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 receptors, 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 immunosuppressants. 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, presenting 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 language of biochemistry is made as accessible as possible 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 processes 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 discoveries 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 evolution 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 problems ask students to suggest or describe a chemical mechanism; Data interpretation problems ask students 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 provided 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 important 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 building 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 unexpected 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 pathological 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)