`PRINCIPLES OF
`
`BIOCHEMISTRY
`
`©*
`
`‘S DAVID L. NELSON
`
`' MICHAEL M. COX
`
`MPI EXHIBIT 1036 PAGE 1
`
`MPI EXHIBIT 1036 PAGE 1
`
`
`
`
`
`Publisher: ara Tenney
`Acqui ition Editor: Katherine Ahr
`De elopment Editor: Morgan Ryan
`Marketing Manager: Sarah Martin
`Marketing Director: John Britch
`Project Editor: .Jane O' eill
`De ign Manager: Blake Logan
`Text Desig ner: Rae Grant
`Cover Designer: Yuichiro Nishizawa
`Page Makeup: Paul Lacy
`Illustration Coordinator: Shawn Churchman
`Illustrations: Fine Line Illustrations
`Molecular Graphics/Cover Illustration: .Jean-Yves Sgro
`Photo Editor: Vikii Wong
`Production Coordinator: Paul Rohloff
`Media & Supplements Editors: Jeffrey Cipriani, Melanie Mays,
`Media Developers: Sumanas, Inc.
`Composition: TechBooks
`Manufacturing: RR Donnelley & Sons Company
`
`ick Tymoczko
`
`On the cover: The F 1 ATPase, part of a complex responsible for ATP
`synthesis in eukaryotic mitochondria. See Chapter 19.
`
`Library of Congress Control Number: 2004101716
`
`ISBN : 0-7167-4339-6
`EAN: 97807167743392
`
`© 2005, 2000, 1993, 1982 by W. H. Freeman and Company
`All rights reserved.
`
`Printed in the United States of America
`
`Fourth printing
`
`W. H. Freeman and Company
`41 Madison A venue
`New York, NY l00IO
`Houndmills, Basingstoke RG2 I 6XS, England
`
`www.whfreeman.com
`
`MPI EXHIBIT 1036 PAGE 3
`
`
`
`xiv
`
`Contents
`
`- - - - - - ~CONTENTS
`Contents in Brief
`
`Preface v
`1 The Foundations of Biochemistry 1
`
`STRUCTURE AND CATALYSIS 45
`2 Water 47
`3 Amino Acids, Peptides, and Proteins 75
`4 The Three-Dimensional Structure of Proteins us
`5 Protein Function 157
`6 Enzymes 190
`7 Cart>ohydrates and Glycobiology 238
`8 Nucleotides and Nucleic Acids 273
`9 DNA-Based Information Technologies 306
`10 Lipids 343
`11 Biological Membranes and Transport 369
`12 Biosignaling 421
`
`II BIOENERGETICS AND METABOLISM 481
`13 Principles of Bioenergetics 489
`14 Glycolysis, Gluconeogenesis, and the Pentose
`Phosphate Pathway 521
`15 Principles of Metabolic Regulation: Glucose and
`Glycogen 560
`16 The Citric Acid Cycle 601
`17 Fatty Acid Catabolism 631
`18 Amino Acid Oxidation and the Production
`of Urea 656
`19 Oxidative Phosphorylation and
`Photophosphorylation 690
`20 Carbohydrate Biosynthesis in Plants and
`Bacteria
`751
`21 Lipid Biosynthesis 787
`22 Biosynthesis of Amino Acids, Nucleotides, and
`Related Molecules 833
`23 Hormonal Regulation and Integration of
`Mammalian Metabolism 881
`
`INFORMATION PATHWAYS 921
`Ill
`2· Genes and Chromosomes 923
`DNA Metabolism 948
`2
`RNA Metabolism 995
`2
`Protein Metabolism 1034
`2
`?8 Regulation of Gene Expression 1081
`
`Appendix A Common Abbreviations in the Biochemical Research
`Literature A-1
`Appendix B Abbreviated Solutions to Problems AS-1
`Glossary G-1
`Credits C-1
`Index 1-1
`
`1 The Foundations of Biochemistry 1
`1.1 Cellular Foundations 3
`('\'!Is \n' t lw SI 111<·! 11r;il 1111d l•'t11\l'I in11al I l1111 s of \II I ,1vl11g
`;l
`Organisms
`Ct'llu lar Di111<'11sin11s An' l.im11l•d by O:>.~i,tc •11
`()i ITusion
`I
`Tlwn' /\n' Tim'<' Dist mrt I ln111ni11s of Lite•
`r,
`f:.w•//1•1·icll1<1 mli Is the• !\lost Sill(liPd Prnka1yot11· ! 'c•II
`l~ukuryot ir C'<'lls I la\'<' n V;iri<'IY of l\k111lirn1u111!-l t >rg,1111 •llc "l,
`Whkh Can lk lsnlnl t•d for Si 11dy
`fi
`Th<' C,vt oplasm Is Ori,tn11iz<•d h,v tit<' C,vtnsi,.plf'irn1 ;111d I:,
`I ligltly Dy 11at11iC'
`!l
`IO
`Cells Build S11prnn1ol<•1·11lar St rnr t 11n•s
`111 Vitro Slucli('S Mny Ov<'rlool,. li11port;111I l 11lr•raC'I IOllli :11111J11g
`Mol<'<'lll<'s
`I I
`
`1.2 Chemical Foundations 12
`11io111ol('('llil'S /\rr Co111po1111cls or Ca rho11 w1111 ;i V;,rl!'I y of
`Funclio11al Groups 1;3
`Cells Contain a LJ11ivc•rs:il S<•t of' S111all Mo l< •,·1 111•1-1
`1'1
`Marromokcul<'s /\r<' I Ii<' Major Const ii 111•111 s of' Cl'l ls
`Box 1- 1 Molecular Weight, Molecular Mass, and Their
`Correct Units 15
`T h r cc-Dimc11sional SLl'UCLI H'C Is lksf'rilwd l1y Co111ig11rat ir111
`ancl Confonnalion 16
`Box 1-2 Louis Pasteur and Optical Activity: In Vino, Verltas 19
`:w
`' lnlcraclions bclwecn f3io1110IP<·1ilcs /\re SI l'l'POSpPc·il'ir-
`
`I r,
`
`1.3 Physical Foundations 21
`Living Organism s 8xisl in a Dynamic Stf'a<ly Stal<•, Nr•vr•r at
`l~quilibrium wilh Their Surrou ndings 2 1
`Organisms Transform Energy and M alL<'r frorn Ttl<•ir
`Surround ings 22
`The Flow o r Eleclrons Provides Energy for Orga11is111s i2
`Crcaling and Maintaining Order Requires Work and
`Energy 23
`Energy Coupling Links Reaclions in Biology 2:~
`Box 1-3 Entropy: The Advantages of Being Disorganized 24
