《生物化学》课程教学资源（书籍文献）Biochemistry, EIGHTH EDITION 2015, Jeremy M. Berg, John L. Tymoczko, Gregory J. Gatto, Jr. Lubert Stryer

Biochemistry EIGHTH EDITION Jeremy M.Berg John L.Tymoczko Gregory J.Gatto,Jr. Lubert Stryer H聚&aN A Macmillan Education Imprint

Biochemistry Jeremy M. Berg John L. Tymoczko Gregory J. Gatto, Jr. Lubert Stryer EIGHTH EDITION

ABOUT THE AUTHORS JEREMY M.BERG received his B.S.and M.S Molecular Biology of Cancer,and Exercise degrees in Chemistry from Stanford (where he did Biochemistry and coteaches an introductory course. research with Keith Hodgson and Lubert Stryer) Energy Flow in Biological Systems.Professor and his Ph.D.in Chemistry from Harvard with Tymoczko received his B.A.from the University of Richard Holm.He th completed a postdoctora try fron fellowship with Carl Pabo in Biophysics at Johns Hopkins University School of Medicine.He was an Ben May Institute for Cancer Research.He then had Assistant professor in the Department of Chemistry a postdoctoral position with Hewson Swift of the at Johns Hopkins from 1986 to 1990.He then moved Department of Biology at the University of Chicago Hopkins University School of Medicine The focus of his rese rch has been on steroid rec ep as Professor and Director of the Department of tors,ribonucleoprotein particles,and proteolyti Biophysics and Biophysical Chemistry.where he processing enzymes. remained until 2003.He then became Director of the National Institute of General Medical Sciences GREGORY J.GATTO,JR.,received his A.B. at the National Institutes of Health.In 2011,he degree in Cher from Princeton University moved to the Uni versity of Pitts rgh where he orked with Mar tin F.Se is now Professor of Computational and Systems was awarded the Everett S.Wallis Prize in Organic Biology and Pittsburgh Foundation Professor and Chemistry.In 2003.he received his M.D.and Ph.D Director of the Institute for Personalized Medicine degrees from the Johns Hopkins University School He served as President of the American Society for of Medicine,where he studied the structural biology Bi d Molecular Biology rom2011-2013 of peroxis mal targeting sign l ition with He is a of the American Assoc iation for the Jeremy M.Berg and received d the Mic chael A.Shanoff Advancement of Science and a member of the Institute Young Investigator Research Award.He completed a of medicine of the national academy of Sciences. postdoctoral fellowship in 2006 with Christopher T. He received the American Chemical Society Award Walsh at Harvard Medical School,where he studied in Pure Chemistry(1994)and the Eli Lilly Award the biosynthesis of the macrolide immunos for Fundamental Re earch in Biological Ch uppres. s.Heis urentlyaSeniorScientificlnvestigato (1995),was named Maryland Outstanding Young in the Heart Failure Discovery Performance Unit at Scientist of the Year (1995).received the Harrison GlaxoSmithKline Howe Award(1997),and received public service awards from the Biophysical Society,the Americar LUBERT STRYER is Winzer Professor of Cell Society for Biochem and Mole ular Biology ynd the ,in the School of Medicine nd American Chemi Professor of Neurobiology,Emeritus,at Stanford for Cell Biology.He also received numerous teaching University.where he has been on the faculty awards.including the W.Barry Wood Teaching since 1976.He received his M.D.from Harvard Award (selected by medical students).the graduate Medical School.Professor stryer has received many Student Teaching Award,and the Professor's Teaching wards for his research on the interplay of light and for the nces. oauth life,including the Eli Lilly Award fo Fund with Stephen J.Lippard,of the textbook Principles of menta Research in Biological Chemistry,the Distinguished Bioinorganic Chemistry. Inventors Award of the Intellectual Property Owners Association,and election to the National Academy of IOHN L.TYMOCZKO is Towsley Profes Sciences and the American Philosophical Society.He Carleton Colleg whe ere he has taugh as awarded the Nat onal Medal of Science in2006 The publication of his first edition of Biochemistry in Biochemistry Laboratory,Oncogenes and the 1975 transformed the teaching of biochemistry

