Jeremy M. Berg
Transcript of Jeremy M. Berg
INTERNATIONAL SEVENTH EDITION
I
Jeremy M. Berg
John L. Tymoczko
Lubert Stryer ,~-
with Gregory J. Gatto, Jr.
II W. H. Freeman and Company · New York palgrave macmitlan
I
. / THE MOLECULAR DESIGN OF LI FE mistry: An Evolving Science 1
Composition and Structure 25
•""'''n•·•no Proteins and Proteomes 67
RNA, and the Flow of Genetic Information 113
~:v..,••nr•na Genes and Genomes 145
~::vr••nr•no Evolution and Bioinformatics 181
< Hemoglobin: Portrait of a Protein in Action 203
· · Enzymes: Basic Concepts and Kinetics 227
Catalytic Strategies 261
Regulatory Strategies 299
Carbohydrates 329
Lipids and Cell Membranes 357
Membrane Channels and Pumps 383
Signal-Transduction Pathways 415
n TRANSDUCING AND STORING ENERGY Metabolism: Basic Concepts and Design 443
....... · Glycolysis and Gluconeogenesis 469
> 1 The Citric Acid Cycle 51 5
·••••••· 8 Oxidative Phosphorylation 543 ••••···19 The Light Reactions of Photosynthesis 585
• \ 20 The Calvin Cycle and the Pentose Phosphate · Pathway 609
Glycogen Metabolism 637
Fatty Acid Metabolism 663
Protein Turnover and Amino Acid Catabolism 697
Pari m SYNTHESIZING THE MOLECULES OF UFE 24 The Biosynthesis of Amino Acids 729
25 Nucleotide Biosynthesis 761
26 The Biosynthesis of Membrane Lipids and Steraids 787
27 The Integration of Metabolism 821
28 DNA Replication, Repair, and Recombination 849
RNA Synthesis and Processing 883
30 Protein Synthesis 921
31 The Control of Gene Expression in Prokaryotes 957
32 The Control of Gene Expression in Eukaryotes 973
Part IV RESPONDING TO ENVIRONMENTAL 33 Sensory Systems 995
34 The Immune System 1017
35 Molecular Motors 1 049
36 Drug Development 1 073
CONTENTS
P~re V
Part I THE MOlECULAR DESIGN OF UFE
Chapter 1 Biochemistry: An Evolving Science
1.1 Biochemical Unity Underlies Biologkai Diversity
1.2 DNA lllustrates the lnterplay Between Form and Function DNA is constructed from four building blocks
Two single strands ofDNA combine to form a double helix
DNA structure explains heredity and the storage of information
1.3 Concepts from Chemistry Explain the Properties of Biological Molecules The double helix can form from its component strands
Covalent and noncovalent bonds are important for the structure and stability of biological molecules
The double helix is an expression of the rules of chemistry
T4e laws of thermodynamics govern the behavior of biochemical systems
Heat is released in the formation of the double helix
Acid-base reactions are central in many biochemical processes
Acid-base reactions can disrupt the double helix
Buffers regulate pH in organisms and in the laboratory
1.4 The Genomic Revolution ls Transforming Biochemistry and Medicine The sequencing of the human genome is a landmark in human history
Genome sequences encode proteins and patterns of express10n
Individuality depends on the interplay between genes and environment
APPENDIX: Visualizing Molecular Structures I: Small Molecules
Chapter 2 Protein Composition and Structure
2.1 Proteins Are Built from a Repertoire of 20 Amino Acids
2.2 Primary Structure: Amino Acids Are Unked by Peptide Bonds to Form Polypeptide Chains Proteins have unique amino acid sequences specified by genes
Polypeptide chains are flexible yet conformationally restricted
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2.3 Secondary Structure: Polypeptide Chains Can 3.2 Amino Acid Sequences of Proteins Can Fold into Regular Structures Such As the Alpha Be Determined Experimentally 81 Helix, the Beta Sheet, and Turns and loops 38 Peptide sequences can be determined by automated The alpha helix is a coiled structure stabilized Edman degradation 82 by intrachain hydrogen bonds 38 Proteins c<m be specifically cleaved into small Beta sheets are stabilized by hydrogen bonding between peptides to facilitate analysis 84 polypeptide strands 40 Genomic and proteomic methods are complementary 86 Polypeptide chains can change direction by 3.3 lmmunology Provides lmportant Techniques making reverse turns and loops 42 with Which to lnvestigate Proteins 86 Fibrous proteins provide structural support for Antihoclies to specifi.c proteins can be generated 86 cells and tissues 43
Monoclonal antihoclies with virtually any 2.4 Tertiary Structure: Water-Soluble Proteins desired specificity can be readily prepared 88 Fold into Compact Structures with Proteins can be detected and quantified by using an Nonpolar Cores 45 enzyme-linked immunosorbent assay 90
2.5 Quaternary Structure: Polypeptide Chains Western blotting permits the detection of
Can Assemble into Multisubunit Structures 48 proteins separated by gel electrophoresis 91
2.6 The Amino Acid Sequence of a Protein Fluorescent markers make the visualization of
Determines lts Three-Dimensional Structure 49 proteins in the cell possible 92
Amino acids have different propensities for 3.4 Mass Spectrometry ls a Powerful Technique forming alpha helices, beta sheets, and beta turns 50 for the ldlentification of Peptides and Proteins 93
Protein folding is a highly cooperative process 52 The mass of a protein can be precisely determined
Proteins fold by progressive stabilization of by mass spectrometry 93
intermediates rather than by random search 52 Peptides can be sequenced by mass spectrometry 95
Prediction of three-dimensional structure from ·Individual proteins can be identified by
sequence remains a great challenge 54 mass spect:rometry 96
Some proteins are inherently unstructured and 3.5 Peptiides Can Be Synthesized by can exist in multiple conformations 54 Automated Solid-Phase Methods 97 Protein misfolding and aggregation are associated 3.6 Three-Dimensional Protein Structure with some neurological diseases 55
Can Be Determined by X-ray Crystallography Protein modification and cleavage confer and NMR Spectroscopy 100 new capabilities 57
X-ray crystallography reveals three-dimensional APPENDIX: Visualizing Molecular Structures II: Proteins 60 structure in atomic detail 100
Nuclear magnetic resonance spectroscopy can reveal the st:ructures of proteins in solution 103
Chapter 3 Exploring Proteins and Proteomes 67
The proteome is the functional representation of Chapter ~~ DNA, RNA, and the Flow of the genome 68 Information 113 3.1 The Purification of Proteins ls an Essential
4.1 A Nucleic Acid Consists of Four Kinds of First Step in Understanding Their Function 68
Bases Linked to a Sugar-Phosphate Backbone 114 The assay: How do we recognize the protein that we are looking for? 69 RNA and DNA differ in the sugar component and
one of the bases 114 Proteins must be released from the cell to be purifi.ed 69
Nucleotides are the monomeric units of nucleic acids 115 Proteins.can be purified according to solubility, size, charge, ~d binding affinity 70 DNA molecules are very long 117
Proteins can be separated by gel electrophoresis and 4.2 A Pair of Nucleic Acid Chains with displayed 73 Complementary Sequences Can Form a A protein purification scheme can be quantitatively Double-Helical Structure 117 evaluated 77 The double helix is stabilized by hydrogen bonds and
Ultracentrifugation is valuable for separating van der W aals interactions 117 biomolecules and determining their masses 78 DNA can assume a variety of structural forms 119 Protein purification can be made easier with the use Z-DNA is a left-handed double helix in which of recombinant DNA technology 80 backhone phosphates zigzag 120
Contents xvii
moleeules are eireular and supereoiled 121 5.2 Recombinant DNA Technology Has Revolutionized All Aspects of Biology 154
121 Restrietion enzymes and DNA ligase are key tools in
Double Helix Facilitates the Aceurate forming reeombinant DNA moleeules 154
n of Hereditary Information 122 Plasmids and lambda phage are ehoiee veetors for
