• • • eremy M Berg W H Freem an and Company • New York SIXTH I r-c • • Publisher: Sara Tenney Senior Acquisitions Editor: Kate Ahr Marketing Managers: Sarah Martin, John Britch Senior Developmental Editor: Susan Moran Media Editor: Alysia Baker Supplements Editors: Nick Tymoczko, Deena Goldman Photo Editor: Bianca Moscatelli Design Manager: Diana Blume Text Designer: Patrice Sheridan Senior Project Editor: Georgia Lee Hadler Manuscript Editor: Patricia Zimmerman Illustrations: Jeremy Berg with Network Graphics Senior Illustration Coordinator: Bill Page Production Coordinator: Susan Wein Composition: Techbooks Printing and Binding: RR Donnelley Library of Congress Cataloging-in-Publication Data Berg, Jeremy Mark Biochemistry / Jeremy M Berg, John L Tymoczko, Lubert Stryer 6th ed p cm Includes bibliographical references and index ISBN 0-7167-H724-5 hardcover Biochemistry Tymoczko, John L., II Stryer, Lubert III Title QP514.2.S662006 572 dc22 2005052751 ISBN: 0-7167-8724-5 EAN: 9780716787242 ©2007, 2002 by W H Freeman and Company; © 1975, 1981, 1988, 1995 by Lubert Stryer All rights reserved Printed in the United States of America First printing W H Freeman and Company 41 Madison Avenue New York, NY 10010 Houndmills, Basingstoke RG21 6XS, England www.whfreeman.com To our teachers and our students About the Authors JEREMY M BERG received his B.S and M S degrees in C hemi stry 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 fellow ship with Carl Pabo in Biophysics at Johns H opkins 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 M edi cine as Professo r and Director of the Department of Biophysics and Biophysical Chemistry, where he remained until 2003 In 2003, he became the Director of the National Institute of General Medical Sciences at the National Institutes of Health He is recipient of the American C hemical Society Award in Pure C hemistry (1994 ), the Eli Lilly Award for Fundamental Research in Biological Chemistry (1995), the Maryland Outstanding Young Scientist of the Year (1995), and the Harrison Howe Award (1997 ) While at Johns Hopkins, he received the W Barry Wood Teaching Award (selected by medical students as award recipient), the Graduate Student Teaching Award, and the Professor's Teaching Award for the Preclini cal Sciences He is coauthor, with Stephen 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 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 and the Distinguished Inventors Award of the Intellectual Property Owners' Association He was elected to the National Academy of Sciences in 1984 He currently chairs the Scientific Advisory Boards of two biotechnology companies Affymax, Inc , and Senomyx, Inc and serves on the Board of the McKnight Endowment Fund for Neuroscience The publication of his first edition of Biochemistry in 1975 transformed the teaching of biochemistry PREFACE he more we learn, the m ore we discover connection s threading through our biochemical world In wri tin g th e sixth edi t ion, we have made every effort to present these connections in a way that will help first -time students of biochemistry understand the subj ect and h ow very relevan t it is to their lives Emphasis on Physiological Relevance Biochemistry is returning to its roots to renew the study of its role in physiology, with the tools of m olecular biology and the information gained from gene sequencing in hand In the sixth edition, we emphasize that an understanding of biochemical pathways is the underpinning for an understanding of physiological systems Biochemical pathways make m ore sense to students when they understand how these pathways relate to the physiology of familiar acti vities such as di gesti on, respiration, and exercise In this edition, particularly in the chapters on m etabolism, we have taken several steps to ensure that students have a view of the bigger picture: • Discussions of m etabolic regulation emphasize the everyday conditions that determine regul ation: exercise versus rest; fed versus fasting • New pathway-integration figures show how multiple pathways work together under a specific condition, such as during a fast • More