iv JEREMY M. BERG received his B.S. and M.S. degrees in Chemistry from Stanford (where he did research with Keith Hodgson and Lubert Stryer) and his Ph.D. in Chemistry from Harvard with Richard Holm. He then completed a postdoctoral fellowship with Carl Pabo in Biophysics at Johns Hopkins University School of Medicine. He was an Assistant Professor in the Department of Chemistry at Johns Hopkins from 1986 to 1990. He then moved to Johns Hopkins University School of Medicine as Professor and Director of the Department of Biophysics and Biophysical Chemistry, where he remained until 2003. He then became Director of the National Institute of General Medical Sciences at the National Institutes of Health. In 2011, he moved to the University of Pittsburgh where he is now Professor of Computational and Systems Biology and Pittsburgh Foundation Professor and Director of the Institute for Personalized Medicine. He served as President of the American Society for Biochemistry and Molecular Biology from 2011–2013. He is a Fellow of the American Association for the Advancement of Science and a member of the Institute of Medicine of the National Academy of Sciences. He received the American Chemical Society Award in Pure Chemistry (1994) and the Eli Lilly Award for Fundamental Research in Biological Chemistry (1995), was named Maryland Outstanding Young Scientist of the Year (1995), received the Harrison Howe Award (1997), and received public service awards from the Biophysical Society, the American Society for Biochemistry and Molecular Biology, the American Chemical Society, and the American Society for Cell Biology. He also received numerous teaching awards, including the W. Barry Wood Teaching Award (selected by medical students), the Graduate Student Teaching Award, and the Professor’s Teaching Award for the Preclinical Sciences. He is coauthor, with Stephen J. Lippard, of the textbook Principles of Bioinorganic Chemistry. JOHN L. TYMOCZKO is Towsley Professor of Biology at Carleton College, where he has taught since 1976. He currently teaches Biochemistry, Biochemistry Laboratory, Oncogenes and the Molecular Biology of Cancer, and Exercise Biochemistry and coteaches an introductory course, Energy Flow in Biological Systems. Professor Tymoczko received his B.A. from the University of Chicago in 1970 and his Ph.D. in Biochemistry from the University of Chicago with Shutsung Liao at the Ben May Institute for Cancer Research. He then had a postdoctoral position with Hewson Swift of the Department of Biology at the University of Chicago. The focus of his research has been on steroid recep￾tors, ribonucleoprotein particles, and proteolytic processing enzymes. GREGORY J. GATTO, JR., received his A.B. degree in Chemistry from Princeton University, where he worked with Martin F. Semmelhack and was awarded the Everett S. Wallis Prize in Organic Chemistry. In 2003, he received his M.D. and Ph.D. degrees from the Johns Hopkins University School of Medicine, where he studied the structural biology of peroxisomal targeting signal recognition with Jeremy M. Berg and received the Michael A. Shanoff Young Investigator Research Award. He completed a postdoctoral fellowship in 2006 with Christopher T. Walsh at Harvard Medical School, where he studied the biosynthesis of the macrolide immunosuppres￾sants. He is currently a Senior Scientific Investigator in the Heart Failure Discovery Performance Unit at GlaxoSmithKline. LUBERT STRYER is Winzer Professor of Cell Biology, Emeritus, in the School of Medicine and Professor of Neurobiology, Emeritus, at Stanford University, where he has been on the faculty since 1976. He received his M.D. from Harvard Medical School. Professor Stryer has received many awards for his research on the interplay of light and life, including the Eli Lilly Award for Fundamental Research in Biological Chemistry, the Distinguished Inventors Award of the Intellectual Property Owners’ Association, and election to the National Academy of Sciences and the American Philosophical Society. He was awarded the National Medal of Science in 2006. The publication of his first edition of Biochemistry in 1975 transformed the teaching of biochemistry. ABOUT THE AUTHORS

PREFACE ryaee students can see how biochemistry works in the body and under different conditions,and Clinical are stu elping nev stry i Evolutionary perspective.Dis cussions of evolution ewoven into the h ext,Just as evolu To complement the straightforward language and organization of concepts in the text,figures illustrate lar eyo milesto in the evolution of life as a way to provide context for the cesses and molecules being discussed.(For a full list,see p.x) Physiological relevance.It has always been ou goal to help students connect biochemistry to thei practice Every apt own lives on a variety of scales.Pathways and pro- tudents to r cesses are presented in a physiological context so skills and appl the concents described in the text End-of-chant 100% 004 problems are divided into three categories to address blem-solving skills:Mechanism prob ems a stu s to suggest or describe a ch emica con 50% ire studen s to co chapters.Further problem-solvin is pro vided online,on the Biochemistry LaunchPad.(For more details on LaunchPad resources.see p.viii) A variety of molecular st ures all molecular uctures in the book with few e ceptions,have been selected and rendered by Jeremy Berg and Gregory Gatto to emphasize the aspect of structure most impor. 10 tant to the topic at hand.Students are introduced to real sicrenderingsofmolcudlsthroughamoleculg in the appendi ces to( tey are wel olicitly to the key fea of a model tation of fuels use as a funct (幼 and often include pDB numbers so the reader can bic exercise inte eased exerc se inte access the file used in generating the structure from the Protein Data Bank website(www.pdb.org).Students