in DNA density established the validity DNA cloning in baeteria 155
hypothesis 123 Baeterial and yeast artifieial ehromosomes 157
helix ean be reversibly melted 124 Speeifie genes ean be cloned from digests of
ls Replicated by Polymerases genomieDNA 157
lnstructions from Templates 125 Complementary DNA prepared from mRNA ean be expressed in hast eells 160
eatalyzes phosphodiester-bridge 125
Proteins with new funetions ean be ereated through direeted ehanges in DNA 162
126 Reeombinant methods enable the exploration of the
Expression ls the Transformation of funetional effeets of disease-eausing mutations 163 ation into Functional Molecules 127 5.3 Complete Genomes Have Been
of RNA play key roles in gene expression 127 Sequenced and Analyzed 163 RNA is synthesized by RNA polymerases 128 The genomes of organisms ranging from baeteria to
take instruetions from DNA templates 130 multieellular eukaryotes have been sequeneed 164 begins near promoter sites and ends at The sequeneing of the human genome has
130 been finished 165
131 Next-generation sequeneing methods enable the rapid determination of a whole genome sequenee 166
Acids Are Encoded by Groups of C?mparative genomies has become a powerful
Bases Starting from a Fixed Point 132 researeh tool 166
133 5.4 Eukaryotic Genes Can Be Quantitated and Manipulated with Considerable Precision 167
134 Gene-expression levels ean be eomprehensively · eode is nearly universal 135 examined 167
Eukaryotic Genes Are Mosaics of New genes inserted into eukaryotie eells ean be
and Exons 135 effieiently expressed 169
136 Transgenie animals harbor and express genes
eneode protein domains 137 introdueed into their germ lines 170 Gene disruption provides clues to gene function 170 RNA interferenee provides an additional tool for disrupting gene expression 171
5 Exploring Genes and Genomes 145 Tumor-indueing plasmids ean be used to introduee
Exploration of Genes Relies on new genes into plant eells 172
146 Humangene therapy holds great promise for medieine 173
enzymes split DNA into speeifie fragments 147 fragments ean be separated by gel Chapter 6 Exploring Evolution and
and visualized 147 Bioinformatics 181
149 6.1 Homologs Are Descended from a
and genes ean be synthesized by Common Ancestor 182
solid-phase methods 150 6.2 Statistkai Analysis of Sequence DNA sequenees ean be greatly amplified Alignments Can Detect Homology 183
ehain reaetion 151 The statistieal signifieanee of alignments ean be
a powerful teehnique in medieal diagnosties, estimated by shuffling 185 and studies of moleeular evolution 152 Distant evolutionary relationships ean be detected
for reeombinant DNA teehnology through the use of substitution matriees 186 used to identify disease-eausing Databases ean be searehed to identify homologaus
153 sequenees 189
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6.3 Examination of Three-Dimensional Additional globins are encoded in the human genome 219 Structure Enhances Our Understanding of APPENDIX: Binding Models Can Be Formulated in Evolutionary Relationships 190 Quantitative Terms: the Hill Plot and the Cancerted Model 221
T ertiary structure is more conserved than primary structure 191 Chapter 8 Enzymes: Basic Concepts and Knowledge of three-dimensional structures can Kinetics 227 aid in the evaluation of sequence alignments 192 8.1 Enzymes Are Powerful and Highly Repeated motifs can be detected by aligning Specific Catalysts 228 sequences with themselves 192
Many enzymes require cofactors for activity 229 Convergent evolution illustrates common solutions
Enzymes can transform energy from one form to biochemical challenges 193
into another 229 Comparison of RNA sequences can be a source of
8.2 Free Energy ls a Useful Thermodynamic insight into RNA secondary structures 194
6.4 Evolutionary Trees Can Be Constructed Function for Understanding Enzymes 230 The free-energy change provides information about on the Basis of Sequence Information 195 the spontaneity but not the rate of a reaction 230
6.5 Modern Techniques Make the Experimental The standard free-energy change of a reaction is Exploration of Evolution Possible 196 related to the equilibrium constant 231 Ancient DNA can sometimes be amplified Enzymes alter only the reaction rate and not the and sequenced 196 reaction equilibrium 232 Molecular evolution can be examined experimentally 197 8.3 Enzymes Aceeierate Reactions by Facilitating
Chapter 7 Hemoglobin: Portrait of a the Formation of the Transition State 233 The formation of an enzyme-substrate complex is
Protein in Action 203 the first step in enzymatic catalysis 234
7.1 Myoglobin and Hemoglobin Bind Oxygen . The active sites of enzymes have some at lron Atoms in Heme 204 common features 235
Changes in heme electronic structure upon oxygen The binding energy between enzyme and substrate binding are the basis for functional imaging studies 205 is important for catalysis 237
The structure of myoglobin prevents the release of 8.4 The Michaelis-Menten Equation Describes reactive oxygen species 206 the Kinetic Properties of Many Enzymes 237 Human hemoglobin is an assembly of four Kinetics is the study of reaction rates 237 myoglobin-like subunits 207 The steady-state assumption facilitates a description 7.2 Hemoglobin Binds Oxygen Cooperatively 207 of enzyme kinetics 238
Oxygen binding markedly changes the quaternary Variations in KM can have physiological consequences 240 structure of hemoglobin 209 KM and V max values can be determined by Hemoglobin cooperativity can be potentially explained several means 240 by several models 210 KM and V max values are important enzyme Structural changes at the heme groups are characteristics 241 transmitted to the <Xtßt- <Xzßz interface 212 kcatiKM is a measure of catalytic efficiency 242 2,3-Bisphosphoglycerate in red cells is crucial in Most biochemical reactions include multiple substrates 243 determining the oxygen affinity ofhemoglobin 212 Allosteric enzymes do not obey Carbon monoxide can disrupt oxygen transport by Michaelis-Menten kinetics 245 hemoglobin 213
8.5 Enzymes Can Be lnhibited by Specific 7.3 Hydrogen Ionsand Carbon Dioxide Promote Molecules 246 the Release of Oxygen: The Bohr Effect 214 Reversible inhibitors are kinetically distinguishable 247 7.4 Mutations in Genes Encoding Hemoglobin Irreversible inhibitors can be used to map Subunits Can Result in Disease 216 the active site 249
Sickle-cell anemia results from the aggregation of Transition-state analogs arepotent inhibitors mutated deoxyhemoglobin molecules 217 ofenzymes 251
Thalassemia is caused by an imbalanced production of Catalytic antihoclies demonstrate the importance of selective hemoglobin chains 218 binding of the transition state to enzymatic activity 251
The accumulation of free alpha-hemoglobin Penicillin irreversibly inactivates a key enzyme in chains is prevented 219 bacterial cell-wall synthesis 252
Enzymes are Classified on the Basis of Reactions That They Catalyze
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263 possesses a highly reactive serine residue 263
=nl'i=tiri>flt·rvr>~m action proceeds in two steps linked .· ) < bound intermediate 264
. < , is part of a catalytic triad that also includes p~~~~(lme and aspartate 265
·=·=ow=·•••"' triads are found in other hydrolytic enzymes 268
triad has been dissected by '''"'"'"''"'''rc•rrc•n mutagenesis 270
-.:v:».''"'···'""' aspartyl, and metalloproteases are other classes of peptide-cleaving enzymes 271
''"'"'""'"''" inhibitors are important drugs 272
274 :Y.i:!<t.u'-''1!1'- anhydrase contains abound zinc ion
tij'$:~~ntlal for catalytic activity 275
.,.,.,,<,<dl'VI>l" entails zinc activation of a water molecule 276
shuttle facilitates rapid regeneration of
