《生物化学》课程教学资源（书籍文献）经典教材 Lehninger Principles of Biochemistry, SIXTH EDITION, David L. Nelson, Michael M. Cox

Lehninger SIXTH EDITION Principles of Biochemistry David L.Nelson Michael M.Cox

Media Connections www.courses.bfwpub.com/lehninger6e Binding Curve for Myoglobin .Technique Animations(10 total)reveal the Molecular Structure Tutorial:Oxygen-Binding experimental techniques available to Proteins-Hemoglobin:Oxygen Transport researchers today Living Graphs(15 total)allow students to onddin alter the parameters in key equations and Hill Equation graph the results. re Tutorials Molecular Structure Tutorials (9 total)guide mm -Defects in Hb Lead MHC Molecules Technique Animation:Immunoblotting selbalch Equation Chapter 6 Enzymes pan Competitive Inhibitor Architecture-Amino Acids Uncompetitive Inhibitor Technique Animation:SDS Gel Electrophoresis Mixed Inhibitor ure of Proteins Mechanism Animation:Chymotrypsin Mechanism Protein Architecture Sequence and Primary Living Graph:Lineweaver-Burk Equation Structure Protein Architecture. The a Helis Protein Architecture-The B Sheet ing Blocks of Amino Acids Protein ArchitectureTurn Protein architecture -Introduction to Tertiary Technique Animation:Dideoxy Sequencing of DNA -Tertiary Structure of Endonucleases mations Protein Architecture-Tertiary Structure of Large Globular Proteins Reporter Constructs Protein Architecture-Quaterary Structure Polymerase Chain Reaction

Media Connections Below is a chapter-by-chapter list of the media resources available on the Instructor’s CD-ROM and website www.courses.bfwpub.com/lehninger6e. • Mechanism Animations (12 total) show key reactions in detail. • Technique Animations (10 total) reveal the experimental techniques available to researchers today. • Living Graphs (15 total) allow students to alter the parameters in key equations and graph the results. • Molecular Structure Tutorials (9 total) guide students through concepts using three￾dimensional molecular models. New animations will be added throughout the life of the edition. Chapter 2 Water Living Graph: Henderson-Hasselbalch Equation Chapter 3 Amino Acids, Peptides, and Proteins Molecular Structure Tutorials: Protein Architecture—Amino Acids Technique Animation: SDS Gel Electrophoresis Chapter 4 The Three-Dimensional Structure of Proteins Molecular Structure Tutorials: Protein Architecture—Sequence and Primary Structure Protein Architecture—The Helix Protein Architecture—The Sheet Protein Architecture—Turn Protein Architecture—Introduction to Tertiary Structure Protein Architecture—Tertiary Structure of Fibrous Proteins Protein Architecture—Tertiary Structure of Small Globular Proteins Protein Architecture—Tertiary Structure of Large Globular Proteins Protein Architecture—Quaternary Structure Chapter 5 Protein Function Molecular Structure Tutorial: Oxygen-Binding Proteins—Myoglobin: Oxygen Storage Living Graphs: Protein-Ligand Interactions Binding Curve for Myoglobin Molecular Structure Tutorial: Oxygen-Binding Proteins—Hemoglobin: Oxygen Transport Living Graphs: Cooperative Ligand Binding Hill Equation Molecular Structure Tutorials: Oxygen-Binding Proteins—Hemoglobin Is Susceptible to Allosteric Regulation Oxygen-Binding Proteins—Defects in Hb Lead to Serious Genetic Disease MHC Molecules Technique Animation: Immunoblotting Chapter 6 Enzymes Living Graphs: Michaelis-Menten Equation Competitive Inhibitor Uncompetitive Inhibitor Mixed Inhibitor Mechanism Animation: Chymotrypsin Mechanism Living Graph: Lineweaver-Burk Equation Chapter 8 Nucleotides and Nucleic Acids Molecular Structure Tutorial: Nucleotides, Build￾ing Blocks of Amino Acids Technique Animation: Dideoxy Sequencing of DNA Chapter 9 DNA-Based Information Technologies Molecular Structure Tutorial: Restriction Endonucleases Technique Animations: Plasmid Cloning Reporter Constructs Polymerase Chain Reaction FEP.indd Page 2 19/10/12 12:57 PM user-F408 /Users/user-F408/Desktop

Synthesizing an Oligonucleotide Array Carbamoyl Phosphate Synthetase I Mechanism Argininosuccinate Synthetase Mechanism Yeast Two-Hybrid Systems Creating a Transgenic Mouse Living Graph:Free-Energy Change for Chapter Membranes and Transport Transport of an Ion Molecular Structure Tutorial:Bacteriorhodopsir Change for Transport Free-Energy Change for Transport of an Ion ChapterCarbohydrate Biosynthesisin Molecular On/Off Switches Chapter 22 Biosynthesis of Amino Acids,Nucleotides, and Related Molecules Mechanism Animations: ic nd Biode mica ea Tryptophan Synthase Mechanism Thymidylate Synthase Mechanism Free-Energy of Hydrolysis of ATP 0m050 onal Packaging of Mechanism Animations Phosphohexose Isomerase Mechanism Chapter 25 DNA Metabolism Alcohol Dehydrogenase Mechanism Molecular Structure Tutorial:Restriction Endonucleases Thiamine Pyrophosphate Mechanism Animation: ihtRraiCaecaaiesnhae Nucleotide Polymerization by DNA Polymerase DNA Synthesis Mechanism Chapter 26 RNA Metabolism Animation:mRNA Splicing Molecular Structure Tutorial:Hammerhead Ribozvme Animation:Life Cvcle of an mRNA Chapter18Amino Acid xidationand therodf rea Mechanism Animations: Pyridoxal Phosphate Reaction Mechanism