v For several generations of students and teachers, Biochemistry has been an invaluable resource, pre￾senting the concepts and details of molecular structure, metabolism, and laboratory techniques in a streamlined and engaging way. Biochemistry’s success in helping students learn the subject for the first time is built on a number of hallmark features: • Clear writing and simple illustrations. The lan￾guage of biochemistry is made as accessible as possi￾ble for students learning the subject for the first time. To complement the straightforward language and organization of concepts in the text, figures illustrate a single concept at a time to help students see main points without the distraction of excess detail. • Physiological relevance. It has always been our goal to help students connect biochemistry to their own lives on a variety of scales. Pathways and pro￾cesses are presented in a physiological context so students can see how biochemistry works in the body and under different conditions, and Clinical Application sections in every chapter show students how the concepts they are studying impact human health. The eighth edition includes a number of new Clinical Application sections based on recent dis￾coveries in biochemistry and health. (For a full list, see p. xi) • Evolutionary perspective. Discussions of evolution are woven into the narrative of the text, just as evolu￾tion shapes every pathway and molecular structure described in the text. Molecular Evolution sections highlight important milestones in the evolution of life as a way to provide context for the processes and molecules being discussed. (For a full list, see p. x) • Problem-solving practice. Every chapter of Biochemistry provides numerous opportunities for students to practice problem-solving skills and apply the concepts described in the text. End-of-chapter problems are divided into three categories to address different problem-solving skills: Mechanism prob￾lems ask students to suggest or describe a chemical mechanism; Data interpretation problems ask stu￾dents to draw conclusions from data taken from real research papers; and chapter integration problems require students to connect concepts from across chapters. Further problem-solving practice is pro￾vided online, on the Biochemistry LaunchPad. (For more details on LaunchPad resources, see p. viii) • A variety of molecular structures. All molecular structures in the book, with few exceptions, have been selected and rendered by Jeremy Berg and Gregory Gatto to emphasize the aspect of structure most impor￾tant to the topic at hand. Students are introduced to realistic renderings of molecules through a molecular model “primer” in the appendices to Chapters 1 and 2 so they are well-equipped to recognize and interpret the structures throughout the book. Figure legends direct students explicitly to the key features of a model, and often include PDB numbers so the reader can access the file used in generating the structure from the Protein Data Bank website (www.pdb.org). Students RQ A B Maximal aerobic effort Light aerobic effort 100% Carbohydrate utilization 50% 0% 100% Fat utilization 50% 0% 1.0 0.9 0.8 0.7 Figure 27.12 An idealized representation of fuels use as a function of aerobic exercise intensity. (A) With increased exercise intensity, the use of fats as fuels falls as the utilization of glucose increases. (B) The respiratory quotient (RQ) measures the alteration in fuel use. PREFACE

vi Preface 120oA 1000 B 800 Myosin Vdimer 40o 74 nm e300(56 the c 61-2065,2003 plore molecular str es further online thro which ate 3D models watchin of molecules and view alternative renderings Glycosylation functions in nutrient sensing In this revision of Biochemistry.we focused on build- (Chapter 11) ing on the strengths of the previous editions to present .The structure of a SNARE complex(Chapter 12) biochemistry in an even more clear and streamlined The mechanism of ABC transporters(Chapter 13) manner,as well as incorporating exciting new advance from the e field we ha update The structure of the gap junction(Chapter 13) explana ons of basic concepts and b The stru or activation of the B-adrenergic Excessive fructose consumption can lead to patho- Enviror mental factors that influence human logical conditions(Chapter 16) biochemistry (Chapter 1) .Alterations in the glycolytic pathway by cancer cells .Genome editing(Chapter 5) (Chapter 16) Horizontal gene transfer events that may explain unex pected branches of the evolutionary tree(Chapter 6) n a key Control of chloroplast ATP synthase(Chapter 19) .Activation of rubisco by rubisco activase(Chapter 20) omplex brings the

vi Preface can explore molecular structures further online through the Living Figures, in which they can rotate 3D models of molecules and view alternative renderings. In this revision of Biochemistry, we focused on build￾ing on the strengths of the previous editions to present biochemistry in an even more clear and streamlined manner, as well as incorporating exciting new advances from the field. Throughout the book, we have updated explanations of basic concepts and bolstered them with examples from new research. Some new topics that we present in the eighth edition include: • Environmental factors that influence human biochemistry (Chapter 1) • Genome editing (Chapter 5) • Horizontal gene transfer events that may explain unex￾pected branches of the evolutionary tree (Chapter 6) • Penicillin irreversibly inactivating a key enzyme in bacterial cell-wall synthesis (Chapter 8) • Scientists watching single molecules of myosin move (Chapter 9) • Glycosylation functions in nutrient sensing (Chapter 11) • The structure of a SNARE complex (Chapter 12) • The mechanism of ABC transporters (Chapter 13) • The structure of the gap junction (Chapter 13) • The structural basis for activation of the b-adrenergic receptor (Chapter 14) • Excessive fructose consumption can lead to patho￾logical conditions (Chapter 16) • Alterations in the glycolytic pathway by cancer cells (Chapter 16) • Regulation of mitochondrial ATP synthase (Chapter 18) • Control of chloroplast ATP synthase (Chapter 19) • Activation of rubisco by rubisco activase (Chapter 20) Time (sec) 0 10 3020 40 50 60 70 9080 100 110 Position (nm) 1200 1000 800 600 400 200 (A) Catalytic domain Myosin V dimer 74 nm Actin (B) Figure 9.48 Single molecule motion. (A) A trace of the position of a single dimeric myosin V molecule as it moves across a surface coated with actin filaments. (B) A model of how the dimeric molecule moves in discrete steps with an average size of 74 6 5 nm. [Data from A. Yildiz et al., Science 300(5628)2061–2065, 2003.] Figure 12.39 SNARE complexes initiate membrane fusion. The SNARE protein synaptobrevin (yellow) from one membrane forms a tight four-helical bundle with the corresponding SNARE proteins syntaxin-1 (blue) and SNAP25 (red) from a second membrane. The complex brings the membranes close together, initiating the fusion event. [Drawn from 1SFC.pdb.]