`KN, and 6 G AJ·e M easures of a Reaction's TPndt•nc:y t,,
`Proceed Spontaneously 26
`Enzymes Promote Sequences o f Chemical R<•act ions 2fj
`Metabolism Is ReguJated to Achieve Balance and
`Economy 27
`
`1.4 Genetic Foundations 28
`Genetic Continujty Is Vested in Single D~A .\fo)N·ulcs 2!J
`The Structure of DNA Allows for Its Replication and ftepair
`with Near-Perfect Fidelity 29
`The Linear Sequence in D:-.:A EncodPs Proteius \\'Ith Tt1rPf,-
`Dimensional Structures 29
`
`1.5 Evolutionary Foundations 31
`Changes in the Hereditary Instructions Allo\\ Evolutic,n 31
`Biomolecules First Arose by ChNru<:al Evolution 32
`Chemical Evolution Can Be Sirnulati::d m the Laborntory 32
`RNA or Related Precursors \lar HavP Been the first <ienes
`:32
`and Catalysts
`Biological E,·olution Began More Til.in ·1nree and
`a Half Billion Years Ago 34
`The Fir:,t Cell \\ as Probably a Ghemoheterotroph 34
`Eukaryotic Cells E-.ohed from Prokaryotes in ~eraJ
`~,ages 34
`.\lolecular Aliatom) ReHals Ernlutionary Relat onships 36
`
`MPI EXHIBIT 1036 PAGE 4
`
`
`
`Functional Genomics Shows the Allocations of' Genes to
`Specific Cellular Processes 38
`Genomic Comparisons Will Have Increasing lmporlance in
`Human Biology and Medicine 38
`
`I STRUCTURE AND CATALYSIS 45
`2 Water 47
`2.1 Weak Interactions in Aqueous Systems 47
`Hydrogen Bonding Gives Water Its Unusual Properties 47
`Waler Fo1111s Hydrogen Bonds with Polar Solutes 49
`Water Interacts Electrostatically with Charged Solutes 50
`Entropy Increases as Crystalline Substances Dissolve 51
`onpolar Gases Are Poorly Soluble in Water 52
`Nonpolar Compow1ds Force Energetically Unfavorable
`Changes in the Structure of Water 52
`van der Waals Interactions ATe Weak Interatomic
`Attractions 54
`Weak Interactions Are Crucial to Macromolecular Structure
`and Function 54
`Solutes Affect the Colligative Properties of Aqueous
`Solutions 56
`Box 2-1 Touch Response In Plants: An Osmotic Event 59
`
`2.2 Ionization of Water, Weak Acids, and Weak Bases 60
`Pure Water ls Slightly Ionized 60
`The Ionization of Water Is Expressed by an Equilibrium
`Constant 61
`The pH Scale Designates the H+ and OH(cid:173)
`Concentrations 61
`Box 2-2 The Ion Product of Water: Two Illustrative Problems 62
`Weak Acids and Bases Have Characteristic Dissociation
`Constants 63
`Titration Curves Reveal the pKa of Weak Acids 64
`
`2.3 Buffering against pH Changes In Blologlcal Systems 65
`Buffers Are Mixtures of Weak Acids and Their Conjugate
`Bases 6G
`A Simple Expression Relates pH, pKa, and Buffer
`Concentration 66
`Weak Acids or Bases Buffer Cells and Tissues against pH
`Changes 07
`Box 2-3 Solving Problems Using the Henderson-Hasselbalch
`Equation 67
`Box 2-4 Blood, Lungs, and Buffer: The BlcartJonate Buffer
`System 69
`
`2.4 Water as a Reactant 69
`2.5 The Fitness of the Aqueous Environment for Living
`Organisms 70
`
`3 Amino Acids, Peptides, and
`Proteins 75
`3.1 Amino Acids 75
`Al11i110 Ac·irls 8han• Colllmon 81 ruct ural fpat 111·(•s 7G
`Thr• A111i110 Adel ltc,sid1ws i11 l'rolc•ins Arc
`1, 81 <·rc•oisornc•rs 77
`A111i1w Ar-ids Can Be• Classificcl by ll Group 78
`IJ1ll'o1nr11011 A111i110 Adels Also ilavc• l111porla11t 1-'u11clions 80
`A111i11u Ac·irls Can Ac·I as A<·icls a11d BasPs 8 I
`
`Contents
`
`xv
`
`Box 3- 1 Absorption of Ught by Molecules: The Lambert-Beer
`Law 82
`Amino Acids Have Characteristic Titration Curves 82
`Titration Curves Predict th e Electric Charge of Amino
`Acids 84
`Amino Acids Differ in Their Acid-Base Properties 84
`
`3.2 Peptides and Proteins 85
`Peptides Are Chains of Arni.no Acids 85
`Peptides Can Be Distinguished by Their Ionization
`Behavior 86
`Biologically Active Peptides and Polypeptides Occur in a
`Vast Range of Sizes 86
`Polypeptides Have Characteristic Amino Acid
`Compositions 87
`Some Proteins Contain Chemical Groups Other Than
`Arni.no Acids 88
`There Are Several Levels of Protein StructW"e 88
`3.3 Working with Proteins 89
`Proteins Can Be Separated and Purified 89
`Proteins Can Be Separated and Characterized by
`Electrophoresis 92
`Unseparated Proteins Can Be Quantified 94
`
`3.4 The Covalent Structure of Proteins 96
`The Function of a Protein Depends on Its Amino Acid
`Sequence 96
`The Amino Acid Sequences of Millions of Proteins Have
`Been Determined 96
`Short Polypeptides Are Sequenced Using Automated
`Procedures 97
`Large Proteins Musl Be Sequenced in ma.lier Segments 99
`Amino Acid Sequences Can Also Be Deduced by Other
`Methods 100
`Box 3-2 Investigating Proteins with Mass Spectrometry 102
`SmaU Peptides and Proteins Can B
`hcmically
`Synthesized 104
`Alnino Acid Sequences Provide Important Bioch mica!