physiologically relevant examples have been added throughout the book This physiological perspective is also evident in th e new chapter on drug development The use of a foreign compound to inhibit a specific enzyme som etimes has surprising physiological consequences that reveal new physiological principles FAT CELL BLOOD FASTING or D IAB ETES - Glycerol Fatty acids , Triacylglycerol G~erol LIVER CELL I Fatty aCI.d S Glycerol Glucose • _+- Fatty acids Fatty acids ~ Ace tyl CcA Ketone bodies HEART·MUSCLE CELL RENAL· CORTEX CELL BRAIN CELL DURING STARVATION Ketone bodies,= = Active pathways: Acetyl CoA Fatty acid oxidation, Chapter 22 Formation of ketone bod ies, Cha pter 22 Gluconeogenesis, Chapter 16 Ketone bodies acetyl CcA Chapter 22 Cit ric acid cycle, Chapter 17 Oxidative phosphorylation, Chapter 18 Figure 22.21 Pathway Integration: Liver supplies ketone bodies to the peripheral t issues During fa sting or in untreat ed diabet ics th e liver converts fatty aci ds into keto ne bodies whi ch are a fuel source fo r a number of ti ssues Ket one bodies are t he predo m inant fue l during starvati on v vi Prefa ce A Molecular Evolutionary Perspective Evolutionary perspectives greatly enabl e and enhance the study of biochemistry As Theodosius Dobzhansky noted, "nothing in biology makes sense except in the light of evolution " In the course of evolution, mutations altered many protei ns and biochemical motifs so that they perform different functions while maintaining their core biochemical elements By exa mining related protein s, we hi ghli ght essenti al chemi cal features as well as the specialization necessary for particular functions The tracks of evolution are clear from the analysis of gene and protein sequences As seq uence analysis becomes more important, the field of biochemistry is shifting from a science performed alm ost entirel y in the laboratory to one that may also be explored through computers , by using information gathered from genomics and proteo mi cs Thi s shi ft is manifest in th e current edi tion and can be seen most clearl y in C hapter 6, "E xploring E volution and Bioinformatics," which develops the co nceptual basis for comparing protein and nucl eic ac id sequ ences Protein co mpari so ns are a frequent source of insight throughout the book, especiall y for illuminatin g relations between stru cture and fun ction • How drugs relate to other topics in the bookkineti cs, enzyme inhibitors, membrane receptors, metaboli c regulation, lipid synth esis, and signal transduction • How the body's defen ses respond to foreign compounds, especiall y the defenses provided by the biochemical pathways of xenobiotic metabolism • The importance of admini stration, distribution, metaboli sm , excretion (ADME), and toxicology in drug development • How the drug-development process works from target identification through clinical trials • H ow the concepts and tools of genomics are used in the development of drugs New Clinical Applications W e have added a number of new exa mples from medical science to the already abundant selection of such examples (indicated by the icon above) (For a full list see p x.) N ew topics include: • Diseases of protein misfolding (C hapter 2) • Human gene therapy (Chapter 5) • Aggregan and osteoarthritis (Chapter 11 ) New Chapters: Hemoglobin and Drug Development • T he use of erythropoieti n (EPO) to tTeat anemia and its abuse by athletes (Chapter 11 ) Two new chapters illustrate the relation between stru cture and fun cti on by using a classic exampl e and a contemporary one • The use of monoclonal antibodies to target epidermal-growth -factor receptors in the treatment of colon and breast can cers (Chapter] 4) Chapter 7: Hemoglobin: Portrait of a Protein in Action • Role of exercise in building defenses against superoxide radicals (Chapter 18) This classic example, used to convey the relation between stru cture and function, returns in an expanded treatment New insights include: • Oxygen transport during rest and d uring exercise • Th e physiology of oxygen and CO transport • The mol ecular basis of sickle-cell anemia and thalassemia • Balancing