Preface vii The role of the pentose phosphate pathway in rapid The role of excess choline in the development of cell growth(Chapter 20) heart disease(Chapter 26) .Biochemical characteristics of muscle fiber types (Chapter 21) .Cycling of the LDLreceptor is regulated(Chapter 26) The role of ceramide metabolism in stimulating .Alteration of fatty acid metabolism in tumor cells tumor growth (Chapter 26) (Chapter 22) The extraordinary power of DNA repair systems .Biochemical basis of neurological symptoms of illustrated by Deinococcus radiodurans(Chapter 28) phenylketonuria(Chapter 24) .Ribonucleotide reductase as a chemotherapeuti &pWdkasafiganbngtyTk target( hapter 25)

Preface vii • The role of the pentose phosphate pathway in rapid cell growth (Chapter 20) • Biochemical characteristics of muscle fiber types (Chapter 21) • Alteration of fatty acid metabolism in tumor cells (Chapter 22) • Biochemical basis of neurological symptoms of phenylketonuria (Chapter 24) • Ribonucleotide reductase as a chemotherapeutic target (Chapter 25) • The role of excess choline in the development of heart disease (Chapter 26) • Cycling of the LDL receptor is regulated (Chapter 26) • The role of ceramide metabolism in stimulating tumor growth (Chapter 26) • The extraordinary power of DNA repair systems illustrated by Deinococcus radiodurans (Chapter 28) • The structural details of ligand binding by TLRs (Chapter 34)

MEDIA AND ASSESSMENT ∞LaunchPad ata.developin conecting dge to real scen ance w All of the new media resources for Biochemistry will be the available in our new system. in the classr oom)and aligned assessment questions www.macmillanhighered.com/launchpad/berg8e for auizzes and exams Newly Updated Clicke LaPad dynamic.fully integrated learnin rings together l of our teaching an students' ce.It ins the full sof Word and orenidentsandins PowerPoint (PPT) Newly Updated Lecture PowerPoints have been NEW Case Studies are a series of biochemistry case studies you can integrate into your course. ed e case study gives students practice in working with ncluding key illu that instructors can adapt to their teaching styles. Updated Layered PPTs dec all and ent comstep-bytp. Updated" xtbook Im es and Tables as high . T to ensure maximum clarity and visibility. The Clinical Co R The L Gregory 0 dent have learned in the book tonove medicalsitu ations.Students read clinical case studies and use basic biochemistry concepts to solve the Hundreds of self-graded practice prob- lems allow students to test their understanding of concepts explained in the text,with immedi ate feedback. The metabolic map helps students under. stand the principles and at oplications of the core metabolic pathways.Students can work through guided tutorials with embedded fAMbyTo-ikec The e side (top)a Jmol tutorials by Jeffrey Cohlberg,California by b es on the side of each of the extracellula State University at long beach.teach students

viii All of the new media resources for Biochemistry will be available in our new system. www.macmillanhighered.com/launchpad/berg8e LaunchPad is a dynamic, fully integrated learning environment that brings together all of our teaching and learning resources in one place. It also contains the fully interactive e-Book and other newly updated resources for students and instructors, including the following: • NEW Case Studies are a series of biochemistry case studies you can integrate into your course. Each case study gives students practice in working with data, developing critical thinking skills, connecting topics, and applying knowledge to real scenarios. We also provide instructional guidance with each case study (with suggestions on how to use the case in the classroom) and aligned assessment questions for quizzes and exams. • Newly Updated Clicker Questions allow instruc￾tors to integrate active learning in the classroom and to assess students’ understanding of key concepts during lectures. Available in Microsoft Word and PowerPoint (PPT). • Newly Updated Lecture PowerPoints have been developed to minimize preparation time for new users of the book. These files offer suggested lectures including key illustrations and summaries that instructors can adapt to their teaching styles. • Updated Layered PPTs deconstruct key concepts, sequences, and processes from the textbook images, allowing instructors to pres￾ent complex ideas step-by-step. • Updated Textbook Images and Tables are offered as high-resolution JPEG files. Each image has been fully optimized to increase type sizes and adjust color saturation. These images have been tested in a large lecture hall to ensure maximum clarity and visibility. • The Clinical Companion, by Gregory Raner, The University of North Carolina at Greensboro and Douglas Root, University of North Texas, applies concepts that students have learned in the book to novel medical situ￾ations. Students read clinical case studies and use basic biochemistry concepts to solve the medical mysteries, applying and reinforcing what they learn in lecture and from the book. • Hundreds of self-graded practice prob￾lems allow students to test their understanding of concepts explained in the text, with immedi￾ate feedback. • The Metabolic Map helps students under￾stand the principles and applications of the core metabolic pathways. Students can work through guided tutorials with embedded assessment questions, or explore the Metabolic Map on their own using the dragging and zooming functionality of the map. • Jmol tutorials by Jeffrey Cohlberg, California State University at Long Beach, teach students MEDIA AND ASSESSMENT Figure 34.3 Recognition of a PAMP by a Toll-like receptor. The structure of TLR3 bound to its PAMP, a fragment of double-stranded RNA, as seen from the side (top) and from above (bottom). Notice that the PAMP induces receptor dimerization by binding the surfaces on the side of each of the extracellular domains. [Drawn from 3CIY.pdb]