Synthesizing an Oligonucleotide Array Screening an Oligonucleotide Array for Patterns of Gene Expression Yeast Two-Hybrid Systems Creating a Transgenic Mouse Chapter 11 Biological Membranes and Transport Living Graphs: Free-Energy Change for Transport Free-Energy Change for Transport of an Ion Chapter 12 Biosignaling Molecular Structure Tutorial: Trimeric G Proteins— Molecular On/Off Switches Chapter 13 Bioenergetics and Biochemical Reaction Types Living Graphs: Free-Energy Change Free-Energy of Hydrolysis of ATP Chapter 14 Glycolysis, Gluconeogenesis, and the Pentose Phosphate Pathway Mechanism Animations: Phosphohexose Isomerase Mechanism Alcohol Dehydrogenase Mechanism Thiamine Pyrophosphate Mechanism Chapter 16 The Citric Acid Cycle Mechanism Animation: Citrate Synthase Mechanism Chapter 17 Fatty Acid Catabolism Mechanism Animation: Fatty Acyl–CoA Synthetase Mechanism Chapter 18 Amino Acid Oxidation and the Production of Urea Mechanism Animations: Pyridoxal Phosphate Reaction Mechanism Carbamoyl Phosphate Synthetase I Mechanism Argininosuccinate Synthetase Mechanism Chapter 19 Oxidative Phosphorylation and Photophosphorylation Living Graph: Free-Energy Change for Transport of an Ion Molecular Structure Tutorial: Bacteriorhodopsin Chapter 20 Carbohydrate Biosynthesis in Plants and Bacteria Mechanism Animation: Rubisco Mechanism Chapter 22 Biosynthesis of Amino Acids, Nucleotides, and Related Molecules Mechanism Animations: Tryptophan Synthase Mechanism Thymidylate Synthase Mechanism Chapter 24 Genes and Chromosomes Animation: Three-Dimensional Packaging of Nuclear Chromosomes Chapter 25 DNA Metabolism Molecular Structure Tutorial: Restriction Endonucleases Animation: Nucleotide Polymerization by DNA Polymerase DNA Synthesis Chapter 26 RNA Metabolism Animation: mRNA Splicing Molecular Structure Tutorial: Hammerhead Ribozyme Animation: Life Cycle of an mRNA Chapter 28 Regulation of Gene Expression Molecular Structure Tutorial: Lac Repressor FEP.indd Page 3 19/10/12 12:57 PM user-F408 /Users/user-F408/Desktop

Lehninger Principles of Biochemistry SIXTH EDITION David L.Nelson Michael M.Cox Professor of Biochemistry Professor of Biochemistry University of Wisconsin-Madison University of Wisconsin-Madisor W.H.FREEMAN AND COMPANY-New York

FMTOC.indd Page i 11/10/12 9:54 AM user-F408 /Users/user-F408/Desktop Lehninger Principles of Biochemistry David L. Nelson Professor of Biochemistry University of Wisconsin–Madison Michael M. Cox Professor of Biochemistry University of Wisconsin–Madison SIXTH EDITION W. H. FREEMAN AND COMPANY • New York

About the Authors David L.Nelson.bom in fairmont.minnes of th full professor of biochemistry in 1982.He was for eight years the Director of the Center for Biology Education at th the signal tran ductions that regulate ciliary motion and exocytosis the protozoan Paramec The enzymes of signa nvid L.Nelson and Michael M.Co denyme purification,mm Dave Nelson has a distinguished record as a lec particularly on the RecA protein,designing purificatior turer and research supervisor.For 40 years he has and assay methods that are still in use,and illuminating has also taught a survey of biochemistry for nursing central theme of his research graduate cou g. top honors theses and has re for his outstand focus has been the mechanism of RecA protein mediated ing te acher-Schola DNA ange,the role ATP in he RecA sya the Unterkofler Excellence in Teaching Award from the Part of the research program now focuses on organisms University of Wisconsin System.In 199 -1992 he was a has pegun to teach the histor of biochemistr to under For almost 30 rs he has taught (with Dave Nelson)the survey of biochemistry to undergraduates and has ngate S on DNA S Michael M.CoX was born in Wilmington,Delaware.In been the biolog nd in piring hi ogram to draw talente istry.After graduating from the University of Delaware biochemistry undergraduates into the laboratory at ar ersity to do ms early st e of their collegiate He the Dreyfus Teacher-Scholar Award,the 1989 Eli Lilly He moved to the University of Wisco nsin-Madison ir Award in Biological Chemistry and the 2009 Regent 99 3 and became a full pro Cox's doctoral resea rch was on general acid and provide new guidelines for undergraduate biochemistry alyzed reac n ron.H nobbies include turning 18 nd in the