`I 06
`Information
`
`3.5 Protein Sequences and Evolution 106
`Protein Scqu nccs Can Elucidate the llistory o[ Life on
`Earth 107
`
`4 The Three-Dimensional Structure of
`Proteins 116
`··
`4.1 Overview of Protein Structure 116
`A Protein's Conformation Is Stabilized Largely by Weak
`Int ractions
`11 7
`The Peptide Bond ls Rigid and Planar
`
`I 18
`
`4.2 Protein Secondary Structure 120
`The a I lelix Is a Common Protein Secondary Structure 120
`Amino Acid Sequence Affc ·Ls a 11 !ix Si ability 121
`Box 4-1 Knowing the Right Hand from the Left 122
`The /3 011fon11ation Organizes Polypcptid
`hains into
`Sheets 123
`/3 Turns ArP Con11non in Prol Pins 123
`Co111111011 SPcondary Slrncturt's I lave• Characteristic Bond
`Angles and Amino Aeid Contc>nl 124
`
`4.3 Protein Tertiary and Quaternary Structures 125
`Fibrous ProlPins Arc Ad~1plcd for a Stnrclural Func:Lio11 126
`
`MPI EXHIBIT 1036 PAGE 5
`
`
`
`xvi
`
`Contents
`
`Box 4-2 Permanent Wa¥1ng Is Blochemlcal EnllnNrfnC 127
`Structural Diversity R<'nrcts FurwtiomJI lhv<-ro;lf y 111 rn,,t,ular
`Proteins 129
`Box 4-3 Why Sallors, Explorers, and College Students Sfloulcl Elt
`Their Fresh Fruits and Vegetables 130
`Myoglobi11 Provi<led Early Ch1r•s abo11I lh<• CnrnplP,cily ,,f
`rnobular Protrin 8 tn1r l\1r<•
`I '.J2
`Glol>ular Proteins II ave ,1 Vari<•! y or TN! i;1ry 81ru,111rr·s 1 :11
`Box 4- 4 Methods for Determining the Three-Dlmentlonal StructuN
`of a Protein 136
`Analysis of Many Olobular Proteins Rr•vrals Comrnrm
`Structural Pctlterns J:JS
`Protein Motifs Ar<> the Basis for Protr•in 8lnwt11ral
`Classi!kation 14 I
`Protein Quaternary Structur!'s lfa11gr from Simr,I1• IJm1ns tr,
`Larg(' Complexes 144
`There J\r(' Limits to the Siz<' of Proteins
`
`I4/i
`
`4.4 Protein Denaturatlon and Folding 147
`Loss of Protein Structu re Result.~ in Loss of Functir,n 147
`Arni.no Acicl Sequence Detennines 1'C'rt1ary S!nlf'l11n· 14fS
`Polypeptides Fold Rapidly by a Stepwise Pr0<•f'SS 148
`Box 4- 5 Death by Mlsfoldlng: The Prton Diseases 150
`Some Proteins Undergo Assisted folding 15 1
`
`5 Protein Function 157
`5.1 Reversible Binding of a Protein to a Upnd:
`Oxygen-Binding Proteins 158
`I f)i3
`Oxygen Can Be Bound Lo a Herne Prosthetic Group
`I F;O
`Myoglobin I las a Single Binding Site for Oxygen
`Protein-Ligand lnteracLions Can Be Described
`Quantitatively 160
`Protein Structure Affects How Ligands Bind 162
`Oxygen Is Transported in Blood by Hemoglobin
`l 62
`H emoglobin Subunits Are Structurally Similar to
`Myoglobin 163
`Hemoglobin Undergoes a Structural Change on Binding
`Oxygen 164
`Hemoglobin Binds Oxygen Cooperatively 164
`Cooperative Ligand Binding Can Be Described
`Quantitatively 167
`'Iwo Models Suggest Mechanisms for Cooperative
`Binding 167
`Box 5-1 Carbon Monoxide: A Stealthy KIiier 168
`Hemoglobin Also Transports H+ and CO2 170
`Oxygen Binding to Hemoglobin Is Regulated by
`2,3-Bisphosphoglycerate J 71
`Sick.le-Cell Anemia Is a Molecular Disease of Hemoglobin 172
`
`5.2 Complementary Interactions between Proteins and
`Ligands: The Immune System and lmmunogJobullns 174
`The Immune Response Features a Specialized Array of <A;lls
`and Proteins 1 75
`Self Is Distinguished from Nonself by the Display of Peptides
`on Cell Surfaces 176
`Antibodies Have 'Iwo Identical Antigen-Binding Sites 178
`Antibodies Bind Tightly and SpeciJically to Antigen 180
`The Antibody-Antigen Inter action Is the Basis for a Varlet>·
`of Important Analytical Procedur es 180
`
`5.3 Protein Interactions Modulated by Chemical Energy:
`Actln, Myosln, and Molecular Motors 182
`The Major Proteins of Muscle Are Myosin and Aetin J fs2
`Addi! ional Proteins Organize thf' 11un and Thick filami:nt~
`into Ordered Structures 184
`
`My,111111 '1111, k J,'1l:1111••r1fJ11 Hlltf1 nl11t1P, At tlr, 'n,1,.