:=:==~~!'ll"·"''-Ll''"'form of the enzyme 277 :rin'""'ro-Prlt evolution has generated zinc-based
sites in different carbonic anhydrases 279
., Restrietion Enzymes Catalyze Highly ~~~~P.eCITIC DNA-Cieavage Reactions .279
'"""""""'"' is by in -line displacement of 3' -oxygen phosphorus by magnesium-activated water 280
:=:==..:,::: enzymes require magnesium for ·····==:•=•.····==. activity 282
? complete catalytic apparatus is assembled · .·.·.·.··.·.·. complexes of cognate DNA molecules,
specificity 283
===~=~~~"·•-'-"'u DNA is protected by the addition of methyl to specific bases 285
n restriction enzymes have a catalytic core in gqi'l}rrlon and are probably related by horizontal
transfer 286
Myosins Harness Changes in Enzyme ·an to Couple ATP Hydrolysis to
'·'""''r""'"'Cal Work 287
of the transition state for A TP hydrolysis ~se:oci1ate:d with a substantial conformational change
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The altered conformation of myosin persists for a substantial period of time
Myosinsare a family of enzymes containing P-loop structures
Chapter 10 Regulatory Strategies
Allosterically regulated enzymes do not follow
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Michaelis-Menten kinetics 301
A TCase consists of separable catalytic and regulatory subunits 301
Allosteric interactions in A TCase are mediated by large changes in quaternary structure 302
Allosteric regulators modulate the T -to-R equilibrium 305
10.2 lsozymes Provide a Means of Regulation Specific to Distinct Tissues and Developmental Stages 306
1 0.3 Covalent Modification ls a Means of Regulating Enzyme Activity 307 Kinases and phosphatases control the extent of protein phosphorylation 308
Phosphorylation is a highly effective means of regulating the activities of target proteins 310
Cyclic AMP activates protein kinase A by altering the quaternary structure 311
A TP and the target protein bind to a deep cleft in the catalytic subunit of protein kinase A 312
1 0.4 Many Enzymes Are Activated by Specific Proteolytic Cleavage 312 Chymotrypsinogen is p.ctivated by specific cleavage of a single peptide bond 313
Proteolytic activation of chymotrypsinogen leads to the formation of a substrate-binding site 314
The generation of trypsin from trypsinogen leads to the activation of other zymogens 315
Some proteolytic enzymes have specific inhibitors 316
Blood clotting is accomplished by a cascade of zymogen activations 317
Fibrinogen is converted by thrombin into a fibrin clot 318
Prothrombin is readied for activation by a vitamin K-dependent modification 320
Hemophilia revealed an early step in clotting 321
The clotting process must be precisely regulated 321
Chapter 11 Carbohydrates 329
11.1 Monosaccharides Are the Simplest Carbohydrates 330 Many common sugars exist in cyclic forms
Pyranose and furanose rings can assume different conformations
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Glucose is a reducing sugar 335 A membrane lipid is an amphipathic molecule
Monosaccharides are joined to alcohols and containing a hydrophilic and a hydrophobic moiety 363 amines through glycosidic bonds 336 12.3 Phospholipids and Glycolipids Readily Phosphorylated sugars are key intermediates in Form Bimolecular Sheets in Aqueous Media 364 energy generation and biosyntheses 336 Lipid vesicles can be formed from phospholipids 365 11 .2 Monosaccharides Are Linked to Form Lipid bilayers are highly impermeable to ions and Complex Carbohydrates 337 most polar molecules 366 Sucrose, lactose, and maltose are the common 12.4 Proteins Carry Out Most Membrane disaccharides 337 Processes 367 Glycogen and starch are storage forms of glucose 338 Proteins associate with the lipid bilayer in a Cellulose, a structural component of plants, is made variety of ways 367 of chains of glucose 338 Proteins interact with membranes in a variety 11.3 Carbohydrates Can Be Linked to Proteins ofways 368 to Form Glycoproteins 339 Some proteins associate with membranes through
Carbohydrates can be linked to proteins through covalently attached hydrophobic groups 371 asparagine (N-linked) or through serine or Transmembranehelices can be accurately threonine (0-linked) residues 340 predicted from amino acid sequences 371 The glycoprotein erythropoietin is a vital hormone 340 12.5 Lipids and Many Membrane Proteins Proteoglycans, composed of polysaccharides and Diffuse Rapidly in the Plane of the protein, have important structural roles 341 Membrane 373 Proteoglycans are important components of cartilage 342 The fluid mosaic model allows lateral movement Mucins are glycoprotein components of mucus 343 but not rotation through the membrane 374 Protein glycosylation takes place in the lumen of the Membrane fluidity is controlled by fatty acid endoplasmic reticulum and in the Golgi complex 343 _ composition and cholesterol content 374 Specific enzymes are responsible for oligosaccharide Lipid rafts are highly dynamic complexes formed assembly 345 between cholesterol and specific lipids 375 Blood groups are based on protein glycosylation All biological membranes are asymmetric 375 patterns 345 12.6 Eukaryotic Cells Contain Compartments Errors in glycosylation can result in pathological Bounded by Interna! Membranes 376 conditions 346 Oligosaccharides can be "sequenced" 346
11.4 Leetins Are Specific Carbohydrate-Binding Chapter 13 Membrane Channels and Pumps 383 Proteins 347
The expression of transporters largely defines the Leetins promote interactions between cells 348 metabolic activities of a given cell type 384 Leetins are organized into different classes 348
13.1 The Transport of Molecules Across a Influenza virus binds to sialic acid residues 349 Membrane May Be Active or Passive 384
Chapter 12 Lipids and Cell Membranes 357 Many molecules require protein transporters to cross membranes 384
Many common features underlie the diversity of Free energy stored in concentration gradients can be
biological membranes 358 quantified 385
'12.1 Fatty Acids Are Key Constituents of 13.2 Two Families of Membrane Proteins Lipids 358 Use ATP Hydrolysis to Pump Ions and
Fatty a~Jd names are based on their parent hydrocarbons 358 Molecules Across Membranes 386
F atty acids vary in chain length and degree of P~type ATPases couple phosphorylation and
unsaturation 359 conformational changes to pump calcium ions across membranes 386
12.2 There Are Three Common Types of Digitalis specifically inhibits the Na+ -K+ pump Membrane Lipids 360 by blocking its dephosphorylation 389 Phospholipids are the major dass of membrane lipids 360 P-type ATPases are evolutionarily conserved and Membranelipids can include carbohydrate moieties 361 play a wide range of roles 390 Cholesterol is a lipid based on a steroid nucleus 362 Multidrug resistance highlights a family of Archaeal membranes are built from ether lipids with membrane pumps with ATP-binding cassette branched chains 362 domains 390
Contents xxi
Permeas'e ls an Archetype of Insulinbinding results in the cross-phosphorylation
~ That Use One and activation of the insulin receptor 426
Gradient to Power the Formation The activated insulin-receptor kinase initiates a
392 kinase cascade 426
Channels Can Rapidly Transport Insulin signaling is terminated by the action of
Membranes 394 phosphatases 429
are mediated by transient changes 14.3 EGF Signaling: Signai-Transduction
K+ permeability 394 Pathways Are Poised to Respond 429 conductance rneasurements reveal EGF binding results in the dimerization of the
of single channels 395 EGF receptor 429
of a potassium ion channel is an The EGF receptor undergoes phosphorylation of
for many ion-channel structures 395 its carboxyl-terminal tail 431
of the potassium ion channel reveals EGF signaling leads to the activation of Ras, a
ion specificity 396 small G protein 431