David L. Nelson, born in Fairmont, Minnesota, received his BS in Chemistry and Biology from St. Olaf College in 1964 and earned his PhD in Biochemistry at Stan￾ford Medical School under Arthur Kornberg. He was a postdoctoral fellow at the Harvard Medical School with Eugene P. Kennedy, who was one of Albert Lehninger’s first graduate students. Nelson joined the faculty of the University of Wisconsin–Madison in 1971 and became a full professor of biochemistry in 1982. He was for eight years the Director of the Center for Biology Education at the University of Wisconsin–Madison. Nelson’s research has focused on the signal trans￾ductions that regulate ciliary motion and exocytosis in the protozoan Paramecium. The enzymes of signal transductions, including a variety of protein kinases, are primary targets of study. His research group has used enzyme purification, immunological techniques, electron microscopy, genetics, molecular biology, and electrophysiology to study these processes. Dave Nelson has a distinguished record as a lec￾turer and research supervisor. For 40 years he has taught an intensive survey of biochemistry for advanced biochemistry undergraduates in the life sciences. He has also taught a survey of biochemistry for nursing students, and graduate courses on membrane struc￾ture and function and on molecular neurobiology. He has sponsored numerous PhD, MS, and undergraduate honors theses and has received awards for his outstand￾ing teaching, including the Dreyfus Teacher–Scholar Award, the Atwood Distinguished Professorship, and the Unterkofler Excellence in Teaching Award from the University of Wisconsin System. In 1991–1992 he was a visiting professor of chemistry and biology at Spelman College. His second love is history, and in his dotage he has begun to teach the history of biochemistry to under￾graduates and to collect antique scientific instruments for use in a laboratory course he teaches. Michael M. Cox was born in Wilmington, Delaware. In his first biochemistry course, Lehninger’s Biochemistry was a major influence in refocusing his fascination with biology and inspiring him to pursue a career in biochem￾istry. After graduating from the University of Delaware in 1974, Cox went to Brandeis University to do his doc￾toral work with William P. Jencks, and then to Stanford in 1979 for postdoctoral study with I. Robert Lehman. He moved to the University of Wisconsin–Madison in 1983 and became a full professor of biochemistry in 1992. Cox’s doctoral research was on general acid and base catalysis as a model for enzyme-catalyzed reac￾tions. At Stanford, he began work on the enzymes involved in genetic recombination. The work focused particularly on the RecA protein, designing purification and assay methods that are still in use, and illuminating the process of DNA branch migration. Exploration of the enzymes of genetic recombination has remained the central theme of his research. Mike Cox has coordinated a large and active research team at Wisconsin, investigating the enzymology, topol￾ogy, and energetics of genetic recombination. A primary focus has been the mechanism of RecA protein–mediated DNA strand exchange, the role of ATP in the RecA sys￾tem, and the regulation of recombinational DNA repair. Part of the research program now focuses on organisms that exhibit an especially robust capacity for DNA repair, such as Deinococcus radiodurans, and the applications of those repair systems to biotechnology. For almost 30 years he has taught (with Dave Nelson) the survey of biochemistry to undergraduates and has lectured in graduate courses on DNA structure and topology, protein-DNA interactions, and the bio￾chemistry of recombination. More recent projects have been the organization of a new course on professional responsibility for first-year graduate students and the establishment of a systematic program to draw talented biochemistry undergraduates into the laboratory at an early stage of their collegiate career. He has received awards for both his teaching and his research, including the Dreyfus Teacher–Scholar Award, the 1989 Eli Lilly Award in Biological Chemistry, and the 2009 Regents Teaching Excellence Award from the University of Wisconsin. He is also highly active in national efforts to provide new guidelines for undergraduate biochemistry education. His hobbies include turning 18 acres of Wis￾consin farmland into an arboretum, wine collecting, and assisting in the design of laboratory buildings. About the Authors David L. Nelson and Michael M. Cox iv FMTOC.indd Page iv 10/10/12 7:30 AM user-F408 /Users/user-F408/Desktop

A Note on the Nature of Science ideas that a sciont report these ob ervations with complete honesty. c met Is a ny a colle scientific method. othesis and er iment path,a scientist poses a Seience is both a way of thinking about the natura hypothesis,then subjects it toexperimental test.Many of such thinking.The and st science now directly from its reliance on ideas that car by James Watson and francis Crick led to the hypothesis that have predictive ress of science rests the discovery of DNA and RNA o on a found ational assumption that is often unstated but Watson and Crick produced their DNA structure through a process of building and calculations used data collected by othe to this underlying assumption as the scientists.Many be method of dis Science could not succeed in a universe that played 1831 voyage on HM.S Beagle among them)helped to cata log its the can be reproducibly substantiated and(2)can be used launch pr to ther planets An analog of hypothesis s that sci and exper nent I and ded tated translation or the information in me ger RN different from those applied by no Not but it may lack extensive experimental substantiation ity often plays a role. The than a hunch.It i and of I catalysts by Thoma oberyanons t on an red to exploit them tion can also lead to important advances.The polymeras is thus a s for further advance hain reaction (PCR a central part of bi dated on many fronts.it can be accept d as a fact during a road trip in northern Califomia in 1983. In one what nstitutes science se man paths to oscientific discovery ca n seen or y whe er or not it blishad in th peer-revie rely on rep scientific jourals worldwid e pu ush some 1.4 millior of the ideas. insights,and experimental acts tha orma tion that is the birthright of ev human being by scientists anywhere in the world.All can be Scientists are individuals who rigorously apply Iby other scientists to build new hypotheses and the nake A lead to inlorm Ton tha pline does not make one a scientist.nor does the lack ing our universe requires hard work.At the same time of such a degree prevent one from making important no human endeavor is more exciting and potentially The eding,t nd it