`f1l,11111•r,I If I W.,
`
`l'f1,
`
`'/)JI}
`
`6 Enzymes 190
`1.lAA . . ••• ..... •r.,... ttt
`M'"'' 1-:111.ym,·!! Ari• l'r,lf.! Im,
`J',J
`1-:111.yrrr, !I Ari• f,lar !!1fi, II t,v ttw ICI :11 u,,i, 'fl!('}' <,111;dy11
`,.2,._r..,., .. tn
`I 'f~
`1-;111,y1111~ Af(1•1 I ICI a,111111 f(;ft, , N•ll f':111Jildfrl;.
`f<1•;,r ,,,,,, f(:1t•11 ;ir,!J f-...:111lht,rti Jf;,v•• ,,,,, .,,. ·,,,., t11111'Jy11A11 It
`I 1<•r111,11,,11!. Hy,;
`/\ V••w J•nr,, 11,l•!fl 1-:x1,la111 tl11 (;,:,t.:dytlt f',,w, t 111111 '>fl' dfv !y
`I !iii
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`f11,111111,.1·tl m tt,,. 'fr;,m,it,,,,, ')1;,1, 1:,;
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`l!M
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`8.3&u,NIUllttlctAa•Ap,reedltoUnllll1Ntlnflni
`M ...... 202
`S11l>!1l.rat.1• (j,n,,-, ,1r:,t11,1, Aff,-,1~ tJ ,. J!JtJP r,f f,, 1,1 r,,
`<;,11.,afy;,p,J J(l.-.wri,,11-.
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`Rt-an,,,,, J<;,V· r;:,, I~· J,;;q,r•~#•d <1, m111,I;,I v, 11
`'/Jf.~
`KJn,:r.i,; l1;;.r;i,111••.1•r '> A,,. UY$J 111 '~m'V"'' J-,1 ;,,11,~
`Activilit~ 2lr,i
`80ll e-1 Tf'NSf.,..._ sf u.. Mldl1ll1 Mn•"'• au: n.
`Double Redp,oeal Plot 206
`.\fariy f;11zym1:<> r,iJi;,ly-d ; f(l:W,;ti,;111> 1111.li 'jw,, ,,r tt,r,
`SHt~t rar ' :!t 2'fl
`l'rf;-Sl.f..:WJ:,r SI.av• Y.i1 1:111;s fi~11 l'r1r/11!,J f,•/1[$!•:.i! , , for i:,j/1411
`fl#~r;t1r,n Sll;r,'~ 2''1
`f;nzym,1, Ari; S11l1J<-..i;I. ti, HfN,~r...fr;h; 'ii fr,,,., ''f1>1Jk-
`lnhib1tir,n 2,,_,
`80ll 8-2 IOMdc Tesb fo, ~ l ..... ttoon llled11 d - 21'
`1-:nzymr; Acfr.ily f~:f,':r11lv,11 f,H ~J~
`8.A Examples of EnzymatSc R.eacUoM 213
`111•; Ch,Yln<Jl,rffJ!'IIO J,11:(;ti:,1 .:,1, ft·;,,. . .,,-:,. /11:)!;.titJfl ,uyJ
`fJf!1.ll:ylatfon fJf a $1;1 kl9r.&,;•; 2 J:~
`He,:,;Jdf";l; CNl1:r9/1% lt,rlty;1$1 fit II( £:,l;'At(',Nt ,~udr~ i , /
`1l1f; En,,la<se J~:a,~i,,, 1,f,:;t;r011i<,1r 1:1::f, iiI!:1> j,1.:J J1,s ·• t. 'J
`80ll 6-3 &ldeftce fo, f;nz:Jlle-T~ State
`~ 220
`tys<Jz;·,w; Us,~ Two 17'Jef:1~;1:
`Reac.1.l<>JL'> 2'&
`8.S Regulato,y Enzymes 225
`AJlrJStcriC fat'»,iTllf.;$; {frvJf;(;'jJ (./J111'Jm~ '(A<aJ ( ,.;~ 7/!S i:
`~f:,f';rlY: ti, ... l,AUM!Jt ~i:idfr~ 2'~
`Jo /.!&ny J"«ttff1,a,~ a Jv~.1~t,:rl St,~, h ' -~
`d-" rlj' ;,.:
`Ailoou:ri<; Er!!Z,,1' f; 2'.di
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`.\fi<:t~1J.<s-M1:rit1;11 I~· ~ •;i,K ~7
`S<Jrr e ~1~,r, t~,z. " -i:$ U:~•:71, "'""'•"I~
`l,f,,..jjf~tlf.1T1 ~
`Ph,,ciptlf,()1 <,r1111f~ .ff-r~::< : "~ &..,x:w:1- ;,,;id C~;,"Uf~
`A<.:fr,il,Y <,I Pr,1'.ci: ·• Ws
`• ~w, r.x.q; - ..Ie 1~
`MuJtipk: f '~ )lj~ "~
`(;~J(••.((h Z:-;i)
`S<,crtf; LrrZ' ,,.,~ 4I1'1 ()tt;:,. hrJlerr Ju,-_ I~ itJ'j
`Pff,.,~,. ~-" (;lf~.<19,': ,,c ~ f-r z:,11!.IP. Pr!.-af:
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`MtdlM ~' ~
`
`:,J.d'::fJJAIDV, 11~,;t•~
`
`(A.A~
`
`MPI EXHIBIT 1036 PAGE 6
`
`
`
`Carbohydrates and Glycobiology 238
`7. 1 Monosaccharldes and Dlsaccharldes 239
`The 1\rn Families of Monosaccharides Are Aldoses and
`Ketoses 239
`Monosaccharides Have Asymmetric Centers 239
`The Common Monosaccharides Have Cyclic Structures 240
`Organisms Contain a \ 'ariety of Hexose Derivatives 243
`~1onosarcharides Are Reducing Agents 244
`Disaccharides Contain a Glycosidic Bond 245
`
`7.2 Polysaccharides 247
`Some Homopolysaccharides Are Stored Forms of Fuel 247
`Some Homopolysaccharides Serve Structural Roles 248
`Steric Factors and Hydrogen Bonding ln1luence
`Homopolysaccharide Folding 250
`Bacterial and Algal Cell Walls Contain Structural
`Heteropolysaccharides 252
`Glycosaminog)ycans Are Heteropolysaccharides of the
`Extracellular Matrix 253
`
`7 .3 Glycoconjugates: Proteoglycans, Glycoprotelns, and
`Glycollplds 255
`Proteoglycans Are Glycosaminoglycan-Containing
`Macromolecules of the Cell Surface and
`Extracellular Matrix 256
`Glycoproteins Have Covalently Attached
`Oligosaccharides 258
`Glycolipids and Lipopolysaccharides Are Membrane
`Components 260
`
`7.4 Carbohydrates as Informational Molecules: The Sugar
`Code 261
`Lectins Are Proteins That Read the Sugar Code and Mediate
`Many Biological Processes 262
`Lectin-Carbohydrate Interactions Ar e Very Strong and
`Highly Specific 264
`7.5 Working with Carbohydrates 267
`
`~ Nucleotides and Nucleic Acids 273
`8.1 Some Basics 273
`Nucleotides and Nucleic Acids Have Characteristic Bases
`and Pentoses 273