the production of a and 13 chains • Newly discovered globins • Diseases of altered ubiquination (Parkinson's disease, Angelman syndrome) (Chapter 23) • The use of the proteasome inhibitor bortezomib to treat mu ltiple myeloma (Chapter 23) • Adenosine d eaminase and severe combined immune deficiency (Chapter 25) • Much enhanced discussion of gout (Chapter 25) • Folic acid and spina bifid a (Chapter 25) • Type II diabetes (C hapter 27) Knowledge of biochemical pathways is key to the development of new drugs such as Lipitor, Viagra, and Vioxx In this new chapter, plentifu l case studies illustrate: Chapter 15: Drug Development , • Tumor suppressor genes and p 53 (C hapter 2H) • C hemotherapy targeting DNA repair pathways (Chapter 28) Preface • Diseases of defective RNA spli cing, including thalassemias and retinitis pigmentosa (Chapter 29) • The structure and function of the EGF receptor (Chapter 14) • Innate immunity (Chapter 33) • The structure of the ATP-ADP translocase (Chapter 18) • • VII • Role of glycogen synthase kinase in glycogen regulation (Chapter 21) Recent Advances • The role of perlipin A in fatty acid mobilization (Chapter 22) The sixth edition has been thoroughly updated throughout, including new discussions of the following recent advan ces: • The newly revised structure of fatty acid synthase (Chapter 22) • The nucleation condensation model of protein folding (Chapter 2) • Prokaryotic and eukaryotic replication initiation (Chapter 28) • Using MALDI-TOF mass spectrometry to identify components oflarge protein compl exes (Chapter 3) • DNA polymerase components (Chapter 2S) • Update on the human genome project (Chapter 5) • The trombone model of DNA elongation (Chapter 28) • Comparative genomics (Chapter 5) • Promoter structure in eukaryotes (Chapter 29) • Gene disruption by RNA interference (Chapter 5) • Transcription initiation in eukaryotes (Chapter 29) • Using BLAST searches (Chapter 6) • Lipid rafts (Chapter 12 ) • The carboxy-terminal domain (CTD ) of RNA polymerase (Chapter 29) • Mechanisms of action of several types of membrane channels and pumps such as the acetylcholine receptor (Chapter 13) • The rol e of SNARE proteins in protein targeting (Chapter 30) • Aquaporin (Chapter 13) • The structure of taste receptors for detecting sweetness (Chapter 32) • The insulin receptor pathway (Chapter 14) Insulin receptor In sulin PIP, PDKl (PIP-dependent kinase) Phosphoinositid e 3-kinase IRS- I Akt AlP ADP Activated Akt Figure 14.20 Insulin signaling The binding of insulin to its receptor leads to a seri es of phosphorylations, resulting in the activati on of the kinase Aktl Activated Akt1 diffuses thro ughout the cell to continue the Signal-transduction pathway vii i Preface • Living Figures for most m olecular structures now appear on the Web site in J m ol to allow stud ents to rotate 3- D molecul es and view alternative renderings online Visualizing Molecular Structure As in the fifth edition, all molecular structures have been selected and rendered by one of us , Jeremy Berg T he sixth edition includes new tools to help students read and und erstand molecular stru ctures: End-of-Chapter Problems • A molecular model " primer" explains the different types of protein models and examines their strengths and weaknesses (appendices to Chapters and 2) In addition to general probl ems, the end-of-chapter problems include three categories to fo ster the develop ment of specific skills • Mechanism problems ask students to suggest or elaborate a chemical mechanism • Figure legends direct students explicitly to the key features of a model • Data interpretation problems ask questions about a set of data provided in tabulated or graphic form These problems give students a sense of how scientific conclusions are reached • A greater variety of types of molecular structures are represented , in cluding clearer renderings of membrane proteins • For most molecular models, the name of the file from the Protein Data Bank is given at the end of the figure legend This file name (also known as a PDB ID) allows the reader easy access to the file used in generating the structure from