I n this twenty-first century, a typical science education often leaves the philosophical underpinnings of sci￾ence unstated, or relies on oversimplified definitions. As you contemplate a career in science, it may be useful to consider once again the terms science, scientist, and scientific method. Science is both a way of thinking about the natural world and the sum of the information and theory that result from such thinking. The power and success of science flow directly from its reliance on ideas that can be tested: information on natural phenomena that can be observed, measured, and reproduced and theories that have predictive value. The progress of science rests on a foundational assumption that is often unstated but crucial to the enterprise: that the laws governing forces and phenomena existing in the universe are not subject to change. The Nobel laureate Jacques Monod referred to this underlying assumption as the “postulate of objec￾tivity.” The natural world can therefore be understood by applying a process of inquiry—the scientific method. Science could not succeed in a universe that played tricks on us. Other than the postulate of objectivity, sci￾ence makes no inviolate assumptions about the natural world. A useful scientific idea is one that (1) has been or can be reproducibly substantiated and (2) can be used to accurately predict new phenomena. Scientific ideas take many forms. The terms that sci￾entists use to describe these forms have meanings quite different from those applied by nonscientists. A hypoth￾esis is an idea or assumption that provides a reasonable and testable explanation for one or more observations, but it may lack extensive experimental substantiation. A scientific theory is much more than a hunch. It is an idea that has been substantiated to some extent and provides an explanation for a body of experimental observations. A theory can be tested and built upon and is thus a basis for further advance and innovation. When a scientific theory has been repeatedly tested and vali￾dated on many fronts, it can be accepted as a fact. In one important sense, what constitutes science or a scientific idea is defined by whether or not it is published in the scientific literature after peer review by other working scientists. About 16,000 peer-reviewed scientific journals worldwide publish some 1.4 million articles each year, a continuing rich harvest of informa￾tion that is the birthright of every human being. Scientists are individuals who rigorously apply the scientific method to understand the natural world. Merely having an advanced degree in a scientific disci￾pline does not make one a scientist, nor does the lack of such a degree prevent one from making important scientific contributions. A scientist must be willing to challenge any idea when new findings demand it. The ideas that a scientist accepts must be based on measur￾able, reproducible observations, and the scientist must report these observations with complete honesty. The scientific method is actually a collection of paths, all of which may lead to scientific discovery. In the hypothesis and experiment path, a scientist poses a hypothesis, then subjects it to experimental test. Many of the processes that biochemists work with every day were discovered in this manner. The DNA structure elucidated by James Watson and Francis Crick led to the hypothesis that base pairing is the basis for information transfer in polynucleotide synthesis. This hypothesis helped inspire the discovery of DNA and RNA polymerases. Watson and Crick produced their DNA structure through a process of model building and calculation. No actual experiments were involved, although the model building and calculations used data collected by other scientists. Many adventurous scientists have applied the process of exploration and observation as a path to dis￾covery. Historical voyages of discovery (Charles Darwin’s 1831 voyage on H.M.S. Beagle among them) helped to map the planet, catalog its living occupants, and change the way we view the world. Modern scientists follow a similar path when they explore the ocean depths or launch probes to other planets. An analog of hypothesis and experiment is hypothesis and deduction. Crick rea￾soned that there must be an adaptor molecule that facili￾tated translation of the information in messenger RNA into protein. This adaptor hypothesis led to the discovery of transfer RNA by Mahlon Hoagland and Paul Zamecnik. Not all paths to discovery involve planning. Serendip￾ity often plays a role. The discovery of penicillin by Alex￾ander Fleming in 1928 and of RNA catalysts by Thomas Cech in the early 1980s were both chance discoveries, albeit by scientists well prepared to exploit them. Inspira￾tion can also lead to important advances. The polymerase chain reaction (PCR), now a central part of biotechnology, was developed by Kary Mullis after a flash of inspiration during a road trip in northern California in 1983. These many paths to scientific discovery can seem quite different, but they have some important things in common. They are focused on the natural world. They rely on reproducible observation and/or experiment. All of the ideas, insights, and experimental facts that arise from these endeavors can be tested and repro￾duced by scientists anywhere in the world. All can be used by other scientists to build new hypotheses and make new discoveries. All lead to information that is properly included in the realm of science. Understand￾ing our universe requires hard work. At the same time, no human endeavor is more exciting and potentially rewarding than trying, and occasionally succeeding, to understand some part of the natural world. A Note on the Nature of Science v FMTOC.indd Page v 10/10/12 7:30 AM user-F408 /Users/user-F408/Desktop

