 Protein Synthesis		893
30.1 Protein Synthesis Requires the Translation of Nucleotide Sequences into Amino Acid Sequences		894
	The synthesis of long proteins requires a low error frequency	894
	Transfer RNA molecules have a common design	895
	Some transfer RNA molecules recognize more than one codon because of wobble in base-pairing	897
30.2 Aminoacyl Transfer RNA Synthetases Read the Genetic Code		898
	Amino acids are first activated by adenylation	898
	Aminoacyl-tRNA synthetases have highly discriminating amino acid activation sites	899
	Proofreading by aminoacyl-tRNA synthetases increases the fidelity of protein synthesis	900
	Synthetases recognize various features of transfer RNA molecules	901
	Aminoacyl-tRNA synthetases can be divided into two classes	901
30.3 The Ribosome Is the Site of Protein Synthesis		902
	Ribosomal RNAs (5S, 16S, and 23S rRNA) play a central role in protein synthesis	903
	Ribosomes have three tRNA-binding sites that bridge the 30s and 50s subunits	905
	The start signal is usually AUG preceded by several bases that pair with 16S rRNA	905
	Bacterial protein synthesis is initiated by formylmethionyl transfer RNA	906
	Formylmethionyl-tRNA_f is placed in the P site of the ribosome in the formation of the 70S initiation complex	907
	Elongation factors deliver aminoacyl-tRNA to the ribosome	907
	Peptidyl transferase catalyzes peptide-bond synthesis	908
	The formation of a peptide bond is followed by the GTP-driven translocation of tRNAs and mRNA	909
	Protein synthesis is terminated by release factors that read stop codons	910
30.4 Eukaryotic Protein Synthesis Differs from Bacterial Protein Synthesis Primarily in Translation Initiation		911
	Mutations in initiation factor 2 cause a curious pathological condition	913
30.5 A Variety of Antibiotics and Toxins Can Inhibit Protein Synthesis		913
	Some antibiotics inhibit protein synthesis	914
	Diphtheria toxin blocks protein synthesis in eukaryotes by inhibiting translocation	914
	Ricin fatally modifies 28S ribosomal RNA	915
30.6 Ribosomes Bound to the Endoplasmic Reticulum Manufacture Secretory and Membrane Proteins		915
	Protein synthesis begins on ribosomes that are free in the cytoplasm	916
	Signal sequences mark proteins for translocation across the endoplasmic reticulum membrane	916
	Transport vesicles carry cargo proteins to their final destination	918
CHAPTER 31 The Control of Gene Expression in Prokaryotes		925
31.1 Many DNA-Binding Proteins Recognize Specific DNA Sequences		926
	The helix-turn-helix motif is common to many prokaryotic DNA-binding proteins	927
31.2 Prokaryotic DNA-Binding Proteins Bind Specifically to Regulatory Sites in Operons		927
	An operon consists of regulatory elements and protein-encoding genes	928
	The lac repressor protein in the absence of lactose binds to the operator and blocks transcription	929
	Ligand binding can induce structural changes in regulatory proteins	930
	The operon is a common regulatory unit in prokaryotes	930
	Transcription can be stimulated by proteins that contact RNA polymerase	931
31.3 Regulatory Circuits Can Result in Switching Between Patterns of Gene Expression		932
	The λ repressor regulates its own expression	932
	A circuit based on the λ repressor and Cro forms a genetic switch	933
	Many prokaryotic cells release chemical signals that regulate gene expression in other cells	933
	Biofilms are complex communities of prokaryotes	934
31.4 Gene Expression Can Be Controlled at Posttranscriptional Levels		935
	Attenuation is a prokaryotic mechanism for regulating transcription through the modulation of nascent RNA secondary structure	935
CHAPTER 32 The Control of Gene Expression in Eukaryotes		941
32.1 Eukaryotic DNA Is Organized into Chromatin		943
	Nucleosomes are complexes of DNA and histones	943
	DNA wraps around histone octamers to form nucleosomes	943
32.2 Transcription Factors Bind DNA and Regulate Transcription Initiation		945
	A range of DNA-binding structures are employed by eukaryotic DNA-binding proteins	945
	Activation domains interact with other proteins	946
	Multiple transcription factors interact with eukaryotic regulatory regions	946
	Enhancers can stimulate transcription in specific cell types	946
	Induced pluripotent stem cells can be generated by introducing four transcription factors into differentiated cells	947
32.3 The Control of Gene Expression Can Require Chromatin Remodeling		948
	The methylation of DNA can alter patterns of gene expression	949
	Steroids and related hydrophobic molecules pass through membranes and bind to DNA-binding receptors	949
	Nuclear hormone receptors regulate transcription by recruiting coactivators to the transcription complex	950
	Steroid-hormone receptors are targets for drugs	951
	Chromatin structure is modulated through covalent modifications of histone tails	952
	Histone deacetylases contribute to transcriptional repression	953
32.4 Eukaryotic Gene Expression Can Be Controlled at Posttranscriptional Levels		954
	Genes associated with iron metabolism are translationally regulated in animals	954
	Small RNAs regulate the expression of many eukaryotic genes	956
Part IV RESPONDING TO ENVIRONMENTAL CHANGES
CHAPTER 33 Sensory Systems		961
33.1 A Wide Variety of Organic Compounds Are Detected by Olfaction		962
	Olfaction is mediated by an enormous family of seven-transmembrane-helix receptors	962
	Odorants are decoded by a combinatorial mechanism	964
33.2 Taste Is a Combination of Senses That Function by Different Mechanisms		966
	Sequencing of the human genome led to the discovery of a large family of 7TM bitter receptors	967
	A heterodimeric 7TM receptor responds to sweet compounds	968