the Protein Data Bank W eb site (http ://www.rcsb org/pdb/ ) At thi s site, a variety of tools for visualizing and analyzing the stru cture are availabl e (A) • Chapter integration problems require students to use information from several chapters to reach a solution These problems reinforce a student's awaren ess of the interconnectedness of the different aspects of biochemi stry Brief solutions to these problems are presented at the end of the book; expanded solutions are available in the accompanying Student Companion (8) Heme Iron atom ~ Figure 2.48 Three-dimensional structure of myoglobin {Al A ribbon diagram shows that the protein consists largely of a hel ices {Bl A space-filling model in the same orientation shows how ti ghtly packed the fol ded protein is Notice that the heme group is nestled into a crevice in t he compact protein with on ly an edge exposed One hel ix is blue to allow comparison of the two structural dep ictions [Drawn from lA6N.pdb.] Molecular Evolution This ico n signals the start of many discussions that hi ghlight protein commonalities or other molecular evolutionary insights that provide a framework to help students organize information Why this set of 20 amino acids' (p 33) Is the genetic code universal? (p 126) Increasing sophistication of glycogen phosphorylase regulation (p 604) Many exons encode protein domains (p ] 28) The ", -amylase family (p 606) Fetal hemoglobins (p 192) A recurring motif in the activation of carboxyl groups (p 623) A dditional globins (p 197) Prokaryotic co unterparts of the ubiquitin path way and the proteasome (p 655) Catalytic triads in hydrolytic enzymes (p 24~) A famil y of pyridoxal -dependent enzymes (p 660) iVlajor classes of peptide-cleaving enzymes (p 251 ) Evolution of the urea cycle (p 664) Zinc-based active sites in carbonic anhydrases (p 258) A co mmo n catalytic core in lype II restric tion enzymes (p 266 ) Aspartate aminotran sferase, prototype of PLP -dependent enzymes P-Ioop NTPase domains (p 270) (p 687) A commo n catalyti c co re in protei n kinases (p 288 ) Feedback inhibition (p 698) Why might human blood types differ? (p 3] 5) Recurring steps in purine rin g synthesis (p 15) Archaeal membranes (p 331) lZibonucleotide redu ctases (p 720) P-type ATPases (p 354 and p 3:;8) Increase in urate levels during primate evol ution (p 726) ATP -binding cassette domains (p 35~) Using sequence co mparison s to understand Na The P -Ioop NTPase domain in nitrogenase (p 6R 2) t and Ca The cytochrome P450 superfamily (p 752) I channels (p 366) D N A polymerases (p 794) Small G proteins (p 398) Helicases (p 798) Evolution of metabolic pathways (p 429 ) Thymine and fidelity of geneti c message (p Why is glucose a prominent fuel ? (p 43:;) Evolutionary relationship of recombinases and topoisomerases A common binding site in dehydroge nases (p 448) ~09) (p 814) T he maj or facilitator (MF) superfamily of transporters (p 457) Evolution of spliceosome-catal yzed splicing (p 850) Isozymic forms of lactate dehydrogenase (p 469) C lasses of aminoacyl-tRNA synthetases (p 865) Evolutionary relationship of glycolysis and gluconeogenesis (p 469) Composition of t he primordal ribosom e (p R69) Homologous G proteins (p 877) Decarboxylati on of ,, -ketoglutarate and pyruvate (p 48:;) A family of protein s with common li gand binding domains (p 899) Evolution of succinyl eoA synthetase (p 487) Evolutionary history of the citric acid cycle (p 495) Independent evolution of DNA -binding sites of regulatory proteins (p 900) Endosymbiotic origins of mitochondria (p 504) CpG islands (p 907) Conservation of cytochrom e c stru cture (p 52 0) Iron response elements (p 16) Common features of ATP synthase and G protei ns (p 527) The odorant rece pto r fa mily (p 923) Related uncoupling proteins (p 533) Photoreceptor evolution (p 936) Evolution of chloroplasts (p 543) The immunoglobulin fold (p 952) Evolutionary origins of photosynthesis (p 560) Relationship of actin to hexokinase and prokaryotic proteins (p 9Xb) Evolu tion of the C pathway (p 576) Tubulins in P-loop NTPase family (p 990) • • IX • x x XIV Contents C hromatin Stru cture Is Modulated