Preface A,ometeronth施sixth oition of to the molecular mechanisms of disease.highlighting the cing huma sand the f volume of new information from high-throughput DNA This theme is interwoven through many chapters and sequencing.,and the manipulatio serves to integrate the discussion of metabo sm.We alsc bioche stry student.Our goal here is to strike a balance toinclude and exciting ings withou ole in our ais in bic chemistry runs in parallel with the development o pet trate an important principle of bioche ter tools and techniques.We have therefore highlighte in a eoea Based tnfo richness of factual material now available about bio significantly revised to include the latest advances in mation no longe meta genomics and next-generation sequencing single metabolite ay he ,1 art of ma g the text and the art pathways in a thre lim onal network of metaboli dents learing biochemistry for the first time.To thos the book, e of these changes will be With everyre on of this texthook we have striver the effe of regulation upon the activities that made to on the new material that we have added reflects our incre of the ways in which biochemistry is understood and tory mecha today.The authors have ng the ritten together for and their degr dati ble fo ether w300 sands of students at the the control and timing of DNA synthesis and the cell University of Wisconsin-Madison over those years have se tha integrate the meta lism of car peen an endless sou of ideas about to prese changes in the environment and in different cell types inspired us.We hope that this sixth edition ofe majo will in turn enlighten and inspire current students of bio perhaps lea d some of them to New Art The most obvious change to the book is the mped art program. drawing on modemn graphic resources to our subject as clear as humanly possible.Many od in style.Defining features of the new art program include: Smarter renditions of classic figures are easier to interpret and learn from;

vi As we complete our work on this sixth edition of Lehninger Principles of Biochemistry, we are again struck by the remarkable changes in the field of biochem￾istry that have occurred between editions. The sheer volume of new information from high-throughput DNA sequencing, x-ray crystallography, and the manipulation of genes and gene expression, to cite only three examples, challenges both the seasoned researcher and the first-time biochemistry student. Our goal here is to strike a balance: to include new and exciting research findings without making the book overwhelming for students. The primary criterion for inclusion is that the new finding helps to illus￾trate an important principle of biochemistry. The image on our cover, a map of the known meta￾bolic transformations in a mitochondrion, illustrates the richness of factual material now available about bio￾chemical transformations. We can no longer treat meta￾bolic “pathways” as though they occurred in isolation; a single metabolite may be simultaneously part of many pathways in a three-dimensional network of metabolic transformations. Biochemical research focuses more and more upon the interactions among these pathways, the regulation of their interactions at the level of gene and protein, and the effects of regulation upon the activities of a whole cell or organism. This edition of LPOB reflects these realities. Much of the new material that we have added reflects our increas￾ingly sophisticated understanding of regulatory mecha￾nisms, including those involved in altering the synthesis of enzymes and their degradation, those responsible for the control and timing of DNA synthesis and the cell cycle, and those that integrate the metabolism of car￾bohydrates, fats, and proteins over time in response to changes in the environment and in different cell types. Even as we strive to incorporate the latest major advances, certain hallmarks of the book remain unchanged. We continue to emphasize the relevance of biochemistry to the molecular mechanisms of disease, highlighting the special role that biochemistry plays in advancing human health and welfare. A special theme is the metabolic basis of diabetes and the factors that predispose to the disease. This theme is interwoven through many chapters and serves to integrate the discussion of metabolism. We also underscore the importance of evolution to biochemistry. Evolutionary theory is the bedrock upon which all biologi￾cal sciences rest, and we have not wasted opportunities to highlight its important role in our discipline. To a significant degree, research progress in bio￾chemistry runs in parallel with the development of bet￾ter tools and techniques. We have therefore highlighted some of these crucial developments. Chapter 9, DNA￾Based Information Technologies, in particular, has been significantly revised to include the latest advances in genomics and next-generation sequencing. Finally, we have devoted considerable attention to making the text and the art even more useful to stu￾dents learning biochemistry for the first time. To those familiar with the book, some of these changes will be obvious as soon as you crack the cover. With every revision of this textbook, we have striven to maintain the qualities that made the original Lehninger text a classic—clear writing, careful explanations of diffi￾cult concepts, and insightful communication to students of the ways in which biochemistry is understood and practiced today. The authors have written together for almost 25 years and taught introductory biochemistry together for nearly 30. Our thousands of students at the University of Wisconsin–Madison over those years have been an endless source of ideas about how to present biochemistry more clearly; they have enlightened and inspired us. We hope that this sixth edition of Lehninger will in turn enlighten and inspire current students of bio￾chemistry everywhere, and perhaps lead some of them to love biochemistry as we do. Preface New Art The most obvious change to the book is the completely revamped art program. Our goal throughout has been to improve pedagogy, drawing on modern graphic resources to make our subject as clear as humanly possible. Many figures illustrate new topics, and much of the art has been reconceived and modernized in style. Defining features of the new art program include: u Smarter renditions of classic figures are easier to interpret and learn from; Chaperonins in protein folding FMTOC.indd Page vi 10/10/12 7:30 AM user-F408 /Users/user-F408/Desktop ADP ADP ADP ADP ADP ADP GroES GroEL ADP ADP ADP ADP ADP ADP 7Pi 7Pi 7 7 ATP 7 7 (a) (b) Native protein Slow-folding intermediate or Folding intermediate delivered by Hsp70-ADP Folding intermediate delivered by Hsp70-ADP ATP ATP ATP ATP ATP ATP ATP hydrolysis ATP hydrolysis ATP ATP ADP ADP ADP ADP ADP ADP ADP ADP ADP ADP ADP ADP ATP ATP ATP ATP ATP ATP ATP GroES