how to create models of proteins in Jmol based end-of-chapter questions in the book,giving stu- on data from the Protein Data Bank.By working dents a way to practice applying chapter content in an online environment. stude this i Flashcards are an interactive tool that allows eaTtoue students to study key terms from the book. and function of enzymes LearningCurve is a self-asse ts Living figures allow students to explore protein thei derstan structure in 3-D scanm and rotate th erstanding of mapa the with different display style stick,ribbon,backbone)by means of a user-friendly interface. Updated Student Companion orials by Neil D.Clarke help [1-4641-8803-31 aiti For each chapter of the textbook,the Student Companior cove includes: Chapter Learning Objectives and Summary me ment Probler including multiple proteins choice.short-answer.matching questions,and chal- NEW animations show students biochemical pro- lenge problems,and their answers cesses in motion.The eighth edition includes many ded Solutions to end-of-chapter problems new animations Online end-of-ch stions are assignable ndf-raded ix

ix how to create models of proteins in Jmol based on data from the Protein Data Bank. By working through the tutorial and answering assessment ques￾tions at the end of each exercise, students learn to use this important database and fully realize the relationships between the structure and function of enzymes. • Living figures allow students to explore protein structure in 3-D. Students can zoom and rotate the “live” structures to get a better understanding of their three-dimensional nature and can experiment with different display styles (space-filling, ball-and￾stick, ribbon, backbone) by means of a user-friendly interface. • Concept-based tutorials by Neil D. Clarke help students build an intuitive understanding of some of the more difficult concepts covered in the textbook. • Animated techniques help students grasp experi￾mental techniques used for exploring genes and proteins. • NEW animations show students biochemical pro￾cesses in motion. The eighth edition includes many new animations. • Online end-of-chapter questions are assignable and self-graded multiple-choice versions of the end-of-chapter questions in the book, giving stu￾dents a way to practice applying chapter content in an online environment. • Flashcards are an interactive tool that allows students to study key terms from the book. • LearningCurve is a self-assessment tool that helps students evaluate their progress. Students can test their understanding by taking an online multiple￾choice quiz provided for each chapter, as well as a general chemistry review. Updated Student Companion [1-4641-8803-3] For each chapter of the textbook, the Student Companion includes: • Chapter Learning Objectives and Summary • Self-Assessment Problems, including multiple￾choice, short-answer, matching questions, and chal￾lenge problems, and their answers • Expanded Solutions to end-of-chapter problems in the textbook

MOLECULAR EVOLUTION es or other mo r evolutionary insights Only Lamino acids make up proteins(p.29) Glycogen synthase is homologous to glycogen Why this set of 20 amino acids?(p.35) phosphorylase(p.631) Sickle-cell trait and malaria(p.206 A recurring motif in the activation of carboxyl groups (D.649) Additional human globin genes (p.208) Catalytic triads in hydrolytic enzymes(p.258) Prokaryotic counterparts of the ubiquitin pathway and the proteasome(p.686)】 A family of pyridoxal-dependent enzymes(p.692) Evolution of the urea cycle(p.696) P-loop NTPase domains(p.280 The P-loop NTPase domain in nitrogenase(p.716) Conserved catalytic core in protein kinases (p.298) Conserved amino acids in transaminases determine amino Why do different human blood types exist?(p.331) acid chirality(p.721) Feedback inhibition(p.731) Archaeal membranes(p.346) nthesis(p.749) Ion pumps(p.370 Rib P-type ATPases(p.374) Increase in urate levels during primate evolution (p.761) ATP-binding cassettes(p.374) Deinococcus radiodurans illustrates the power of dna repair systems (p.828) DNA polymerases(p.829) Metabolism in the RNA world (p.444) Thymine and the fidelity of the genetic message(p.849) Why is glucose a prominent fuel?(p.451) Sigma factors in bacterial transcription(p.865) NAD*bindings Similarities in transcription between archaea and eukaryotes (p.876) Evolution of glycolysis and gluconeogenesis(p.487) Evolution of spliceosome-catalyzed splicing(p.888) The a-ketoglutarate dehydrogenase complex(p.505) Classes of aminoacyl-tRNA synthetases(p.901) Domains of succinylCoA synthetase(p.507) Composition of the primordial ribosme(p.903) Evolution of the citric acid cycle(p.516) HomologousG proteins(p.908) Mitochondrial evolution(p.525) A family of proteins with common ligand-binding domains Conserved structure of cytochrome(p.541) (p.930) Common features of AT andGproteins(p.548) The independent evolution of DNA-binding sites of regulatory proteins(p.931) PnCP-)ndb Key principles of gene regulation are similar in bacteria and Related uncoupling proteins(p.556) archaea(p.937) Chloroplast evolution(p.568) CpG islands(p.949) Evolutionary originsof photosynthesis(p.584) onse elements(p.955) Evolution of the C4 pathway (p.601) miRNAs in gene evolution (p.957) The odorant-receptor family (p.963 The relationship of the Calv Photoreceptor evolution(p.973) Increasing sophisti cation of glycogen phosphorylase regulation(p.629) eationship of tubulin to prokaryotic proteins(p.1023) ◆