`Phosphodiester Bonds Link Successive Nucleotides in
`Nucleic Acids 276
`111e Properties of Nucleotide Bases Affect the Three-
`Dimensional Structu re of Nucleic Acids 278
`
`8.2 Nuclelc Acid Structure 279
`DNA Stor es Genetic Information 280
`IJNA Molecules Have Distinctive Base Composilions 28 1
`DNA Is a Double J lclix 282
`DNA Can Occur iJ1 Differ ent Three-Dimensional
`l~orms 283
`Cc•rtain DNA Sequences Adopt Unusual Structures 285
`Messengt•r HNAs Code for Polypeptide Chains 287
`Many lcNAs Have More Complex Three-Dimensional
`Structures 288
`
`8.3 Nuclelc Acid Chemistry 291
`1){.i_ublc-lf<'lical DNA and HNA Ca11 Be Denatured 29 I
`NuclPic Ac-ids from Different Species Can 1-'or m I lybricls 292
`N1~clc>otidPs and Nucleic Acids Undergo No1wnzyrnatic
`l'ransfonnations 293
`Some 13asc•s of DNA Ar<• Methylated 296
`
`Contents
`
`xvii
`
`The Sequences of Long DNA Strands Can Be Determined 296
`The Chemical Synthesis of DNA Has Been Automated 298
`8.4 Other Functions of Nucleotides 300
`Nucleotides Carry Chemical Energy in Cells 300
`Adenine Nucleotides Are Components of Many Enzyme
`Cofactors 301
`Some Nucleotides Are Regulatory Molecules 302
`
`9 DNA-Based Information Technologies 306
`9.1 DNA Cloning: The Basics 306
`Restriction Endonucleases and DNA Ligase Yield
`Recombinant DNA 307
`Cloning Vectors Allow Amplification of Inserted DNA
`Segments 311
`Specific DNA Sequences Are Detectable by
`Hybridization 31 4
`Expression of Cloned Genes Produces Large Quantities of
`Protein 315
`Alterations in Cloned Genes Produce Modified Proteins 316
`
`9.2 From Genes to Genomes 317
`DNA Libraries Provide Specialized Catalogs of Genetic
`Information 318
`The Polymerase Chain Reaction Amplifies Specific DNA
`Sequences 319
`Genome Sequences Provide the Ultimate Genetic
`Libraries 321
`Box 9-1 A Potent Weapon In Forensic Medicine 322
`
`9.3 From Genomes to Proteomes 325
`Sequence or Structural Relationships Provide Information on
`Protein Function 325
`Cellular Expression Patterns Can Reveal the Cellular
`Function of a Gene 326
`Detection of Protein-ProteiJ1 Interactions Helps to Define
`Cellular and Molecular FuncLion 327
`
`9.4 Genome Alterations and New Products of
`Biotechnology 330
`A Bacterial Plant Parasite Aids Cloning in Plants 330
`Manipulation of Animal Cell Genomes Provides Information
`on Chromosome Structure and Gene Expression 333
`New Technologies Promise to Expedite the Discovery of
`New Pharmaceuticals 335
`Box 9- 2 The Human Genome and Human Gene Therapy 336
`Recombinant DNA Technology Yields New Products and
`Challmgcs. 338
`
`Lipids 343
`10
`10.1 Storage Lipids 343
`Fatty Acids Arc l lydrocarbon D rivativcs 343
`Triacylglycerols Are F'atty Acid Esters of Glycrrol 345
`Triacylglyccrols Provide Stored Energy and Insulation 346
`Many r oods Contain 'Iriacylglyccrols 346
`Box 10- 1 Sperm Whales: Fatheads of the Deep 347
`Waxes Serve as Energy Stores and Water Repellents 348
`
`10.2 Structural Lipids In Membranes 348
`Glycerophospholipids Arc Derivatives or Phosphatidic
`Acicl 349
`Som Phospholipicls I lave Ether-Linked fatty Acids 349
`Chloroplasts onlain Galactolipids and Sulfolipicls 35 1
`Archa bacteria Contain Uniqur Membrane Lipids 352
`Sphingolipicls Arc Derivalives of Sphingosinc 352
`
`MPI EXHIBIT 1036 PAGE 7
`
`
`
`XVIII
`
`Contents
`
`Sphit~nlipids nt ('<•II Surfm•ps An • Sil es of Biolo1,tkal
`:1G:I
`H1•1·o~ni1 ion
`l'hnsphnlipids and Sphi11golipi<ls Ar<' P PRnHl<'ct in
`:Jr>4
`l.ysns,,nll'S
`Sl!•rols Ha\'<' Four l·'11s<'d Ci1rhnn Hings 3:l4
`Box 10- 2 lnhertted Human Diseases Resulting from Abnormal
`Accumulations of Membrane Lipids 356
`
`10.3 Uplds as Signals, Cofactors, and Pigments 357
`1'hosphat idyli11osi1llls and Splli11gosilw D<' rivativ1•s Acl as
`1111 racl'll11lnr Si~nals
`:lS7
`Eicosanoids Carry MrssngPs 10 Nrarhy Cells 368
`S11'roid Hnrm n1w s Carry M<'sSc\Rf'S be t.wC'r-11 TissuC's 369
`Plants lls0 l'hosphatidyli11osi1 o ls, St1•roids , and
`Ekns;moidlik1· Cnmpmmds in Si~nali11g
`:JOO
`:1(i0
`\ 'i1ami11s A nnct I) An • Honnonc l'rl'cm-sors
`Vi1rnnins E a nd K an<l t lw Lipid (,.)11i11011es Arr Oxidalion-
`lkd1wt inn Corac1 ors ao2
`n olidwls Ac-t iw1t f' Sngnr Pn•r11rsor for BiosynthC'sis 363
`
`10.4 Working with lipids 363
`:364
`Lipid l~xt.rnr tinn Ht>quirr-s Orp.anif' ~o lv011Ls
`Adsorption Chromat ography Sepnrat<'s Lipids or Different
`I 'ola rity
`:J(i!)