Prefare vii Figures that pair molecular models with c ca this ho interally consistent: A Figures with numbered,annotated steps help explain complex pro s:in many cases we text out of the legends Summary figures help the student to keep the big picture in mind while learning the specifics Updated Genomics Modern genomic techniques have transformed an thirpplicaChapterDNA-d tion Technologies has been completely revised neoporatethecaesteaenehok Many othe from these methods.Among the new genomic methods discussed in this edition are Next-generation DNA sequencing.including the Illumina and 454 sequencing methods and platforms (Chapter 9) Applications of genomics,including the use of migrations and with inherited diseases (Chapter ciated Forensic genoty Next-generation reversible terminator sequencing New Science Every chapter has been thoroughly revised and updatec to include both the most important advances in bio this edition are: Prebiotic evolution,black smokers,and the RNA world (Chapter 1) 4 Intrinsically disordered proteins(Chapter) (Chapter 6

u Figures that pair molecular models with schematic cartoons, generated specifically for this book, use shapes and color schemes that are internally consistent; u Figures with numbered, annotated steps help explain complex processes; in many cases, we have moved descriptive text out of the legends and into the figure itself; u Summary figures help the student to keep the big picture in mind while learning the specifics. Updated Genomics Modern genomic techniques have transformed our understanding of biochemistry. In this edition, we have dramatically updated our coverage of genomic methods and their applications. Chapter 9, DNA-Based Informa￾tion Technologies, has been completely revised to incorporate the latest genomic methods. Many other chapters have been updated to reflect advances gained from these methods. Among the new genomic methods discussed in this edition are: u Next-generation DNA sequencing, including the Illumina and 454 sequencing methods and platforms (Chapter 9) u Applications of genomics, including the use of haplotypes to trace human migrations and phylogenetics to locate human genes associated with inherited diseases (Chapter 9) u Forensic genotyping and the use of personalized genomics in medicine (Chapter 9) Next-generation reversible terminator sequencing New Science Every chapter has been thoroughly revised and updated to include both the most important advances in bio￾chemistry and information needed in a modern bio￾chemistry text. Among the new and updated topics in this edition are: u Prebiotic evolution, black smokers, and the RNA world (Chapter 1) u Intrinsically disordered proteins (Chapter 4) u Transition-state analogs and irreversible inhibition (Chapter 6) u Blood coagulation pathways in the context of enzymatic regulation (Chapter 6) Binding of the intrinsically disordered carboxyl terminus of p53 to its binding partners Preface vii Fuel metabolism in the liver during prolonged fasting or in uncontrolled diabetes mellitus FMTOC.indd Page vii 09/10/12 1:57 PM user-F408 /Users/user-F408/Desktop 1 7 3 6 2 48 9 5 Acetyl-CoA Pi Oxaloacetate Amino acids NH3 Glucose 6-phosphate Phosphoenol￾pyruvate Citrate Acetoacetyl-CoA Ketone bodies Urea Glucose Fatty acids Protein degradation yields glucogenic amino acids. Glucose is exported to the brain via the bloodstream. Excess ketone bodies end up in urine. Fatty acids (imported from adipose tissue) are oxidized as fuel, producing acetyl-CoA. Ketone bodies are exported via the bloodstream to the brain, which uses them as fuel. Urea is exported to the kidney and excreted in urine. Citric acid cycle intermediates are diverted to gluconeogenesis. Acetyl-CoA accumulation favors ketone body synthesis. Lack of oxaloacetate prevents acetyl-CoA entry into the citric acid cycle; acetyl-CoA accumulates. TACGGTCTC: CCCCCCAGT: dNTP incorporated T (b) (c) (a) 5 3 C T A A G C A G C T A A C C T G G T A C G T A C G T A C G T G C A G 5 3 C T A A G C A G C T A C T G T G C A 5 3 C T A A G C A G C T A C T G T G A 5 3 C T A A G C A G C T A C T G T G Guanine nucleotide added; fluorescent color observed and recorded. Cytosine nucleotide added; fluorescent color observed and recorded. Remove labels and blocking groups; wash; add blocked, labeled nucleotides. Remove labels and blocking groups; wash; add blocked, labeled nucleotides. Remove labels and blocking groups; wash; add blocked, labeled nucleotides. Add blocked, fluorescently labeled nucleotides. Adenine nucleotide added; fluorescent color observed and recorded. Thymine nucleotide added; fluorescent color observed and recorded. 300 Cyclin A Sirtuin s100B( ) bb 100 400 0.0 0.5 PONDR score 1.0 0 002 Amino acid residues C terminus N terminus CBP bromo domain (b) )a( )c(

Preface 合petipddtihutiomntyeas 4 24 Scaffold proteins (AKAPS and others)and their 4 regulatory roles (Chapter 12) ane25esandonoaognsreconmbnatioa Reactive oxygen species as byproducts and as signals (Chapter 19) apgrgnotcRApotnense 4 Structure and function of the oxvgen-evolving Mutation-resistant nature of the genetic code metal cluster in PSII(Chapter 19) (Chapter 27) 4 Insig in cholesterol regulation (Chapter 21) DNA looping,combinatorial control,chromatin 4 S)p Integration of carbohydrate and lipid metabolism Creatine phosphate and the role of creatine kinase in moving ATP to the cytosol (Chapter 23) Steroid-binding nuclear receptors (Chapter 28) New Biochemical Methods An appreciation of biochemistry often requires an under Moder genomic methods (Chapter 9) edition are y (PET)to (Chapter 23) Development of bacterial strains with altered genetic codes for site-specific insertion of novel amino acids into proteins (Chapter 27) rate code"(Chanter 7 New Medical Applications 国 rters and their 么indea or amdent to learn boer Ne sion to colorectal cance th and about the molecular mechanisms of disease ular disease atherosclerosis (Chapter 21) Box 4-6,Death by Misfolding:The Prion Diseases P-450 and drug interactions (Chapter 21) Paganini and Ehlers-Danlos syndrome (Chapter 4) 4 HIV prote nd ho Statins by Inhibitin agulation cascade and hemophilia Chapter6 4 eatment of ess with an enzymati terial suicide inhibitor (Chapter 6) on c profloxacin(the antibiotic effective for anthrax) Stem cells (Chapter 28)