of the potassium ion channel explains Activated Ras initiates a protein kinase cascade 432
of transport 399 EGF signaling is terminated by protein phosphatases
requires substantial conformational and the intrinsic GTPase activity of Ras 432
specific ion-channel domains 399 14.4 Many Elements Recur with Variation can be activated by occlusion of the pore: in Different Signai-Transduction
-chain model 400 Pathways 433 receptor is an archetype for 14.5 Defects in Signal-Transduction
ion channels 401 Pathways Can Lead to Cancer and Other
integrate the activities of several ion working in concert 402
Diseases 434
of ion channels by mutations or Monoclonal antihoclies can be used to inhibit
can be potentially life threatening 404 signal-transduction pathways activated in tumors 434
Junctions Allow Ions and Small Protein kinase inhibitors can be effective anticancer drugs 435
to Flow Betvveen Communicating Cells 405 Cholera and whooping cough are due to altered Channels lncrease the Permeability G-protein activity 435
Membranes to Water 406
14 Signai-Transduction Pathways 415 Part U TRANSDUCING AND dependls on molecular circuits 416 STORING ENERGY
meric G Proteins Transmit Chapter 15 Metabolism: Basic Concepts and Reset Themselves 417 and Design 443
binding to 7TM receptors leads to the of heterotrimeric: G proteins 419 15.1 Metabolism ls Composed of Many G proteins transmit signals by binding Coupled, lnterconnecting Reactions 444
proteins 420 Metabolism consists of energy-yielding and stimulates the phosphorylation of many energy-requiring reactions 444
by activating protein kinase A 420 A thermodynamically unfavorable reaction can be driven by a favorable reaction 445
421 15.2 ATP ls the Universal Currency of Free
receptors activate the phosphoinositide cascade 422 Energy in Biologkai Systems 446 ion is a widely used second messenger 423 A TP hydrolysis is exergonic 446 ion often activates the regulatory protein A TP hydrolysis drives metabolism by shifting the
424 equilibrium of coupled reactions 447
lin Signaling: Phosphorylation The high phosphoryl potential of A TP results Are Central to Many from structural differences between ATP and its nsduction Processes 425 hydrolysis products 449
receptor is a dimer that closes around Phosphoryl-transfer potential is an important form insulin molecule 426 of cellular energy transformation 450
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15.3 The Oxidation of Carbon Fuels ls an Many adults are intolerant of milk because they
lmportant Source of Cellular Energy 451 are deficient in lactase 487
Compounds with high phosphoryl-transfer potential Galactose is highly toxic if the transferase is missing 488
can couple carbon oxidation to A TP synthesis 4S2 16.2 The Glycolytic Pathway ls Tightly Ion gradients across membranes provide an Contralied 488 important form of cellular energy that can be Glycolysis in muscle is regulated to meet the need coupled to A TP synthesis 4S3 for ATP 489 Energy from foodstuffs is extracted in three stages 4S3 The regulation of glycolysis in the liver illustrates 15.4 Metabolie Patlhways Contain Many the biochemical versatility of the liver 490
Recurring Motifs 454 A family of transporters enables glucose to enter
Activated carriers exemplify the modular design and and leave animal cells 493
economy of metabolism 4S4 Cancer and exercise training affect glycolysis in a
Many activated carriers are derived from vitamins 4S7 similar fashion 494
Key reactions are reiterated throughout metabolism 4S9 16.3 Glucose Can Be Synthesized from Metabolie processes are regulated in three Nonearbehydrate Precursors 495 principal ways 461 Gluconeogenesis is not a reversal of glycolysis 497 Aspects of metabolism may have evolved from an The conversion of pyruvate into phosphoenolpyruvate RNAworld 463 begins with the formation of oxaloacetate 498
Oxaloacetate is shuttled into the cytoplasm and converted into phosphoenolpyruvate 499
Chapter 16 Glycolysis and Gluconeogenesis 469 The conversion of fructose 1, 6-bisphosphate into
Glucose is generated from dietary carbohydrates 470 fructose 6-phosphate and orthophosphate is an
Glucose is an important: fuel for most organisms 471 irreversible step soo
16.1 Glycoiysis ls an Energy-Conversion The generation of free glucose is an important control point soo
Pathway in Many Organisms 471 Six high-transfer-potential phosphoryl groups are Hexakinase traps glucose in the cell and begins spent in synthesizing glucose from pyruvate S01 glycolysis 471
16.4 Gluconeogenesis and Glycolysis Are Fructose 1,6-bisphosphate is generated from glucose Reciprocally Regulated 502 6-phosphate 473
The six-carbon sugar is cleaved into t:wo Energy charge determines whether glycolysis or
three-carbon fragments 474 gluconeogenesis will be most active S02
Mechanism: Triase phosphate isomerase salvages a The balance bet:ween glycolysis and gluconeogenesis
three-carbon fragment 47S in the liver is sensitive to blood-glucose concentration S03
The oxidation of an alde:hyde to an acid powers Substrate cycles amplify metabolic signals and
the formation of a compound with high produce heat SOS
phosphoryl-transfer potential 476 Lactate and alanine formed by contracting muscle
Mechanism: Phosphorylation is coupled to the are used by other organs SOS
oxidation of glyceraldehyde 3-phosphate by a Glycolysis and gluconeogenesis are evolutionarily
thioester intermediate 478 intertwined S07
A TP is formed by phosphoryl transfer from Chapter 17 The Citric Acid Cycle 515 1, 3-bisphosphoglycerate 479
Additional A TP is gene:rated with the formation of The citric acid cycle harvests high-energy electrons S16 pyruvate 480
Pyruvate Dehydrogenase Links Glycolysis Two ATP molecules are formed in the conversion 17.1
of glucdse into pyruvate 481 to the Citric Acid Cycle 517
NAD+ is regenerated from the metabolism Mechanism: The synthesis of acetyl coenzyme a from
ofpyruvate 482 pyruvate requires three enzymes and five Coenzymes S18
Fermentations provide usable energy in the absence Flexible linkages allow lipoamide to move bet:ween
ofoxygen 484 different active sites S20
The binding site for NAD+ is similar in many 17.2 The Citric Acid Cycle Oxidizes dehydrogenases 48S Two-Carbon Units 521 Fructoseand galactose are converted into glycolytic Citrate synthase forms citrate from oxaloacetate and intermediates 48S acetyl coenzyme A S22
. . ·.· . . · The mechanism of citrate synthase . . . . . undesirable reactions
isomerized into is:ocitrate
ll1ll~,!~~<'·"' is oxidized and decarboxylated to
~~<~~~';~'in"l coenzyme A is formed by the oxidative ii~c~t.bOX)Tlatlon of alpha-ketoglutarate
:::;O<:W~~1p,Ju'·''"' with high phosphoryl-transfer potential !Ierteraxeu from succinyl coenzyme A
~~~:M~~J~arusrn: Succinyl coen:~yme A synthetase ~!Jti~psfor.ms types of biochemical energy
::,Q~i:il«)ac·eta·te is regenerated by the oxidation
acid cycle produces high-transfer-potential ete~::troJ:u;, ATP, and COz
Entry to the Citric Acid Cycle and Metaoonsm Through 11: Are Contralied
n"''"""r"' dehydrogenase complex is regulated :?all9.S1tencat.Ly and by reversible phosphorylation
···==··,, ·· disruption of pyruvate: metabolism is the cause · and poisoning by mercury and arsenic
The Glyoxylate Cycle Enables Plants · Bacteria to Grow on Acetate
18 Oxidative Phosphorylation
Eukaryotic Oxidaitive Phosphorylation Place in Mitochondria
ltO•Chc>ndlna are bounded by a double membrane