`Gas-Liqu id Chromatography R0solve s MixturPs or Volatile
`Lipid lkriviilive's J(ifJ
`Sp ecil'i<' H:-·d rol~•sis Aids in OPterminalion or Lipid
`;3ti5
`St rnc t lff('
`Mass S p0ctrom et,ry Hevc>als Complete Lipid Structure 365
`
`11 Biological Membranes and Transport 369
`11.1 The Composition and Architecture of Membranes 370
`Each 'Type uf M0rnbra11e Has Characte ristic Lipids ,md
`Proteins 370
`All Rinlngical Mr mbranes Share Some 1"undame11t.al
`;37 1
`Prupt>rt ies
`A Lip id BilayC'r b the Basic Struc tural Elem ent of
`M0111bra11es 371
`Pt>ripheral Me m brane Prote ins Are Ea sily Solubiliz ed 373
`Manv Membrane Proteins Span tl10 Lipid Bilaye r 373
`h H0gral Proteins Are Held in the Membrane by Hydrophobic
`Int eractions with Lipids 375
`Tlw Topology of a n lntq~ra l Membrane Protein Can Be
`Predicted from Its Seque nce 376
`Coval\'ntly At taclwd Lipids An chor Some Membrane
`Prot t'ins 378
`11.2 Membrane Dynamics 380
`Acy! ( iroups in the> Bila)'<'r Inte rior /\re Orde red to Va1yi11g
`:380
`Degrf'PS
`TI-ansbilayer Movemen t or Lipids Requi res Catalysis 381
`Lipids and Proteins Diffusl' La t c•rally in the Bilayer 382
`Box 11- 1 Atomic Force Microscopy to Visualize Membrane
`Proteins 384
`Sphi11golipids and Ch olf'stc>rol Clust rr Togethe r in Me mbrane
`:38:3
`Rafts
`Cawolins l)pflne a Special Class ()f MPmbrane Rafts 385
`C0rtaiJ1 Integral Proteins M<'diatP Cell-Cell lnleractions and
`Adhesion
`;JR!)
`Membrane F'usion ls Cent l"dl to Many Biological Processes ;187
`
`11.3 Solute Transport across Membranes 389
`Passi\'f> Tra11s11un Is FacilitaLC'(I by Mt>mbram' Protl'ins 389
`Tra11spurt t>f'S Can B<• (irou1wd into Superfamilies 13ased 0 11
`Tlwir StnH·tures :l!J J
`
`Thr <lh1cos<' Trnnsporte r of Erythrocytl's Mediates Pa.'lsivc
`'Transport :m:1
`Th!' C:hloricl0-Hicarbonat.f> F,xchanger Calaly,:es
`Eler t roneutral Cotransport or Anions across t.he Plasma
`M<.'mhrane
`!l!}G
`Box 11-2 Defectlwe OlueoN HIIWlltt,n.n.p.tln,,_ ,.,_ _,
`Diabetes 398
`Active 'Transport Results in Solute Movement !lWlinst a
`Concmtrntion or E lectroche mical Gradient 397
`P-1'ypc ATPases Und ergo Phosphorylation during Their
`Cata iyt ic Cycles 398
`P-Type Ca:.: ' Pumps Maintain a Low Concentration of
`Calcium in the Cytosol 400
`F-Type ATPas<'s Are Reversible, ATP-Driven Proton
`Pumps 401
`ABC n-ansporters Use ATP to Drive the Ac tive Transport. of
`a Wide Variety of Substrates 402
`Ion Gradients Provide the E ne rgy for Secondary Active
`Transpmt 402
`Box 11-3 A Defecthe Ion Channel In Cystic Fibrosis 403
`Aquaporins Form Hydrophilic Transmembrane Cha nnels for
`the Passage of Water 406
`Jon-Selective Channe ls Allow Rapid Movemen t of Ions across
`Membranes 408
`Ion-Channel Function Is Measure d Electrically 408
`The Structure of a K+ Channe l Reveals the Basis for Its
`Specificity 409
`The Neuronal Na+ Channel ls a Voltage-Gated Ion
`Channe l 410
`The Acetylch oline Receptor Is a Ligand-Gated Io n
`Channe l 41 1
`Defective Ion Channels Can Have Adverse Physio logical
`Consequences 415
`
`12 Biosignaling 421
`12.1 Molecular Mechanisms of Signal Transduction 422
`Box 12- 1 Scatchard Analysis Quantifies the Receptor-Ugand
`Interaction 423
`
`12.2 Gated Ion Channels 425
`Ion Cha nnels Underlie Electrical Signaling in Excitable
`Cells 425
`The Nicotinic Acetylcholine Receptor Is a Ligand-Gated Ion
`Channel 426
`Voltage-Gated Ion Channels Produ ce Neurona l Action
`Pote ntials 427
`Neurons Have Re ceptor Channels That Respond to Diffe rent
`Neurotransmitte rs 428
`
`12.3 Receptor Enzymes 429
`The Insulin Receptor ls a Tyrosin e-Specific Protein
`Kinase 429
`Recepto r Guanylyl Cyclases Ge ne rate the Sec ond Me sse nge r
`cGMP 433