viii Preface u Asymmetric lipid distribution in bilayers (Chapter 11) u Role of BAR superfamily proteins in membrane curvature (Chapter 11) u Scaffold proteins (AKAPS and others) and their regulatory roles (Chapter 12) u Reactive oxygen species as byproducts and as signals (Chapter 19) u Structure and function of the oxygen-evolving metal cluster in PSII (Chapter 19) u Formation and transport of lipoproteins in mammals, including the roles of SREBP SCAP, and Insig in cholesterol regulation (Chapter 21) u Integration of carbohydrate and lipid metabolism by PPARs, SREBPs, mTORC1, and LXR (Chapters 21, 23) u Creatine phosphate and the role of creatine kinase in moving ATP to the cytosol (Chapter 23) u Microbial symbionts in the gut and their influence on energy metabolism and adipogenesis (Chapter 23) u Nucleosomes: their modification and positioning and higher-order chromatin structure (Chapter 24) u DNA polymerases and homologous recombination (Chapter 25) u Loading of eukaryotic RNA polymerase II (Chapter 26) u Mutation-resistant nature of the genetic code (Chapter 27) u Regulation of eukaryotic gene expression by miRNAs (Chapters 26 and 28). u DNA looping, combinatorial control, chromatin remodeling, and positive regulation in eukaryotes (Chapter 28) u Regulation of the initiation of transcription in eukaryotes (Chapter 28) u Steroid-binding nuclear receptors (Chapter 28) New Biochemical Methods An appreciation of biochemistry often requires an under￾standing of how biochemical information is obtained. Some of the new methods or updates described in this edition are: u Modern Sanger protein sequencing and mass spectrometry (Chapter 3) u Mass spectrometry applied to proteomics, glycomics, lipidomics, and metabolomics (Chapters 3, 7, 10) u Oligosaccharide microarrays to explore protein￾oligosaccharide interactions and the “carbohydrate code” (Chapter 7) u Modern genomic methods (Chapter 9) u Genetic engineering of photosynthetic organisms (Chapter 20) u Use of positron emission tomography (PET) to visualize tumors and brown adipose tissue (Chapter 23) u Development of bacterial strains with altered genetic codes for site-specific insertion of novel amino acids into proteins (Chapter 27) New Medical Applications This icon is used throughout the book to denote material of special medical interest. As teach￾ers, our goal is for students to learn biochemistry and to understand its relevance to a healthier life and a healthier planet. Many sections explore what we know about the molecular mechanisms of disease. A few of the new or revised medical applications in this edi￾tion are: u Box 4-6, Death by Misfolding: The Prion Diseases u Paganini and Ehlers-Danlos syndrome (Chapter 4) u HIV protease inhibitors and how basic enzymatic principles influenced their design (Chapter 6) u Blood coagulation cascade and hemophilia (Chapter 6) u Curing African sleeping sickness with an enzymatic suicide inhibitor (Chapter 6) u How researchers locate human genes involved in inherited diseases (Chapter 9) u Multidrug resistance transporters and their importance in clinical medicine (Chapter 11) u Multistep progression to colorectal cancer (Chapter 12) u Cholesterol metabolism, cardiovascular disease, and mechanism of plaque formation in atherosclerosis (Chapter 21) u P-450 and drug interactions (Chapter 21) u HMG-CoA reductase (Chapter 21) and Box 21–3, The Lipid Hypothesis and the Development of Statins u Box 24–1, Curing Disease by Inhibiting Topoisomerases, describing the use of topoisomerase inhibitors in the treatment of bacterial infections and cancer, including material on ciprofloxacin (the antibiotic effective for anthrax) u Stem cells (Chapter 28) FMTOC.indd Page viii 09/10/12 1:57 PM user-F408 /Users/user-F408/Desktop

Preface Special Theme:Understanding Metabolism through Obesity and Diabetes are fast the industrialized world,and we include new material etween obesity cts in Insulin provides an integrating theme throughout the chapters Section 23.4.Obe sity andthe on metabolism and its control,and this will,we hope TORCI in regulating cell growth ents to nind solution Section 235 Obesity the Metabolie Syndr play of metabolism,obesity.and diabetes are: and Type 2 Diabetes,discu ses the role of ectopic Untreated Diabetes Produces Life-Threatening lipids and inflammation in the development of Acidosis (Chanter 2) diabetes with pe 2 Box 71 Blood Glu ts ir diet,and the Diagnosis and Treatment of Diabete introduces hemoglobin glycation and AGE r17 rs inflammation in fat tissu (Chapter 19) Special Theme:Evolution Every time a biochemist studies a developmental pathwa Box 93 Getting to know the Neanderthals ABC Transr Use ATP to Drive the Active e for uhe Transport of a Wide Variety of Substrates (Chapter 11) disease he or she is relving on evolutionary theory fund Signaling Systems of Plants Have Some of the Same Components Used by Microbes and me active site teleu Mammals(Chapter 12) the shared history of every organism on the planet.More 4 the se rch for a neis a sophis foundational conce t to our discipline.Some of the many Section 19.10,The Evolution of Oxygenic Photosynthesis sections and boxes that deal with evolution include: Mitochondria and Chloroplasts Evolved from Section 1.5.Evolutionary Foundations.discusses Endosymbiotic Bacteria (Chapter 19) Photosystems I and II Evolved from Bacterial Photosystems (Chapter 19) RNA Synthesis Offers Important Clues to Biochemical Evolution (Chapter 26) Help Locate Genes Involvec Box 27-1,Exceptions That Prove the Rule:Natural r 9) Variations in the Genetic Code Box 27-2.From an RNA World to a Protein World Opportunitie Box 28-1,Of Fins,Wings,Beaks,and Things