x Only L amino acids make up proteins (p. 29) Why this set of 20 amino acids? (p. 35) Sickle-cell trait and malaria (p. 206) Additional human globin genes (p. 208) Catalytic triads in hydrolytic enzymes (p. 258) Major classes of peptide-cleaving enzymes (p. 260) Common catalytic core in type II restriction enzymes (p. 275) P-loop NTPase domains (p. 280) Conserved catalytic core in protein kinases (p. 298) Why do different human blood types exist? (p. 331) Archaeal membranes (p. 346) Ion pumps (p. 370) P-type ATPases (p. 374) ATP-binding cassettes (p. 374) Sequence comparisons of Na1 and Ca21 channels (p. 382) Small G proteins (p. 414) Metabolism in the RNA world (p. 444) Why is glucose a prominent fuel? (p. 451) NAD1 binding sites in dehydrogenases (p. 465) Isozymic forms of lactate dehydrogenase (p. 487) Evolution of glycolysis and gluconeogenesis (p. 487) The a-ketoglutarate dehydrogenase complex (p. 505) Domains of succinyl CoA synthetase (p. 507) Evolution of the citric acid cycle (p. 516) Mitochondrial evolution (p. 525) Conserved structure of cytochrome c (p. 541) Common features of ATP synthase and G proteins (p. 548) Pigs lack uncoupling protein 1 (UCP-1) and brown fat (p. 556) Related uncoupling proteins (p. 556) Chloroplast evolution (p. 568) Evolutionary origins of photosynthesis (p. 584) Evolution of the C4 pathway (p. 601) The relationship of the Calvin cycle and the pentose phosphate pathway (p. 610) Increasing sophistication of glycogen phosphorylase regulation (p. 629) Glycogen synthase is homologous to glycogen phosphorylase (p. 631) A recurring motif in the activation of carboxyl groups (p. 649) Prokaryotic counterparts of the ubiquitin pathway and the proteasome (p. 686) A family of pyridoxal-dependent enzymes (p. 692) Evolution of the urea cycle (p. 696) The P-loop NTPase domain in nitrogenase (p. 716) Conserved amino acids in transaminases determine amino acid chirality (p. 721) Feedback inhibition (p. 731) Recurring steps in purine ring synthesis (p. 749) Ribonucleotide reductases (p. 755) Increase in urate levels during primate evolution (p. 761) Deinococcus radiodurans illustrates the power of DNA repair systems (p. 828) DNA polymerases (p. 829) Thymine and the fidelity of the genetic message (p. 849) Sigma factors in bacterial transcription (p. 865) Similarities in transcription between archaea and eukaryotes (p. 876) Evolution of spliceosome-catalyzed splicing (p. 888) Classes of aminoacyl-tRNA synthetases (p. 901) Composition of the primordial ribosome (p. 903) Homologous G proteins (p. 908) A family of proteins with common ligand-binding domains (p. 930) The independent evolution of DNA-binding sites of regulatory proteins (p. 931) Key principles of gene regulation are similar in bacteria and archaea (p. 937) CpG islands (p. 949) Iron-response elements (p. 955) miRNAs in gene evolution (p. 957) The odorant-receptor family (p. 963) Photoreceptor evolution (p. 973) The immunoglobulin fold (p. 988) Relationship of tubulin to prokaryotic proteins (p. 1023) This icon signals the start of the many discussions that highlight protein commonalities or other molecular evolutionary insights. MOLECULAR EVOLUTION

CLINICAL APPLICATIONS sthe sar ofi thetextdtiobrieer clinical correlations appear in the text as appropriate. Osteogenesis imperfecta(p.6) Triose phosphate isomerase deficiency (p.454) Protein-misfolding(.56 Excessive fructose cons mption(p.66) Protein modification and scurvy(p.57) Lactose intolerance (p.467) Antigen/antibody detection with ELISA(p.82) Galactosemia(p.468) Synthetic peptides asdrugs(p.92) Aerobic olycolysis and cancer (p 474) PCR in diagnostics and forensics (p.142) sedeficiency(p.512) Gene therapy (p.164) Aptamers in biotechnology and medicine(p.187) Functional magnetic resonance i imaging(p.193) Beriberi and mercury poisoning(p.515) 2.3-BPG and fetal hemoglobin (p.201) Frataxin mutations cause Friedreich's ataxia(p.531) Carbon monoxide poisoning (p.201) species(ROS)are implicated inavariety Sickle-cell anemia(p.205) Thalassemia(p.207) ROS may be mportant in signal transduction(p.540) Aldehyde dehydrogenase deficiency(p.228) IF1overexpression and cancer(p.554) Brown adipose tissue(p.555) Action of penicillin (p.239) Protease inhibitors (p.263) Mild uncouplers sought as drugs(p.557) Carbonic anhydrase Mitochondrial diseases(p.557) Isozymes as a sign of tissue damage (p.293) Trypsin inhibitor helps prevent pancreatic damage(p.302) Gluc Emphysema(p.303) p.303) ing involv ade of zymogen activations Developing drugs for type 2 diabetes (p.636) Vitamin K(p.306) Glycogen-storage diseases(p.637) Chanarin-Dorfman syndrome(.648) Antithrombin and hemorrhage (p.307) Carnitine deficiency (p.650) Hemophilia(p.308) Zellweger syndrome (p.657 Monitoring change glycosylated hemoglobin(p.321) Diabetic ketosis(p.659) Erythropoietin(p.327 Ketogenic diets to treat epilepsy (p.660) Hurler disease(p.327) Mucins(p.329) p.661 acids may contribute to pathological conditions Blood g groups(p.331) I-cell disease(p.332) Influenza virus binding(p.335) Effects of aspirin on signaling pathways(p.669) Clinical applications of lipo es(p.349) Diseases resulting from defects in transporters of amino Aspirin and ibuprofen (p.353) acids(p.682) Diseases resulting from defects in E3 proteins(p.685) Digitalis and congestive heart failure(p.373) Multidrug resistance (p 374) Drugs target the ubiquitin-proteasome system(p.687) Long OT syndrome(p.388) Using pro tuberculosis(p.687) Signal-transduction pathways and cancer (p.416) Monoclonal antibodies as anticancer drugs(p.416) Inherited defects of the urea cycle(hyperammonemia) Protein kinase inhibitors as anticancer drugs(p.417) (p.697) G-proteins,cholera and whooping cough(p.417) Alcaptonuria,maple syrup urine disease,and Vitamins(p.438) phenylketonuria (p.705)