Through Covalent Modifications of Histone Tail s Histone Deacetylases Contribute to Transcriptional Repression 31.4 Gene Expression Can Be Controlled at Posttranscriptional Levels 910 912 913 Attenuation Is a Prokaryotic M echanism for Regu lating Transcription Through the M odulati on of Nascent RNA Secondary Structure 913 Genes Associated with Tron Metabolism Are Tran slationally Reg ulated in Animals 14 Part IV RESPONDING TO ENVIRONMENTAL CHANGES Chapter 32 Sensory Systems 32.1 A Wide Variety of Organic Compounds Are Detected by Olfaction Olfaction Is Mediated by an Enorm ous Family of Seven · Transmembrane- Heli x Receptors Odorants Are Decoded hy a C:ombinatori al M echanism 921 922 Sequencing of the Human Genome Led to the Discovery of a Large Family of TM llitter Receptors A H eterod imeric 7TM Receptor Responds to Sweet Com pounds Umami the T aste of Glutamate and Aspartate, Is M ediated by a H eterod imeric Receptor Related to the Sweet Receptor Salty Tastes Are Detected Primarily by the P assage ofS()(lium Tons Through C:ha.nnels Sour Tastes Ari se from the Effects of H yd rogen Ions (Acids) on Channels 32.3 Photoreceptor Molecules in the Eye Detect Visible Light Rhodopsin , a Speciali zed 7TM Receptor, Absorbs Visible Light 924 926 927 929 930 930 931 931 932 Light Abso rption Induces a Specific Isom erization of llound 11-cis - Retinal 933 L ight - Jnduced L owerin g of the C:alcium Level Coordinates R ecovery 934 Color Vision Is M ediated by Three Cone Receptors That A re H omologs of Rhodopsin 32.4 Hearing Depends on the Speedy Detection of Mechanical Stimuli 936 937 H r Cells Use a Connected Bundle of Stereocilia to D etect Tiny M otions 937 Mechanosen sory C hannels H ave Been Identified in Drosophilio and Vertebrates 939 32.5 Touch Includes the Sensing of Pressure, Temperature, and Other Factors 939 Studies of Capsaicin Reveal a Receptor for Sen si ng High Temperatures and Other Painful Stimuli 940 More Sen sory Systems Remain to be Studied 941 Chapter 33 The Immune System 945 Tnn ate Immunity Is an Evolution arily Ancient Defense System 946 Th e Adaptive Tm mune System Responds h y Using the Principles of Evolution 947 923 F unctional Magnetic Resonance Imagin g Reveals Regions of the Brain P rocessing Sensory Information 32.2 Taste Is a Combination of Senses That Function by Different Mechanisms Rearrangements in the Genes for the G reen and Red Pigments L ead to "Color Blindness" 93S 33.1 Antibodies Possess Distinct Antigen-Binding 949 and Effector Units 33.2 The Immunoglobulin Fold Consists of a Beta-Sandwich Framework with Hypervariable Loops 952 33.3 Antibodies Bind Specific Molecules Through Their Hypervariable Loops 953 X -ray Analyses Have Revealed H ow Antibodies Bind Antigen s 933 Large Antigens Rind Antihodies with Numerous Interactions 954 33.4 Diversity Is Generated by Gene Rearrangements 956 J (Joining) Genes and D (Diversity) Genes Increase Antibody Diversity 956 More Than 10 Antibodies Can Be Formed b y Combinatorial A ssociation and Somatic Mutation 958 The O ligomerization of Antibodies Expressed on th e Surfaces of Immature B Cells Triggers Antibody Secretion 958 Different C lasses of Antibodies Are Formed by the Hopping of V H Genes 960 33.5 Major-Histocompatibility-Complex Proteins Present Peptide Antigens on Cell Surfaces for Recognition by T-Cell Receptors 961 Peptides Presented by MHC Protein s Occupy a Deep Groove Flanked hy Alpha H eli ces 962 Contents x x x v T-Cell Receptors Are Antibody-like Proteins Containing Variable and Constant Regions 963 CDXon Cytotoxic T Cells Acts in Concert with T -Cell Receptors 964 Hel per T Cell s Stimulate Cells That Display Foreign Peptides Bound to Class II MHC Proteins 965 Helper T Cells Rely on the T -Cell Receptor and C D4 to Recognize Foreign Pep tides on Antigen -Presenting Cells M HC Proteins Are Highly Diverse Human Immunodeficiency Viruses Subvert the Immune System by Destroying Helper T Cells 33.6 Immune Responses Against Self-Antigens Are Suppressed 966 968 Chapter 35 Drug Development 1001 35.1 The Development of Drugs Presents Huge Challenges 1002 Drug Candidates Must l.