Preface ix Obesity and its medical consequences—cardiovascular disease and diabetes—are fast becoming epidemic in the industrialized world, and we include new material on the biochemical connections between obesity and health throughout this edition. Our focus on diabetes provides an integrating theme throughout the chapters on metabolism and its control, and this will, we hope, inspire some students to find solutions for this disease. Some of the sections and boxes that highlight the inter￾play of metabolism, obesity, and diabetes are: u Untreated Diabetes Produces Life-Threatening Acidosis (Chapter 2) u Box 7–1, Blood Glucose Measurements in the Diagnosis and Treatment of Diabetes, introduces hemoglobin glycation and AGEs and their role in the pathology of advanced diabetes u Glucose Uptake Is Deficient in Type 1 Diabetes Mellitus (Chapter 14) u Ketone Bodies Are Overproduced in Diabetes and during Starvation (Chapter 17) u Some Mutations in Mitochondrial Genomes Cause Disease (Chapter 19) u Diabetes Can Result from Defects in the Mitochondria of Pancreatic Cells (Chapter 19) u Adipose Tissue Generates Glycerol 3-phosphate by Glyceroneogenesis (Chapter 21) u Diabetes Mellitus Arises from Defects in Insulin Production or Action (Chapter 23) u Section 23.4, Obesity and the Regulation of Body Mass, includes a new discussion of the roles of TORC1 in regulating cell growth u Section 23.5, Obesity, the Metabolic Syndrome, and Type 2 Diabetes, discusses the role of ectopic lipids and inflammation in the development of insulin resistance and the management of type 2 diabetes with exercise, diet, and medication Special Theme: Understanding Metabolism through Obesity and Diabetes Overloading adipocytes with triacylglycerols triggers inflammation in fat tissue, ectopic lipid deposition, and insulin resistance. Special Theme: Evolution Every time a biochemist studies a developmental pathway in nematodes, identifies key parts of an enzyme active site by determining what parts are conserved between spe￾cies, or searches for the gene underlying a human genetic disease, he or she is relying on evolutionary theory. Fund￾ing agencies support the work in nematodes knowing that the insights will be relevant to humans. The conservation of functional residues in an enzyme active site telegraphs the shared history of every organism on the planet. More often than not, the search for a disease gene is a sophis￾ticated exercise in phylogenetics. Evolution is thus a foundational concept to our discipline. Some of the many sections and boxes that deal with evolution include: u Section 1.5, Evolutionary Foundations, discusses how life may have evolved and recounts some of the early milestones in the evolution of eukaryotic cells u Genome Sequencing Informs Us about Our Humanity (Chapter 9) u Genome Comparisons Help Locate Genes Involved in Disease (Chapter 9) u Genome Sequences Inform Us about Our Past and Provide Opportunities for the Future (Chapter 9) u Box 9–3, Getting to Know the Neanderthals u ABC Transporters Use ATP to Drive the Active Transport of a Wide Variety of Substrates (Chapter 11) u Signaling Systems of Plants Have Some of the Same Components Used by Microbes and Mammals (Chapter 12) u The -Oxidation Enzymes of Different Organelles Have Diverged during Evolution (Chapter 17) u Section 19.10, The Evolution of Oxygenic Photosynthesis u Mitochondria and Chloroplasts Evolved from Endosymbiotic Bacteria (Chapter 19) u Photosystems I and II Evolved from Bacterial Photosystems (Chapter 19) u RNA Synthesis Offers Important Clues to Biochemical Evolution (Chapter 26) u Box 27–1, Exceptions That Prove the Rule: Natural Variations in the Genetic Code u Box 27–2, From an RNA World to a Protein World u Box 28-1, Of Fins, Wings, Beaks, and Things FMTOC.indd Page ix 09/10/12 1:57 PM user-F408 /Users/user-F408/Desktop 1 2 3 5 4 6 7 TAGdiet TAGcatabolized TAGdiet  TAGcatabolized Enlarged adipocytes produce macrophage chemotaxis protein (MCP-1). Macrophages infiltrate adipose tissue in response to MCP-1. Macrophages in adipose tissue produce TNFa, which favors export of fatty acids. Adipocytes export fatty acids to muscle, where ectopic lipid deposits form. Ectopic lipid interferes with GLUT4 movement to the myocyte surface, producing insulin resistance. Glucose TAG Small adipocytes Lean Fatty acids ATP Glucose Larger adipocytes Larger adipocytes Larger adipocytes Overweight Fatty acids ATP Glucose Pro-inflammatory state Fatty acids MCP-1 TNFa ATP Glucose Insulin-sensitive muscle with normal glucose transport Insulin-resistant muscle with reduced glucose transport Chronic inflammation Fatty acids