xxviii Contents 767 792 Androgens and estroes are synthesized from 26.1Ph osphatidate Is a Co mon Intermediate pregne 792 6 794 769 CHAPTER 27 The Integration of Metabolism 801 mphospholipis are synthesizedfromctiaed 770 70 802 ment of rain Plays a Key Role in Caloric heart diseas 804 s can g erate phospholipids Signals from the gastrointestinal tract induce feelings ch sphingolipids that 804 contain acidic sugars inregulatclong-tcrmcontolove liversity on lipid structure and s06 ess syndrom e and Tay-Sachs disease ance may factorto 806 774 Dieting is used to combat obesity 807 775 27.3 Diabetes Is a Common Metabolic Disease 26.2 Choles from Acetyl Often Resulting from Obesity Coenzyme A in Three Stages lsulnnitiatcsaomplcxsignal-transduction 808 The synthesis of n te,which i activated a 0 ne synthesi 6 81d Insulin resistance in muscle facilitates pancreatic failure 810 tes result from 5 812 7 ally Alters the Biochemistry terol xercise Benefi 779 813 mitochondrial biogenesis is stimulated by muscular throughout the organism 82 activity 813 by the 784 813 ation Induce Metabolic e of the ldl re Chan sclerosis 8 816 Mutations in the LDL prevent LDLrelease The starved-fed cycle is the physiological response 785 816 。1 Cycling of the LDL receptor is ulated protein degradation starvation minimize against atheroselerosis 181 27.6 Ethanol Alters Energy Metabolism in the nical lev 788 Live g Ethanol metabolism leads to an excess of NADH 820 d。one 788 nol consumption disrupts vitamin nd numbers identify 821 the carbon atoms CHAPTER 28 DNA Replication,Repair, 790 and Recombination 827 widespread and 791 28.1 DNA Replication Proceeds by the leoside 792 828
xxviii Contents CHAPTER 26 The Biosynthesis of Membrane Lipids and Steroids 767 26.1 Phosphatidate Is a Common Intermediate in the Synthesis of Phospholipids and Triacylglycerols 768 The synthesis of phospholipids requires an activated intermediate 769 Some phospholipids are synthesized from an activated alcohol 770 Phosphatidylcholine is an abundant phospholipid 770 Excess choline is implicated in the development of heart disease 771 Base-exchange reactions can generate phospholipids 771 Sphingolipids are synthesized from ceramide 772 Gangliosides are carbohydrate-rich sphingolipids that contain acidic sugars 772 Sphingolipids confer diversity on lipid structure and function 773 Respiratory distress syndrome and Tay–Sachs disease result from the disruption of lipid metabolism 774 Ceramide metabolism stimulates tumor growth 774 Phosphatidic acid phosphatase is a key regulatory enzyme in lipid metabolism 775 26.2 Cholesterol Is Synthesized from Acetyl Coenzyme A in Three Stages 776 The synthesis of mevalonate, which is activated as isopentenyl pyrophosphate, initiates the synthesis of cholesterol 776 Squalene (C30) is synthesized from six molecules of isopentenyl pyrophosphate (C5) 777 Squalene cyclizes to form cholesterol 778 26.3 The Complex Regulation of Cholesterol Biosynthesis Takes Place at Several Levels 779 Lipoproteins transport cholesterol and triacylglycerols throughout the organism 782 Low-density lipoproteins play a central role in cholesterol metabolism 784 The absence of the LDL receptor leads to hypercholesterolemia and atherosclerosis 784 Mutations in the LDL receptor prevent LDL release and result in receptor destruction 785 Cycling of the LDL receptor is regulated 787 HDL appears to protect against atherosclerosis 787 The clinical management of cholesterol levels can be understood at a biochemical level 788 26.4 Important Derivatives of Cholesterol Include Bile Salts and Steroid Hormones 788 Letters identify the steroid rings and numbers identify the carbon atoms 790 Steroids are hydroxylated by cytochrome P450 monooxygenases that use NADPH and O2 790 The cytochrome P450 system is widespread and performs a protective function 791 Pregnenolone, a precursor of many other steroids, is formed from cholesterol by cleavage of its side chain 792 Progesterone and corticosteroids are synthesized from pregnenolone 792 Androgens and estrogens are synthesized from pregnenolone 792 