`
`12.4 G Protein- Coupled Receptors and Second
`Messengers 435
`The /3-Aclrc 11e rgic Receptor Syste m Ac ts through the
`Seto11tl MPSSPng1•r cAMP 435
`The /3-Adre 11e rgic Receptor ls Uesensitized by
`Phosphoryla tion 43H
`Cyclic AMP Arts as a St•c·o1 IC l MPsse>ngl:'r for a Nu mber o f
`-1-1 I
`Regula to ry Molet:t1lt's
`1\vo Sl•coml tvll'SS<'ngers Arr- DNiwd from
`Plwsplu1tidyli11osito ls
`•-t-12
`
`MPI EXHIBIT 1036 PAGE 8
`
`
`
`Contents
`
`xix
`
`( ';1l<i 11111 Is a SProncl Mrssrngr-r in 1-lany Signal
`l'rans<hwt ions 442
`Box 12- 2 FRET: Biochemistry Visualized In a Living Cell 446
`
`A<·I 11al Prc'<'-Ener1-tv ChangPs Depend on Reactant and
`Proclur·t CoIH·<·nl rations 4in
`Standard FrPP-Enr rgy Chanl-(es Are Additive 494
`
`12.5 Multivalent Scaffold Proteins and Membrane Rafts 448
`l'rotf'1n ~1od11l<•s Bind l'ltospltory lat('ci Ty r, S(•r, or T ltr
`l{,•s1<h1Ps in l'.irtnN l'rot ('ins 448
`~1c•mhra1w l{;1ft s and Cavc•ola<' May S<'grrgatc Signaling
`l'rotPillS 4!i l
`
`12.6 Slgnallng In Microorganisms and Plants 452
`Bart<•rial Signaling Entails l'ltosphorylal ion in a 1\vo(cid:173)
`Component SystC'ltl 452
`Signaling Sys I rms of Plan Is I lave Some of 1 he Same
`Components lJs<'d h.v Microbes and Marnmals 452
`Plants lktC'rt EthylC'n(' through a 1\vo-Componenl. System
`ancl a MAPK Cascadr 4G4
`HeceptorlikC' Protf'in Kinases 1)·anscluce Signals from
`Pf'pt ides and 13rassi11osLeroicls 455
`
`12. 7 Sensory Transduction In Vision, Olfactlon, and
`Gustatlon 456
`Light Hyperpolarizes Rod and Cone Cells of Lhe Vertebrate
`Eye 456
`Light 1)·iggers Conformational Changes in the Receptor
`Rhodopsin 457
`Excited Rhodopsin Acts through the G Protein Transclucin
`to Reduce the cGMP ConcentraLion 457
`AmplilicaLion of Lhe Visual Signal Occurs in Lhe Roel and
`Cone Cells 458
`The Visual Signal Is Quickly Terminated 458
`Rhoclopsin Is Desensitized by PhosphorylaLion 459
`Cone Cells Specialize in Color Vision 460
`Vertebrate OlfacLion and GusLation Use Mechanisms Similar
`LO Lhe Visual SysLC111 460
`Box 12-3 Color Blindness: John Dalton's Experiment from the Grave
`461
`G Protein-Coupled Serpentine Receptor Systems Share
`Several Peat11res 462
`Disruplion of G-Protein Signaling Causes Disease 4G4
`
`12.8 Regulat.lon of Transcription by Steroid Hormones 465
`12.9 Regulation of the Cell Cycle by Protein Klnases 466
`The Cell Cyde Has Pour Stages 466
`Lc•vels of Cycli11-Depe11dc nt Protein J(jnascs Oscillate 467
`CIJKs Regulate Cell Division by Phosphor.vialing Critical
`Pr0Lei11s 4 70
`
`12.10 Oncogenes, Tumor Suppressor Genes, and Programmed
`Cell Death 471
`OnC'oge11cs Are Mutant Forms of the Genes for ProtPins T hat
`l{egulat,e the Cell Cycle 47 1
`O(-f(•c:Ls in Tumor Suppressor Genes Remove Normal
`UcsLrai11ts on CeU Division 472
`Apriptusis Is Programmed CeU Suicide 47:J
`
`]) BIOENERGETlCS AND METABOLISM 481
`
`13 Principles of Bioenergetics 489
`13.1 Bloenergetlcs and Thermodynamics 490
`lliologi, ·aJ I·:11l'rgy 'Jhrnsfo1rnaLio11s Obey Lhe Laws of
`'l'lu·n11ody11a111i('s 4!JU
`C<'!Js ft(•quin• Sourc<·s of Fret' Energy 4!-J I
`Tiu• 8ta1 1dard Fn·e-[•;nergy Change ls !Jirectly Helal t•d l o tlw
`J•;4uililiriu111 Co11slal1t 4!-JI
`
`13.2 Phosphoryl Group Transfers and ATP 496
`Tl w Fn•r -1::rn·rgy Chang£' for ATP Hy drolysis Is Large and
`NPgal ive 49n
`01 her l'hosphorylated Compounds and Thiocsters Also Have
`LargP Frf'e Erwrgics of Hydrolysis 497
`Box 13-1 The Free Energy of Hydrolysis of ATP within Cells: The Real
`Cost of Doing Metabolic Business 498
`ATP Providl's Energy by Group Transfers, Not by Simple
`I lyclrolysis 500
`ATP Donates Phosphoryl, Pyrophosphoryl, and Aclenylyl
`Groups 502