xi Osteogenesis imperfecta (p. 46) Protein-misfolding diseases (p. 56) Protein modification and scurvy (p. 57) Antigen/antibody detection with ELISA (p. 82) Synthetic peptides as drugs (p. 92) PCR in diagnostics and forensics (p.142) Gene therapy (p. 164) Aptamers in biotechnology and medicine (p. 187) Functional magnetic resonance imaging (p. 193) 2,3-BPG and fetal hemoglobin (p. 201) Carbon monoxide poisoning (p. 201) Sickle-cell anemia (p. 205) Thalassemia (p. 207) Aldehyde dehydrogenase deficiency (p. 228) Action of penicillin (p. 239) Protease inhibitors (p. 263) Carbonic anhydrase and osteopetrosis (p. 264) Isozymes as a sign of tissue damage (p. 293) Trypsin inhibitor helps prevent pancreatic damage (p. 302) Emphysema (p. 303) Blood clotting involves a cascade of zymogen activations (p. 303) Vitamin K (p. 306) Antithrombin and hemorrhage (p. 307) Hemophilia (p.308) Monitoring changes in glycosylated hemoglobin (p. 321) Erythropoietin (p. 327) Hurler disease (p. 327) Mucins (p. 329) Blood groups (p. 331) I-cell disease (p. 332) Influenza virus binding (p. 335) Clinical applications of liposomes (p. 349) Aspirin and ibuprofen (p. 353) Digitalis and congestive heart failure (p. 373) Multidrug resistance (p. 374) Long QT syndrome (p. 388) Signal-transduction pathways and cancer (p. 416) Monoclonal antibodies as anticancer drugs (p. 416) Protein kinase inhibitors as anticancer drugs (p. 417) G-proteins, cholera and whooping cough (p. 417) Vitamins (p. 438) Triose phosphate isomerase deficiency (p. 454) Excessive fructose consumption (p. 466) Lactose intolerance (p. 467) Galactosemia (p. 468) Aerobic glycolysis and cancer (p. 474) Phosphatase deficiency (p. 512) Defects in the citric acid cycle and the development of cancer (p. 513) Beriberi and mercury poisoning (p. 515) Frataxin mutations cause Friedreich’s ataxia (p. 531) Reactive oxygen species (ROS) are implicated in a variety of diseases (p. 539) ROS may be important in signal transduction (p. 540) IF1 overexpression and cancer (p. 554) Brown adipose tissue (p. 555) Mild uncouplers sought as drugs (p.557) Mitochondrial diseases (p. 557) Glucose 6-phosphate dehydrogenase deficiency causes drug-induced hemolytic anemia (p. 610) Glucose 6-phosphate dehydrogenase deficiency protects against malaria (p. 612) Developing drugs for type 2 diabetes (p. 636) Glycogen-storage diseases (p. 637) Chanarin-Dorfman syndrome (p. 648) Carnitine deficiency (p. 650) Zellweger syndrome (p. 657) Diabetic ketosis (p. 659) Ketogenic diets to treat epilepsy (p. 660) Some fatty acids may contribute to pathological conditions (p. 661) The use of fatty acid synthase inhibitors as drugs (p. 667) Effects of aspirin on signaling pathways (p. 669) Diseases resulting from defects in transporters of amino acids (p. 682) Diseases resulting from defects in E3 proteins (p. 685) Drugs target the ubiquitin-proteasome system (p.687) Using proteasome inhibitors to treat tuberculosis (p. 687) Blood levels of aminotransferases indicate liver damage (p. 691) Inherited defects of the urea cycle (hyperammonemia) (p. 697) Alcaptonuria, maple syrup urine disease, and phenylketonuria (p. 705) CLINICAL APPLICATIONS This icon signals the start of a clinical application in the text. Additional, briefer clinical correlations appear in the text as appropriate