\e Potent Modulators of Their Targets 1002 Drugs Must H ave Suitable Properties to Reach Their Targets 1003 Toxicity Can Limit Drug Effectiveness 1008 969 970 T Cells Are Subjected to Positi ve and Negative Selection in the Thymus 070 Autoimmune Diseases Results from the Generation of Immune Responses Against Self-Antigens 971 The Immune System Plays a Role in Cancer Prevention 97 35.2 Drug Candidates Can Be Discovered by Serendipity, Screening, or Design Chapter 34 Molecular Motors 977 34.1 Most Molecular-Motor Proteins Are Members of the P-Loop NTPase Superfamily A Motor Protein Consists of an ATrase Core and an Extended Structure 978 978 ATP Binding and Hydrolysis Induce Changes in the Conformation and Binding Affinity of Motor Proteins Serendipitous Observations Can Drive Drug Development 1009 Screening Libraries of Compounds Can Yield Drugs or Drug Leads 1011 Drugs Can Be Designed on the Basis of ThreeDimensional StTuctural Information About Their Targets 980 Muscle Is a Complex of Myosin and Actin Actin Is a Polar, Self-Assembling, Dynamic Polymer Motions of Single Motor Proteins Can Be Directly Observed Phosphate Release Triggers the Myosin Power Stroke The Length of the Lever Arm Determines Motor Velocity 982 082 1017 985 Animal M odels Can Be Developed to Test the Validity of Potential Drug Targets 1018 Potential Targets Can Be Identified in the Genomes of Pathogens 1018 Genetic Differences InOuence Individual Responses to Drugs 1019 9R6 987 988 989 980 Kinesin Motion Is Highly Processive 991 993 Proton fl ow Drives Bacterial Flagellar Rotation 993 994 Bacterial Chemotaxis Depends on Reversal of the Direction of F lagellar Rotation 995 Bacteria Swim by Rotating Their Flagella 35.4 The Development of Drugs Proceeds Through Several Stages Microtubules Are Hollow Cylindrical Polymers 34.4 A Rotary Motor Drives Bacterial Motion 1017 Potential Targets Can Be Identified in the Human Proteome 34.3 Kinesin and Dynein Move Along M icrotubules 1014 35.3 The Analysis of Genomes Holds Great Promise for Drug Discovery 34.2 Myosins Move Along Actin Filaments 1009 1020 C linical Trials Are Time Consuming and Expensive 1020 The Evolution of Drug Resistance Can Limit the Utility of Drugs for Infectious Agents and Cancer 1021 Appendices A1 Glossary of Compounds B1 Answers to Problems C1 Index D1 Chapter Biochemistry: An Evolving Science Disease and the genome Studies of the human genome are revealing disea se o rigins and oth er bi ochemi cal myst eri es Human chro moso mes left contain the DNA molecules tha t constitute the human genome The staining pattern serves to q31.2 identify specifi c regions of a chromosome On t he ri ght is a diagram of human chro mosome with band q31.2 indicated by an arrow A gene in thi s reg ion encodes a protein that when ma lfuncti o ning causes cysti c fibrosis [(Left) Alfred Pa sieka / Peter Arn old.] iochemistry is the study of the chemistry oflife processes Since the dis covery that biological molecules such as urea could be synthesized from nonliving components in 1828, scientists have explored the chemistry oflife with great intensity T hrough these investigations, many of the most funda mental mysteries of how living things function at a biochemical level have now been solved However, much remains to be investigated As is often the case, each discovery raises at least as many new questions as it answers Furthermore, we are now in an age of unprecedented opportunity for the application of our tremendous knowledge of biochemistry to problems in medicine, dentistry, agriculture, forens ics, anthropology, environmental sciences, and many other fields We begin our journey into biochemistry with one of the most startling discoveries of the past century: namely, the great unity of all living things at the biochemical level 1.1 Outline 1.1 Biochemica l Unity Underlies Biological Diversity 1.2 DNA Illustrates the Interplay Between Form and Function 1.3 Concepts from Chemistry Explain the Properties of Biological Molecules 1.4 The Genomic Revolution Is Transforming Biochemistry and Medicine Biochemical Unity Underlies Biological Diversity The biological world is magnificently