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Ubiquinol is the entry point for electrons from F ADH2 of flavoproteins 553 Electrons flow from ubiquinol to cytochrome c through Q-cytochrome c oxidoreductase 553 The Q cycle funnels electrons from a two-electron carrier to a one-electron carrier and pumps protons 554 Cytochrome c oxidase catalyzes the reduction of molecular oxygen to water 555 Taxie derivatives of molecular oxygen such as superoxide radical are scavenged by protective enzymes 558 Electrons can be transferred between groups that are not in contact 560 The conformation of cytochrome c has remained essentially constant for more than a billion years 561
18.4 A Proton Gradient Powers the Synthesis of ATP 561 ATP synthase is composed of a proton-conducting unit and a catalytic unit 563 Proton flow through A TP synthase leads to the release of tightly bound A TP: The bindling-ehange mechanism 564 Rotational catalysis is the world' s smallest molecular motor 565 Proton flow araund the c ring powers A TP synthesis 566 A TP synthase and G proteins have several common features 568
18.5 Many Shuttles Allow Movement Across Mitochondrial Membranes 568 Electrons from cytoplasmic NADH enter mitochondria by shuttles 569 The entry of ADP into mitochondria is coupled to the exit of ATP by ATP-ADP translocase 570 Mitochondrial transporters for metabolites have a common tripartite structure 571
18.6 The Regulation of Cellular Respiration ls Governed Primarily by the Need for ATP 572 The complete oxidation of glucose yields about 30 molecules of A TP 572 The rate of oxidative phosphorylation is determined by the need for A TP 573 Regulated uncoupling leads to the generation ofheat 574 Oxidative phosphorylation can be inhibited at many stages 576 Mitochondrial diseases are being discovered 576 Mitochondria play a key role in apoptosis 577 Power transmission by proton gradients is a central motif of bioenergetics 577
Chapter 19 The Light Reactions of Photosynthesis 585
Photosynthesis converts light energy into chemical energy 586
19.1 Photosynthesis Takes Place in Chloroplasts 587 The primary events of photosynthesis take place in thylakoid membranes 587 Chloroplasts arose from an endosymbiotic event 588
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19.2 Light Absorption by Chlorophyll lnduces 20.2 The Activity of the Calvin Cycle Depends Electron Transfer 588 on Environmental Conditions 617 A special pair of chlorophylls initiate charge separation 589 Rubisco is activated by light-driven changes in proton
Cyclic electron flow reduces the cytochrome of the and magnesium ion concentrations 618
reaction center 592 Thioredoxin plays a key role in regulating the
19.3 Two Photosystems Generate a Proton Calvin cycle 618
Gradient and NADPH in Oxygenic The C4 pathway of tropical plants accelerates
Photosynthesis 592 photosynthesis by concentrating carbon dioxide 619
Photosystem li transfers electrons from water to Crassulacean acid metabolism permits growth in
plastoquinone and generates a proton gradient 592 arid ecosystems 620
Cytochrome bflinks photosystem li to photosystem I 595 20.3 The Pentose Phosphate Pathway
Photosystem I uses light energy to generate reduced Generates NADPH and Synthesizes
ferredoxin, a powerful reductant 595 Five-Carbon Sugars 62"1
Ferredoxin-NADP+ reductase converts NADP+ Two molecules ofNADPH are generated in the
intoNADPH 596 conversio:n of glucose 6-phosphate into ribulose
19.4 A Proton Gradient Across the Thylakoid 5-phosphate 621
Membrane Drives ATP Synthesis 597 The pentose phosphate pathway and glycolysis are linked by transketolase and transaldolase 621
The A TP synthase of chloroplasts closely resembles Mechanism: Transketolase and transaldolase stabilize
those of mitochondria and prokaryotes 598 carbanionic intermediates by different mechanisms 624
Cyclic electron flow through photosystem I Ieads to 20.4 The Metabolism of Glucose 6-phosphate the production of A TP instead of NADPH 599
The absorption of eight photons yields one 02, two by the Pentose Phosphate Pathway ls
NADPH, and three A TP molecules 600 Coordinated wlth Glycolysis 626
19.5 Accessory Pigments Funnel Energy into The rate of the pentose phosphate pathway is controlled
Reaction Centers 601 . by the levd ofNADP+ 626
Resonance energy transfer allows energy to move The flow of glucose 6-phosphate depends on the
from the site of initial absorbance to the reaction need for NADPH, ribose 5-phosphate, and A TP 627
center 601 Through the looking-glass: The Calvin cycle and the
Light-harvesting complexes contain additional pentose phosphate pathway are mirror images 629
chlorophylls and carotinoids 602 20.5 Glucose 6-phosphate Dehydrogenase
The components of photosynthesis are highly organized 603 Plays a Key Role in Protection Against Reactive
Many herbicides inhibit the light reactions of Oxygen Species · 629
photosynthesis 604 Glucose 6-phosphate dehydrogenase defi.ciency causes
19.6 The Ability to Convert Light into Chemical a drug-induced hemolytic anemia 629
Energy is Ancient 604 A defi.ciency of glucose 6-phosphate dehydrogenase confers an evolutionary advantage in some circumstances 631
Chapter 20 The Calvin Cycle and Pentose Phosphate Pathway 609 Chapter 21 Glycogen Metabolism 637
20.1 The Calvin Cycle Synthesizes Hexeses Glycogen metabolism is the regulated release and
from Carbon Dioxide and Water 610 storage of glucose 638
Carbon dioxide reacts with ribulose 1,5-bisphosphate 21.1 Glycogen Breakdown Requires the to form two molecules of 3-phosphoglycerate 611 lnterplay of Several Enzymes 639 Rubisc6 activity depends on magnesium and Phosphorylase catalyzes the phosphorolytic cleavage carbamate 612 of glycogen torelease glucose 1-phosphate 639
Rubisco also catalyzes a wasteful oxygenase reaction: Mechanisrn: Pyridoxal phosphate participates in the Catalytic imperfection 613 phosphorolytic cleavage of glycogen 640
Hexosephosphatesare made from phosphoglycerate, A debranching enzyme also is needed for the and ribulose 1,5-bisphosphate is regenerated 614 breakdown of glycogen 641 Three A TP and two NADPH molecules are used to Phosphoglucomutase converts glucose 1-phosphate bring carbon dioxide to the Ievel of a hexose 617 into glucose 6-phosphate 642 Starch and sucrose are the major carbohydrate The liver c:ontains glucose 6-phosphatase, a stores in plants 617 hydrolytic enzyme absent from muscle 643
Contents XXV
ls Regulated by Allosteric The complete oxidation of palmitate yields
Reversible Phosphorylation 643 106 molecules of A TP 671
is regulated by the intracellular :22.3 Unsaturated and Odd-Chain Fatty Acids 643 Require Additional Steps for Degradation 672
produces glucose for use by other An isomerase and a reductase are required for 645 the oxidation of unsaturated fatty acids 672
Odd-chain fatty acids yield propionyl CoA in the 645 final thiolysis step 673
ne and Glucagon Signal the Vitamin B12 contains a corrin ring and a cobalt atom 674 Breakdown 646 Mechanism: Methylmalonyl CoA mutase catalyzes a
the signal for the initiation of rearrangement to form succinyl CoA 675 646 Fatty acidsarealso oxidized in peroxisomes 676
must be rapidly turned off Ketone hoclies are formed from acetyl CoA when 648 fat breakdown predominates 677
of glycogen phosphorylase became Ketone hoclies are a major fuel in some tissues 678 as the enzyme evolved 649 Animals cannot convert fatty acids into glucose 680
ls Synthesized and Degraded 22.4 Fatty Acids Are Synthesized by Fatty Pathways 649 Acid Synthase 680
649 F atty acids are synthesized and degraded by different pathways 680
650 The formation of malonyl CoA is the committed step 651 in fatty acid synthesis 681
Intermediates in fatty acid synthesis are attached to 651 an· acyl carrier protein 681
is an efficient storage form of glucose 651 Fatty acid synthesis consists of a series of condensation,
Breakdown and Synthesis Are reduction, dehydration, and reduction reactions 682
Regulated 652 Fatty acids are synthesized by a multifunctional enzyme complex in animals 683