High homocysteine levels and vascular disease(p.726) The brain plays a key role in caloric homeostasis(p.804) Inherited disorders of porphyrin metabolism(p.737) Diabetes is a common metabolic disease often resulting Anticancer drugs that block the synthesis of thymidylate from obesity (p.807) (p.757) Exercise beneficially alters the biochemistry of cells(p.813) Ribonucleotide reductase is a target for cancer therapy Food intake and starvation induce metabolic changes(p.816) (p.759) Ethanol atersenergy metabolism in the liver(p.81) Adenosine deaminase and severe combined immunodefi- ciency (p.760) Antibiotics that target DNA gyrase(p.839) Gout(p.761) Blocking telomerase to treat cancer(p.845) Lesch-Nyhan syndrome(p.761) Huntington disease(p.850) Defective repair of DNA and cancer(p.850) Folic acid and spina bifida (p.762) Detection of carcinogens (Ames test)(p.852) Enzyme activation in some cancers to generate phospho choline(p.770) Translocations can result in diseases(p.855) Excess choline and heart disease(p.771) Antibiotic inhibitors of transcription(p.869) Gangliosides and cholera(p.773) Burkitt lymphoma and B-cell leukemia(p.876 Diseases of defective RNA splicing(p.884) Vanishing white matter disease(p.913) Respiratory distress syndrome and Tay-Sachs disease(p.774) Antibiotics that inhibit protein synthesis(p.914) Ceramide metabolism stimulates tumor growth(p.775) Diphtheria(.14) Phosphatidic acid phosphatase and lipodystrophy (p.776) Ricin,a lethal protein-synthesis inhibitor(p.915) erosis(p.78 Induced pluripotent stem cells(p.947) Mutations in the LDL receptor(p.785) Anabolic steroids(p.951) LDL receptor cycling is regulated(p.787) Color blindness(p.97) The role of HDLin protecting against(p.787) The use of capsaicin in pain management(p.978) Clinical management of cholesterol levels(p.788) Immune-system suppressants(p.994) Bile salts are derivatives of cholesterol (p.789) MHCand transplantation rejection (p.1002) The cytochrome P450 system is protective(p.791) AIDS(p.1003 Autoimmune diseases(p.1005) Immune system and cancer(p.1005) A tase inhibitors in the trea east and ovariar cancer (n 794) Charcot-Marie-Tooth disease(p.1022) Rickets and vitamin D(p.795) Taxol (p.1023) meostasis is a means of regulating body weight

xii High homocysteine levels and vascular disease (p. 726) Inherited disorders of porphyrin metabolism (p. 737) Anticancer drugs that block the synthesis of thymidylate (p. 757) Ribonucleotide reductase is a target for cancer therapy (p. 759) Adenosine deaminase and severe combined immunodefi￾ciency (p. 760) Gout (p. 761) Lesch–Nyhan syndrome (p. 761) Folic acid and spina bifida (p. 762) Enzyme activation in some cancers to generate phospho￾choline (p. 770) Excess choline and heart disease (p. 771) Gangliosides and cholera (p. 773) Second messengers derived from sphingolipids and diabetes (p. 773) Respiratory distress syndrome and Tay–Sachs disease (p. 774) Ceramide metabolism stimulates tumor growth (p. 775) Phosphatidic acid phosphatase and lipodystrophy (p. 776) Hypercholesterolemia and atherosclerosis (p. 784) Mutations in the LDL receptor (p. 785) LDL receptor cycling is regulated (p. 787) The role of HDL in protecting against arteriosclerosis (p. 787) Clinical management of cholesterol levels (p. 788) Bile salts are derivatives of cholesterol (p. 789) The cytochrome P450 system is protective (p. 791) A new protease inhibitor also inhibits a cytochrome P450 enzyme (p. 792) Aromatase inhibitors in the treatment of breast and ovarian cancer (p. 794) Rickets and vitamin D (p. 795) Caloric homeostasis is a means of regulating body weight (p. 802) The brain plays a key role in caloric homeostasis (p. 804) Diabetes is a common metabolic disease often resulting from obesity (p. 807) Exercise beneficially alters the biochemistry of cells (p. 813) Food intake and starvation induce metabolic changes (p. 816) Ethanol alters energy metabolism in the liver (p. 819) Antibiotics that target DNA gyrase (p. 839) Blocking telomerase to treat cancer (p. 845) Huntington disease (p. 850) Defective repair of DNA and cancer (p. 850) Detection of carcinogens (Ames test) (p. 852) Translocations can result in diseases (p. 855) Antibiotic inhibitors of transcription (p. 869) Burkitt lymphoma and B-cell leukemia (p. 876) Diseases of defective RNA splicing (p. 884) Vanishing white matter disease (p. 913) Antibiotics that inhibit protein synthesis (p. 914) Diphtheria (p. 914) Ricin, a lethal protein-synthesis inhibitor (p. 915) Induced pluripotent stem cells (p. 947) Anabolic steroids (p. 951) Color blindness (p. 974) The use of capsaicin in pain management (p. 978) Immune-system suppressants (p. 994) MHC and transplantation rejection (p. 1002) AIDS (p. 1003) Autoimmune diseases (p. 1005) Immune system and cancer (p. 1005) Vaccines (p. 1006) Charcot-Marie-Tooth disease (p. 1022) Taxol (p. 1023)