	Umami, the taste of glutamate and aspartate, is mediated by a heterodimeric receptor related to the sweet receptor	969
	Salty tastes are detected primarily by the passage of sodium ions through channels	969
	Sour tastes arise from the effects of hydrogen ions (acids) on channels	969
33.3 Photoreceptor Molecules in the Eye Detect Visible Light		970
	Rhodopsin, a specialized 7TM receptor, absorbs visible light	970
	Light absorption induces a specific isomerization of bound 11-cis-retinal	971
	Light-induced lowering of the calcium level coordinates recovery	972
	Color vision is mediated by three cone receptors that are homologs of rhodopsin	973
	Rearrangements in the genes for the green and red pigments lead to “color blindness”	974
33.4 Hearing Depends on the Speedy Detection of Mechanical Stimuli		975
	Hair cells use a connected bundle of stereocilia to detect tiny motions	975
	Mechanosensory channels have been identified in Drosophila and vertebrates	976
33.5 Touch Includes the Sensing of Pressure, Temperature, and Other Factors		977
	Studies of capsaicin reveal a receptor for sensing high temperatures and other painful stimuli	977
CHAPTER 34 The Immune System		981
	Innate immunity is an evolutionarily ancient defense system	982
	The adaptive immune system responds by using the principles of evolution	984
34.1 Antibodies Possess Distinct Antigen-Binding and Effector Units		985
34.2 Antibodies Bind Specific Molecules Through Hypervariable Loops		988
	The immunoglobulin fold consists of a beta-sandwich framework with hypervariable loops	988
	X-ray analyses have revealed how antibodies bind antigens	989
	Large antigens bind antibodies with numerous interactions	990
34.3 Diversity Is Generated by Gene Rearrangements		991
	J (joining) genes and D (diversity) genes increase antibody diversity	991
	More than 10⁸ antibodies can be formed by combinatorial association and somatic mutation	992
	The oligomerization of antibodies expressed on the surfaces of immature B cells triggers antibody secretion	993
	Different classes of antibodies are formed by the hopping of V_H genes	994
34.4 Major-Histocompatibility-Complex Proteins Present Peptide Antigens on Cell Surfaces for Recognition by T-Cell Receptors		995
	Peptides presented by MHC proteins occupy a deep groove flanked by alpha helices	996
	T-cell receptors are antibody-like proteins containing variable and constant regions	998
	CD8 on cytotoxic T cells acts in concert with T-cell receptors	998
	Helper T cells stimulate cells that display foreign peptides bound to class II MHC proteins	1000
	Helper T cells rely on the T-cell receptor and CD4 to recognize foreign peptides on antigen-presenting cells	1000
	MHC proteins are highly diverse	1002
	Human immunodeficiency viruses subvert the immune system by destroying helper T cells	1003
34.5 The Immune System Contributes to the Prevention and the Development of Human Diseases		1004
	T cells are subjected to positive and negative selection in the thymus	1004
	Autoimmune diseases result from the generation of immune responses against self-antigens	1005
	The immune system plays a role in cancer prevention	1005
	Vaccines are a powerful means to prevent and eradicate disease	1006
CHAPTER 35 Molecular Motors		1011
35.1 Most Molecular-Motor Proteins Are Members of the P-Loop NTPase Superfamily		1012
	Molecular motors are generally oligomeric proteins with an ATPase core and an extended structure	1012
	ATP binding and hydrolysis induce changes in the conformation and binding affinity of motor proteins	1014
35.2 Myosins Move Along Actin Filaments		1016
	Actin is a polar, self-assembling, dynamic polymer	1016
	Myosin head domains bind to actin filaments	1018
	Motions of single motor proteins can be directly observed	1018
	Phosphate release triggers the myosin power stroke	1019
	Muscle is a complex of myosin and actin	1019
	The length of the lever arm determines motor velocity	1022
35.3 Kinesin and Dynein Move Along Microtubules		1022
	Microtubules are hollow cylindrical polymers	1022
	Kinesin motion is highly processive	1024
35.4 A Rotary Motor Drives Bacterial Motion		1026
	Bacteria swim by rotating their flagella	1026
	Proton flow drives bacterial flagellar rotation	1026
	Bacterial chemotaxis depends on reversal of the direction of flagellar rotation	1028
CHAPTER 36 Drug Development		1033
36.1 The Development of Drugs Presents Huge Challenges		1034
	Drug candidates must be potent and selective modulators of their targets	1035
	Drugs must have suitable properties to reach their targets	1036
	Toxicity can limit drug effectiveness	1040
36.2 Drug Candidates Can Be Discovered by Serendipity, Screening, or Design		1041
	Serendipitous observations can drive drug development	1041
	Natural products are a valuable source of drugs and drug leads	1043
	Screening libraries of synthetic compounds expands the opportunity for identification of drug leads	1044
	Drugs can be designed on the basis of three-dimensional structural information about their targets	1046
36.3 Analyses of Genomes Hold Great Promise for Drug Discovery		1048
	Potential targets can be identified in the human proteome	1048
	Animal models can be developed to test the validity of potential drug targets	1049
	Potential targets can be identified in the genomes of pathogens	1050
	Genetic differences influence individual responses to drugs	1050
36.4 The Clinical Development of Drugs Proceeds Through Several Phases		1051
	Clinical trials are time consuming and expensive	1052
	The evolution of drug resistance can limit the utility of drugs for infectious agents and cancer	1053
Answers to Problems		A1
Selected Readings		B1
Index		C1

CONTENTS