`Box 13- 2 Firefly Flashes: Glowing Reports of ATP 503
`Assembly of Informational Macromolecules Requires
`Energy 504
`ATP Energizes Active Transport and Muscle
`Contraction 504
`Tra11sphosphorylaLions heLween Nucleotides Occur in All
`Cell Types 505
`Inorganic Polyphosphate Is a Potent ial Phosphoryl Group
`Donor 506
`Biochemical and Chemical Equations Are Not
`lclcnlical 506
`
`13.3 Blologlcal Oxidation-Reduction Reactions 507
`The Plow of J::lectrons Can lJo Biological Work 507
`Oxidation-Reduction Can Be Described as
`l lalf-Reactions 508
`Biological Oxidations OftC'n Involve Dehydrogenation 508
`I-kcluction Potentials MeasurP Affinity for Electrons 509
`Standard HPclur Lion Potentials Can Be Used to Calculate the
`Pree-Energy Change 5 10
`Cellular Oxidation of Glucose to Carbon Dioxide Requires
`SpeC'ializccl Electron Carriers 5 12
`A Pew 1y pl's of Coenzyrnes and Proteins Serve as Universal
`Ele<.:tro11 Carriers 5 12
`NAOH and NADPH Act wiLh DPhyclrog<'nases as Soluble
`Electron Carriers 5 12
`Dietaiy Dclicicncy of Niacin, the Vitamin rorm of NAO ,met
`NADP, Causes Pellagra 5 14
`Plavin NuclPoLides An' Tightly Bound in Plavoproteins 5 15
`
`lycolysis, Gluconeogenesis, and the
`~
`~se Phosphate Pathway 521
`14.1 Glycolysls 522
`An Owrvi<·w: Glycolysis I las 'l\vo Phas0s 523
`The Pr<'paratory PhasP or Glyrolysis
`Requires ATP 525
`Th<' Payoff Phas0 of' Glycolysis Proclures ATP and
`NADH 520
`The Overall Balanc0 8hccL Shows a NN Gain
`of ATI' 533
`Ulyrolysis Is 1111clcr TighL RPgulatio11 53:3
`Ca11cc•rous Tissue I las OPrw1g<'d UIU('OSl' Catabulis111 533
`
`14.2 Feeder Pathways for Gtycolysls 534
`CJlyC'ogl'11 and Star('h An• Dt>grnd1•d by
`Phosphorolysis 534
`DiPtary Polysacr harides and Oisa('charidl's Undergo
`llydrolysis tu MunusaC'dmrid('S 535
`OI hPr Mu11usarcharidPs EnLl'r I ht> GlyC'olytic Pathway at
`Several l'ui11ts 5:Hi
`
`MPI EXHIBIT 1036 PAGE 9
`
`
`
`xx
`
`Contents
`
`14.3 Fates of Pyruvate under Anaerobfc Conditions:
`Fermentation 538
`Pyruvat(' Is thr Terminal Electron Acceptor in Lact.ic Acirl
`Fcmwn\.llt.ion
`f>:l8
`Ethanol ls tlw RPrlucc,d Pmct11ct in Ethanol Fennentation 538
`Box 14- 1 Athletes, Alllgators, and Coelacanths: Gtycolytl1 at
`Limiting Concentrations of O~gen 539
`Thiamine l'yrophosphat.e Carries "Active Aldehyrle"
`Groups 540
`PPnn1•nt;1tio11s Yi<"ld a Variety of Common Foo<ls and
`lnclustrial Clwmir als 54 J
`Box 14-2 Brewtng Beer 542
`
`14.4 Gluconeogenesls 543
`Convnsion of Pyruvatr to Phosphoenolpyruvat.e Requires
`1\vo Exrrgonic !{Pact ions
`!144
`Convc>rsion of l•'ruct osc> 1,6-Bisphosphate to Fructose
`o-l'hnsphatc> ls thr Seconct Bypass 547
`Gonvrrsion of Glucose 6-l'hosphate to Glucose ls the Third
`Bypass 547
`Ghironrog<'nc>sis Is EnC'rgctir.all.v Expensive, But Essential 548
`Citrir Add Cycle Intermediates and Many Amino Acids Are
`Glucogenic 548
`Glycolysis and Gluconcogenesis Are Regulated
`Reciprocally 548
`14.5 Pentose Phosphate Pathway of Glucose Oxidation 549
`The Oxirlative Phase Produces Pentose Phosphates and
`NADPH
`f>50
`Box 14-3 Why Pythagoras Wouldn't Eat Falafel: Glucose
`6-Phosphate Dehydrogenase Deficiency 551
`Tlw Nonoxi<lative Phase Recycles Pentose Phosphates to
`Glucose 6-Phosphate 552
`Wernicke- Korsakoff Syndrome Is Exacerbated by a Defect in
`1'ransketolase 554
`Glucose 6-Phosphat e Is Partitioned between Glycolysis and
`the PPntose Phosphate Pathway 554
`
`15 Principles of Metabolic Regulation:
`Glucose and Glycogen 560
`15.1 The Metabolism of Glycogen In Animals 562
`Glycogen Brcakdow11 Is Catalyzed by Glycogen
`Phosphorylase 562
`Glucose I-Phosphate Can Ente r Glycolysis or, in Live r,
`Replenish Blood Glucose 563
`The Sugar Nucleotide UDP-Glucose Donates Gluc