653 The synthesis of palmitate requires 8 molecules of acetyl
glycogen synthesis by inactivating CoA, 14 molecules ofNADPH, and 7 molecules of A TP 685
synthase kinase 654 Citrate carries acetyl gr~mps from mitochondria to the cytoplasm for fatty acid synthesis 686
655 Several sources supply NADPH for fatty acid synthesis 686
understanding of glycogen-storage Fatty acid synthase inhibitors may be useful drugs 687 is possible 656 22.5 The Elongation and Unsaturation of
22 Fatty Acid Metabolism 663 Fatty Acids Are Accomplished by Accessory Enzyme Systems 687
. •·.······· .. degradation and synthesis mirror each Membrane-bound enzymesgenerate unsaturated fatty acids 688
their chemical reactions 664 Eicosanoid hormones are derived from polyunsaturated
Are Highly Concentrated fatty acids 688
665 22.6 Acetyl CoA Carboxylase Plays a Key Role ........ .· lipids are digested by pancreatic lipases 665 in Controlling Fatty Acid Metabolism 690
· ? . lil'~ds are transported in chylomicrons 666 Acetyl CoA carboxylase is regulated by conditions in
Use of Fatty Acids As Fuel Requires the cell 690
Stages of Proces:sing 667 Acetyl CoA carboxylase is regulated by a variety of
are hydrolyzed by hormone-stimulated hormones 690
667 Chapter 23 Protein Turnever and Amino
are linked to coe:nzyme A before they Acid Catabolism 697 668
carries long-chain activated fatty acids 23.1 Proteins Are Degraded to Amino Acids 698 mitochondrial matrix 669 The digestion of dietary proteins begins in the
· ·••···. CoA, NADH, and FAD Hz are generated in stomach and is completed in the intestine 698
· ··•· round of fatty acid oxidation 670 Cellular proteins are degraded at different rates 699
xxvi Contents
23.2 Protein Turnever ls Tightly Regulated 699 Ubiquitin tags proteins for destruction 699
The proteasome digests the ubiquitin-tagged proteins 701
The ubiquitin pathway and the proteasome have prokaryotic Counterparts 701
Protein degradation can be used to regulate biological function 702
23.3 The First Step in Amino Acid Degradation ls the Removal of Nitrogen 704 Alpha-amino groups are converted into ammonium ions by the oxidative deamination of glutamate 704
Mechanism: Pyridoxal phosphate forms Schiff-base intermediates in aminotransferases 705
Aspartate aminotransferase is an archetypal pyridoxal-dependent transaminase 706
Pyridoxal phosphate enzymes catalyze a wide array of reactions 707
Serine and threonine can be directly deaminated 708
Peripheral tissues transport nitrogen to the liver
23.4 Ammonium Ion ls Converted into Urea in Most Terrestrial V,ertebrates The urea cycle begins w:ith the formation of carbamoyl phosphate
The urea cycle is linked to gluconeogenesis
Urea-cycle enzymes are evolutionarily related to enzymes in other metabolic pathways
lnherited defects of the urea cycle cause hyperammonemia and can lead to brain darnage
Ureais not the only means of disposing of excess nitrogen
23.5 Carbon Atoms of Degraded Amino Acids Emerge As Major Metabolie Intermediates Pyruvate is an entry point into metabolism for a number of amino acids
Oxaloacetate is an entry point into metabolism for aspartate and asparagine
Alpha-ketoglutarate is an entry point into metabolism for five-carbon amino acids
SuccinY,~ coenzyme A is a point of entry for several nonpolar amino acids
Methionine degradation requires the formation of a key methyl donor, S-adenosylmethionine
The branched-chain amino acids yield acetyl CoA, acetoacetate, or propionyl CoA
Oxygenases are required for the degradation of aromatic amino acids
23.6 lnborn Errors of Metabolism Can Disrupt Amino Acid Degradation
708
709
709
711
712
712
713
714
715
716
716
717
717
717
719
721
Part m SYNTHESIZ!NG THE MOlECUlES OF UFE
Chapter 24 The Biosynthesis of Amino Acids 729
Amino acid synthesis requires solutions to three key biochemical problems 730
24.1 Nitrogen Fixation: Microorganisms Use ATP and a Powerful Reductant to Reduce Atmospheric Nitrogen to Ammonia 730 The iron-molybdenum cofactor of nitrogenase binds and reduces atmospheric nitrogen 731
Ammonium ion is assimilated into an amino acid through glutamate and glutamine 733
24.2 Amino Acids Are Made from Intermediates of the Citric Acid Cycle and Other Major Pathways 735 Human beings can synthesize some amino acids but must obtain others from the diet 735
Aspartate, alanine, and glutamate are formed by the addition of an amino group to an alpha-ketoacid 736
A common step determines the chirality of all amino acids
. The formation of asparagine from aspartate requires an adenylated intermediate
Glutamate is the precursor of glutamine, proline, and arginine
3-Phosphoglycerate is the precursor of serine, cysteine, and glycine
Tetrahydrofolate carries activated one-carbon units at several oxidation Ievels
S-Adenosylmethioriine is the major donor of methyl groups
Cysteine is synthesized from serine and homocysteine
High homocysteine Ievels correlate with vascular disease
Shikimate and chorismate are intermediates in the biosynthesis of aromatic amino acids
Tryptophan synthase illustrates substrate channeling in enzymatic catalysis
24.3 Feedback Inhibition Regulates Amino Acid Biosynthesis Branched pathways require sophisticated regulation
An enzymatic cascade modulates the activity of glutamine synthetase
24.4 Amino Acids Are Precursors of Many Biomolecules Glutathione, a gamma-glutamyl peptide, serves as a sulfhydryl buffer and an antioxidant
Nitric oxide, a short-lived signal molecule, is formed from arginine
737
737
738
738
739
740
742
743
743
746
747
747
749
750
751
751
Contents xxvii
synthesized from glycine and succinyl The synthesis of purine nucleotides is controlled by 752 feedback inhibition at several sites 777
in some inherited disorders of The synthesis of deoxyribonucleotides is 754 controlled by the regulation of ribonucleotide
reductase 778
761 25.5 Disruptions in Nucleotide Metabolism Can Cause Pathological Conditions 778 The loss of adenosine deaminase activity results
762 in severe combined immunodeficiency 778
Pyrimidine Ring ls Assembled de Gout is induced by high serum levels of urate 779 < ·· by Salvage Pathways 763 Lesch-Nyhan syndrome is a dramatic consequence
of mutations in a salvage-pathway enzyme 780
763 F olic acid deficiency promotes birth defects such as spina bifida 781
763
763 Chapter 26 The Biosynthesis of Membrane
a ribose ring from PRPP to Lipids and Steroids 787 nucleotide and is converted 16.1 Phosphatidate ls a Common Intermediate
764 in the Synthesis of Phospholipids and Triacylglycerols 788
765 The synthesis of phospholipids requires an activated
765 intermediate 789 recycle pyrimidine bases 766 Sphingolipids are synthesized from ceramide 791
Bases Can Be Synthesized de Gangliosides are carbohydrate-rich sphingolipids Recycled by Salvage Pathways 766 that contain acidic sugars 792
ring system is assembled on ribose Sphingolipids confer diversity on lipid structure and 766 function 793
ring is assembled by successive steps of Respiratory distress syndrome and T ay-Sachs disease by phosphorylation followed by result from the disruption of lipid metabolism 793
767 Phosphatiditic acid phosphatase is a key regulatory 769 enzyme in lipid metabolism 794
770 26.2 Cholesterol ls Synthesized from Acetyl Coenzyme A in Three Stages 795
economize intracellular energy The synthesis of mevalonate, which is activated as 770 isopentenyl pyrophosphate, initiates the synthesis of
bonucleotides Are Synthesized cholesterol 795 of Ribonucleotides Through Squalene (C3o) is synthesized from six molecules of
Mechanism 771 isopentenyl pyrophosphate (Cs) 796
A tyrosyl radical is critical to the action Squalene cyclizes to form cholesterol 797 reductase 771 26.3 The Complex Regulation of
.. other than tyrosyl radical are Cholesterol Biosynthesis Takes Place at . ....