diverse The animal kingdom is rich with species ranging from nearl y microscopic insects to elephants and whales The plant kingdom includes species as small and relatively simple as algae and as large and complex as giant sequoias Unlike animals that mll st eat to survive, plants have the remarkable abi li ty to use sunlight to CHAPTER Biochemi stry: An Evolving Science CH 0H HO C OH HO OH H CH2 0H Glycerol Glucose Sulfa/abus acidica/darius vert carbon dioxide in the air into living tissues This diversity extends further when we descend into the microscopic world Single-celled organ isms such as protozoa, yeast, and bacteria are present with great diversity in water, in soil, and on or within larger organisms Some organi sms can survive and even thrive in seemingl y hostile environments such as h ot springs and glaciers T he microscope revealed a key unify ing feature that underli es thi s d iversity L arge organisms are built up of cells, resembling, to som e extent, single-celled microscopic organ is ms T he construction of animals, plants, and microorganism s from cells suggested that these d iverse organisms mi ght have more in common than is apparent from their outward appearance With the development of bi ochemi stry, this suggestion has been tremendously supported and expanded At the biochemi cal level, all organ isms h ave m an y common features (Figure 1.1) As m ent ioned ea rlier, biochem istry is the study of th e ch emistry of life p rocesses T hese processes entail the interpl ay of two different cl asses of m olecules: large molecules su ch as proteins and nucleic acids, referred to as biological macromolecules, and low -m olecular-weight m olecules such as glu cose and glycerol, referred to as metabolites, that are chemi call y tran sformed in biolog ical processes M embers of both these cl asses of molecul es are common, with m inor variations , to all li ving things For exam p le, deoxyribonucleic acid (DNA ) stores genetic inform ati on in all cellular organisms Proteins, th e m acrom olecul es that are key participants in most bi ological p rocesses, are built from a set of 20 building blocks that are the same in all Arabidapsis thaJiana Homo sapiens Figure 1.1 Biological diversity and similarity The shape o f a key molecule in gene regulatio n (th e TATA-box-bind ing protein) is similar in three ve ry differen t o rganisms that are separated from one another by billions of years of evolution [(Left) Dr T J Beveri dge/V;suals Un limited; (middle) Holt Studios/Photo Researchers; (right) Time Life Pi ctu res / Getty Images.] ·- ~ e cestor to modern organisms can be deduced on the basis of c " -c ' " " " biochemi cal inform ation O ne such path is shown in "§ - , " • , " 1 '" A of strands in the double helix mu st move together F urthermore, the free single strands ex ist in more conformations than possible when bound to gether in a d ouble helix T hus the formation of a double helix from two single strands appears to result in an in crease in order for the system On the basis of this analysis we expect that the double helix cannot form without vi olating the Second Law of Thermodynamics unless heat is released Figure 1.15 Double-helix formation and entropy When solutions contai ning DNA strands with com plem entary sequences are mixed, the stra nds react t o fo rm double helices This process results in a loss of entropy from the system, indicating that heat must be released to the surroundings to avoid vio lating the Second Law of Thermodynamics ... Functional Molecules 11 9 Several Kinds of RNA Play Key Roles in Gene Expression 11 9 All Cellular RNA Is Synthesized by RN A Polymerases 12 0 RNA Polymerases Take Instructiuns from DNA Templates 12 1 Transcription... physiological consequences that reveal new physiological principles FAT CELL BLOOD FASTING or D IAB ETES - Glycerol Fatty acids , Triacylglycerol G~erol LIVER CELL I Fatty aCI.d S Glycerol Glucose... Comprehensively Studied 5.4 Eukaryotic Genes Can Be Manipulated with Considerable Precision 14 14 2 14 2 14 3 14 5 14 6 14 14 9 14 9 15 0 I 51 lSI 15 2 Complementary DNA Prepared frum mR NA Can Be Expressed in