· by other ribonucleotide reductases 773 Several Levels 798 is formed by the methylation of Lipoproteins transport cholesterol and triacylglycerols
774 throughout the organism 801 reductase catalyzes the regeneration The blood levels of certain lipoproteins can serve
a one-carbon carrier 775 diagnostic purposes 802 anticancer drugs block the synthesis Low-density lipoproteins play a central role in
775 cholesterol metabolism 803 The absence of the LDL receptor leads to
776 hypercholesterolemia and atherosclerosis 804 Mutations in the LDL receptor prevent LDL release
777 and result in receptor destruction 805
xxviii Contents
HDL appears to proteet against arteriosclerosis 806 Metabolie adaptations in prolonged starvation
The clinieal management of eholesterollevels ean be minimize protein degradation 838
understood at a bioehemieallevel 807 27.6 Ethanol Alters Energy Metabolism in 26.4 lmportant Derivatives of Cholesterol the Liver 840 lnclude Bile Salts and Steroid Hormones 807 Ethanol metabolism leads to an exeess ofNADH 840
Letters identify the steroid rings and numbers Exeess ethanol eonsumption disrupts vitamin identify the earbon atoms 809 metabolism 842
Stereidsare hydroxylated by-eytoehrome P450 monooxygenases that use NADPH and 02 809 Chapter 28 DNA Replication, Repair, and The eytoehrome P450 system is widespread and Recombination 849 performs a proteetive funetion 810 28.1 DNA Replication Proceeds by the Pregnenolone, a preeursor of many other steroids, is Polymerization of Deoxyribonucleoside formed from eholesterol by cleavage of its side ehain 811 Triphosphates Along a Template 850 Progesterene and eortieosteroids are synthesized from
DNA polymerases require a template and a primer 850 pregnenolone 811
Androgens and estrogens are synthesized from All DNA polymerases have struetural features in
pregnenolone 812 eommon 851
Vitamin D is derived from eholesterol by the Two bound metal ions partieipate in the
ring-splitting aetivity oflight 813 polymerase reaetion 851
The speeifieity of replieation is dietated by
Chapter 27 The Integration of Metabolism 821 eomplementarity of shape between bases 852
27.1 Caloric Homeostasis ls a Means of An RNA primer synthesized by primase enables DNA synthesis to begin 853
Regulating Body Weight 822 One strand ofDNA is made eontinuously, whereas 27.2 The Brain Plays a Key Role in Caloric the other strand is synthesized in fragments 853 Homeostasis 824 DNA ligase joins ends of DNA in duplex regions 854 Signals from the gastrointestinal traet induee feelings TheSeparation ofDNA Strands requires speeifie of satiety 824 helieases and A TP hydrolysis 854. Leptin and insulin regulate long-term eontrol 28.2 DNA Unwinding and Supercoiling Are over ealorie homeostasis 825 Controlled by Topoisomerases 855 Leptin is one of several hormones seereted by The linking number ofDNA, a topologieal property, adipose tissue 826 determines the de~ree of supereoiling 856 Leptin resistanee may be a eontributing faetor T opoisomerases prepare the double helix for to obesity 827 unwinding 858 Dieting is used to eombat obesity 827 Type I topoisomerases relax supereoiled struetures 858 27.3 Diabetes ls a Common Metabolie Disease Type li topoisomerases ean introduee negative Often Resulting from Obesity 828 supereoils through eoupling to A TP hydrolysis 859 Insulin initiates a eomplex signal-transduetion 28.3 DNA Replication ls Highly Coordinated 861 pathway in muscle 828
DNA replieation requires highly proeessive polymerases 861 Metabolie syndrome often preeedes type 2 diabetes 830
The leading and lagging strands are synthesized Exeess fatty aeids in muscle modify metabolism 830 in a eoordinated fashion 862 Insulin resistanee in muscle faeilitates panereatie failure 831 DNA replieation in Escherichia coli begins at a Metabolie derangements in type 1 diabetes result from unique site 864 insulin insuffieieney and glueagon excess 832 DNA synthesis in eukaryotes is initiated at multiple sites 865 'l7.1i Exercise Beneficially Alters the Telomeres are unique struetures at the ends of Biochemistry of Cells 833 linear chromosomes 866
Mitochondrial biogenesis is stimulated by museular aetivity 834 Telomeres are replicated by telomerase, a speeialized
Fuel choice during exercise is determined by the polymerase that earries its own RNA template 867
intensity and duration of aetivity 835 28.4 Many Types of DNA Darnage Can Be 27.5 Food lntake and Starvation lnduce Repaired 867 Metabolie Changes 836 Errors ean arise in DNA replication 867
The starved-fed cycle is the physiological response Bases can be damaged by oxidizing agents, alkylating to a fast 837 agents, and light 868
Contents xxix
can be deteclted and repaired by a Enhancer sequences can stimulate transcription at systems 869 start sites thousands ofbases away 900
of thymine instead of uracil in DNA 29.3 The Transcription Products of Eukaryotic repair of deaminated cytosine 871 Polymerases Are Processed 901
diseases are caused by the expansion RNA polymerase I produces three ribosomal RNAs 901 of three nucleotides 872
RNA polymerase Ill produces transfer RNA 902 are caused by the defective repair
The product of RNA polymerase II, the pre-mRNA 872
transcript, acquires a 5' cap and a 3' poly(A) tail 902
873 Small regulatory RNAs are cleaved from larger precursors 904
ONA Recombination Plays lmportant Roles RNA editing changes the proteins encoded by mRNA 904 Repair, and Other Processes 874 Sequences at the ends of introns specify splice sites
in mRNA precursors 905 874 Splicing consists of two sequential transesterification
reactions proceed through reactions 906 intermediates 875 Small nuclear RNAs in spliceosomes catalyze the
splicing of mRNA precursors 907
883 Transcription and processing of mRNA are coupled 909
Mutations that affect pre-mRNA splicing cause disease 909 comprises three stages: Initiation, Most human pre-mRNAS can be spliced in alternative
and termination 884 ways to yield different proteins 910
885 29.4 The Discovery of Catalytic RNA Was are formed de novo and grow in the Revealing in Regard to Both Mechanism and
· == ::
0 direction 886 Evolution 911 }\'< polymerases backtrack and correct errors 888
to initiate transcription 888 Chapter 30 Protein Synthesis 921 subunits of RNA polymerase recognize
30.1 Protein Synthesis Requires the Translation sites 889
of Nucleotide Sequences into Amino Acid polymerases must unwind the template
helix for transcription to take place 890 Sequences 922
takes place at tramscription bubbles The synthesis of long proteins requires a low error
along the DNA template 890 frequency 922
within the newly transcribed RNA signal Transfer RNA molecules have a common design 923
891 Some transfer RNA molecules recognize more than
messenger RNAs dire:ctly sense metabolite one codon because ofwobble in base-pairing 925
892 30.2 Aminoacyl Transfer RNA Synthetases protein helps to terminate the transcription Read the Genetic Code 927
892 Amino acids are first activated by adenylation 927
inhibit transcription 893 Aminoacyl-tRNA synthetases have highly discriminating
of transfer and ribosomal RNA are amino acid activation sites 928
Proofreading by aminoacyl-tRNA synthetases increases 895 the fidelity of protein synthesis 929
Synthetases recognize various features of transfer RNA
896 molecules 930
of RNA polymerase synthesize RNA in Aminoacyl-tRNA synthetases can be divided into two
cells 897 classes 931
30.3 The Ribosome ls the Site of Protein II promoter region 898 Synthesis 931 protein complex initiates the assembly of Ribosomal RNAs (SS, 16S, and 23S rRNA) play a central
transcription complex 899 role in protein synthesis 932
transcription factoJrs interact with eukaryotic Ribosomes have three tRNA-binding sites that bridge 900 the 30s and 50s subunits 934
:n:xx Contents
The start signal is usually AUG preceded by several 31.3 Regulatory Circuits Can Result in Switching bases that pair with 16S rRNA 934 Between Patterns of Gene Expression 964 Bacterial protein synthesis is initiated by Lambda repressor regulates its own expression 964 formylmethionyl transfer RNA 935 A circuit based on lambda repressor and Cro form Formylmethionyl-tRNAfis placed in the P site of a genetic switch 965 the ribosome in the formation of the 70S Many prokaryotic cells release chemical signals that initiation complex 936 regulate gene expression in other cells 965 Elongation factors deliver aminoacyl-tRNA to the Biofilms are complex communities of prokaryotes 966 ribosome 936
Peptidyl transferase catalyzes peptide-band 31.4 Gene Expression Can Be Contralied at
synthesis 937 Posttranscriptional Levels 967
The formation of a peptide bond is followed by the Attenuation is a prokaryotic mechanism for regulating
GTP-driven translocation of tRNAs and mRNA 938 transcription through the modulation of nascent
Protein synthesis is terminated by release factors RNA secondary structure 967
that read stop codons 940
30.4 Eukaryotic Protein Synthesis Differs Chapter 32 The Control of Gene Expression
from Prokaryotic Protein Synthesis Primarily in Eukaryotes 973
in Translation Initiation 941 32.1 Eukaryotic DNA ls Organized into Mutations in initiation factor 2 cause a curious Chromatin 974 pathological condition 942 Nucleosomes are complexes of DNA and histones 975
30.5 A Variety of Antibiotics and Toxins Can DNA wraps araund histone octamers to form
lnhibit Protein Synthesis 943 nucleosomes 975
Some antibiotics inhibit protein synthesis 943 32.2 Transcription Factars Bind DNA and Diphtheria toxin blocks protein synthesis in eukaryotes Regulate Transcription Initiation 977 by inhibiting translocation 944 A range ofDNA-binding structures are employed
Ricin fatally modifies 28S ribosemal RNA 945 by eukaryotic DNA-binding proteins 977
30.6 Ribosomes Bound to the Endoplasmic Activation domains interact with other proteins 978
Reticulum Manufacture Secretory and Multiple transcription factors interact with eukaryotic
Membrane Proteins 945 regulatory regions 979
Signal sequences mark proteins for translocation across Enhancers can stimulate transcription in specific
the endoplasmic reticulum membrane 945 cell types 979
Transport vesicles carry cargo proteins to their final lnduced pluripotent stem cells can be generated by
destination 947 introducing four transcription factors into differentiated cells 980
32.3 The Control of Gene Expression Can Chapter 31 The Control of Gene Expression Require Chromatin Remedeling 980 in Prokaryotes 957 The methylation ofDNA can alter patterns of gene
31.1 Many DNA-Binding Proteins Recognize expression 981
Specific DNA Sequences 958 Steraids and related hydrophobic molecules pass
The helix-turn-helix motif is common to many through membranesandbind to DNA-binding receptors 982
prokaryotic DNA-binding proteins 959 Nuclear hormone receptors regulate transcription by
31.2 Prokaryotic DNA-Binding Proteins Bind recruiting coactivators to the transcription complex 982
Specifically to Regulatory Sites in Operans 959 Steroid-hormone receptors are targets for drugs 984
An OQeron consists of regulatory elements and Chromatin structure is modulated through covalent
protein-encoding genes 960 modifications of histone tails 985
The lac repressor protein in the absence of lactose Histone deacetylases contribute to transcriptional
binds to the operator and blocks transcription 961 repression 986
Ligand binding can induce structural changes in :n.4 Eukaryotic Gene Expression Can Be regulatory proteins 962 Contralied at Posttranscriptional Levels 987 The operon is a common regulatory unit in Genes associated with iron metabolism are prokaryotes 962 translationally regulated in animals 987
Transcription can be stimulated by proteins that Small RNAs regulate the expression of many contact RNA polymerase 963 eukaryotic genes 989
Contents xxxi
NDING TO 34.1 Antibodies Possess Distinct
NTAL CHANGES Antigen-Binding and Effector Units 1021
34.2 Antibodies Bind Specific Molecules Systems 995 Through Hypervariable Loops 1023
Variety of Organic Compounds The immunoglobulin fold consists of a beta-sandwich framewerk with hypervariable loops 1024
by Olfaction 996 X-ray analyses have revealed how antihoclies
by an enormaus family of bind antigens 1024 helix receptors 996
Large antigens bind antihoclies with numerous decoded by a combinatorial mechanism 998 interactions 1026 ls a Combination of Senses That 34.3 Diversity ls Generated by Gene Different Mechanisms 1000 Rearrangements 1027 the human genome led to the J (joining) genes and D (diversity) genes increase large family of 7TM bitter receptors 1001 antibody diversity 1027
7TM receptor responds to sweet More than 108 antihoclies can be formed by 1002 combinatorial association and somatic mutation 1028
of glutamate and aspartate, is The oligomerization of antihoclies expressed on the heterodimeric receptor related to surfaces of immature B cells triggers antibody secretion 1029
1003 Different classes of antihoclies are formed by
. • ·)· .•. detected primarily by the passage of the hopping of V H genes 1030 · ·••}0:::< through channels 1003
34.4 Major-Histocompatibility-Complex from the effects of hydrogen Proteins Present Peptide Antigens on Cell 1003 Surfaces for Recognition by T-Cell Receptors 1031
Molecules in the Eye Peptides presented by MHC proteins occupy a deep
1004 groove flanked by alpha helices 1032
1004 T -cell receptors are antibody-like proteins cantairring variable and constant regions 1034
1005 CD8 on cytotoxic T cells acts in concert with T -cell receptors 1034
1006 Helper T cells stimulate cells that display foreign
recovery peptides bound to dass II MHC proteins 1036 is mediated by three cone receptors Helper T cells rely on the T -cell receptor and CD4 to
of rhodopsin 1007 recognize foreign peptides on antigen -presenting cells 1036 in the genes for the green and MHC proteins are highly diverse 1038
lead to "color blindness" 1008 Human immunodeficiency viruses subvert the
ring Depends on the Speedy immune system by destroying helper T cells 1039 of Mechanical Stimuli 1009 34.5 The Immune System Contributes to the
.· ·····.· use a connected bundle of stereocilia to Prevention and the Development of Human
motions 1009 Diseases 1040
channels have been identified in T cells are subjected to positive and negative
1010 selection in the thymus 1040
lncludes the Sensing of Pressure, Autoimmune diseases result from the generation and Other Factars 1011 of immune responses agairrst self-antigens 1041
reveal a receptor for sensing The immune system plays a role in cancer prevention 1041 and other painful stimuli 1011 Vaccines are a powerful means to prevent and
1012 eradicate disease 1042
1017 Chapter 35 Molecular Motors 1049
is an evolutionarily ancient 35.1 Most Molecular-Motor Proteins Are 1018 Members of the P-loop NTPase Superfamily 1050
immune system responds by using Molecular motors are generally oligomeric proteins of evolution 1019 with an A TPase core and an extended structure 1050
xxxH Contents
A TP binding and hydrolysis induce changes in the 36.2 D1rug Candidates Can Be Discovered conformation and binding affinity of motor proteins 1052 by Serendipity, Screening, or Design 1081 35.2 Myosins Move Along Actin Filaments 1054 Serendipitous observations can drive drug
Actin is apolar, self-assembling, dynamic polymer 1054 development 1081
Myosin head domains bind to actin filaments 1056 Screening libraries of compounds can yield drugs
Motions of single motor proteins can be directly or drug l1~ads 1083
observed 1056 Drugs can be designed on the basis of
Phosphate release triggers the myosin power strake 1057 three-dimensional structural information
Muscle is a complex of myosin and actin 1057 about their targets 1086
The length of the lever arm determines motor 36.3 Analyses of Genomes Hold Great velocity 1060 Promis~3 for Drug Discovery 1089
35.3 Kinesin and Dynein Move Along Potential targets can be identified in the human
Microtubules 1060 proteom1~ 1089
Microtubules are hollow cylindrical polymers 1060 Animal models can be developed to test the validity of potential drug targets 1090
Kinesin motion is highly processive 1062 Potentiall targets can be identified in the genomes 35.4 A Rotary Motor Drives Bacterial Motion 1064 of pathogens 1090 Bacteria swim by rotating their flagella 1064 Genetic differences influence individual responses
Proton flow drives bacterial flagellar rotation 1064 to drugs 1091
Bacterial chemotaxis depends on reversal of the 36.4 The Development of Drugs Proceeds direction of flagellar rotation 1066 Through Several Stages 1092
Clinical trials are time consuming and expensive 1092 Chapter 36 Drug Development 1073 The evollution of drug resistance can limit
36.1 The Development of Drugs Presents the utility of drugs for infectious agents
Huge Challenges 1074 and canc:er 1094
Drug candidates must be potent modulators of Answers to Problems At their targets 1074
Drugs must have suitable properties to reach their Index Bl targets 1075 Taxicity can limit drug effectiveness 1080