Vitamin D is derived from cholesterol by the ringsplitting activity of light 794 CHAPTER 27 The Integration of Metabolism 801 27.1 Caloric Homeostasis Is a Means of Regulating Body Weight 802 27.2 The Brain Plays a Key Role in Caloric Homeostasis 804 Signals from the gastrointestinal tract induce feelings of satiety 804 Leptin and insulin regulate long-term control over caloric homeostasis 805 Leptin is one of several hormones secreted by adipose tissue 806 Leptin resistance may be a contributing factor to obesity 806 Dieting is used to combat obesity 807 27.3 Diabetes Is a Common Metabolic Disease Often Resulting from Obesity 807 Insulin initiates a complex signal-transduction pathway in muscle 808 Metabolic syndrome often precedes type 2 diabetes 809 Excess fatty acids in muscle modify metabolism 810 Insulin resistance in muscle facilitates pancreatic failure 810 Metabolic derangements in type 1 diabetes result from insulin insufficiency and glucagon excess 812 27.4 Exercise Beneficially Alters the Biochemistry of Cells 813 Mitochondrial biogenesis is stimulated by muscular activity 813 Fuel choice during exercise is determined by the intensity and duration of activity 813 27.5 Food Intake and Starvation Induce Metabolic Changes 816 The starved–fed cycle is the physiological response to a fast 816 Metabolic adaptations in prolonged starvation minimize protein degradation 818 27.6 Ethanol Alters Energy Metabolism in the Liver 819 Ethanol metabolism leads to an excess of NADH 820 Excess ethanol consumption disrupts vitamin metabolism 821 CHAPTER 28 DNA Replication, Repair, and Recombination 827 28.1 DNA Replication Proceeds by the Polymerization of Deoxyribonucleoside Triphosphates Along a Template 828 CHAPTER 26 The Biosynthesis of Membrane Lipids and Steroids 767 CHAPTER 27 The Integration of Metabolism 801 CHAPTER 28 DNA Replication, Repair, and Recombination 827
Contents xxix DNA polymerases require a template and a primer 829 CHAPTER 29 RNA Synthesis and Processing 859 All DNA polymerases have structural features in 829 participate in the polymerase 86d reaction 829 29.1 RNA Polym 861 ed de g62 by pimae nable RNA polymerases backtrack and correct errors 63 A syn egin 831 ndto promoter sites on the 864 831 Sigma subunits s of rNa poly DNA ligase joins ends of DNA in duplex regions 832 promoter sites 865 832 65 833 866 Sequences within the newly transc RNA signal 835 866 the doublehelix for Some messenger RNAs directly sense metabolite 83 867 ype i to 836 868 Some antibiotics inhibit transcription 869 supercoils through coupling to ATP hydrolysis 837 28.3 DNA Replication Is Highly Coordinated 839 870 DNA replication requires highly processive The leadi 839 29.2 Transcription in Eukaryotes Is Highly Regulated 871 ging re ynthesized ina e synth e RNA i rdinated fashion 840 872 Thre DNA replication in Escherichia co begins ata common elements can be found in the RNA 842 moter regio 874 DNA S 843 874 reiuurat the nd of Multiple transcription factors interact with eukaryotic 844 875 transcription 845 g16 28.4 Many Types of DNA Damage Can Be 29 3 The Transcr ription Products of Eukaryotic Repaired Polymerases Are Processed 876 Errors can arise in DNA repli RNA polymerase I produces three ribosomal RNAs 877 aged by ox zing agents,alkylating RNA polymerase IlI produces transfer RNA 877 846 The product of RNA. 878 847 RNA 870 ad of acil in DNA RNA editing changes the proteins encoded by mRNA 879 84g 80 by the defective g co 男 Man tential care an he det their bacteria Smal nucear RNA catalyze the 852 28.5 DNA Recombination Plays Important Roles in f mRNa are counled pair,and Other Proc 852 Most human pre-mRNAS can be spliced in alternative 853 ways to yield different proteins oceed through 854 chanism and Evolutio
Contents xxix DNA polymerases require a template and a primer 829 All DNA polymerases have structural features in common 829 Two bound metal ions participate in the polymerase reaction 829 The specificity of replication is dictated by complementarity of shape between bases 830 An RNA primer synthesized by primase enables DNA synthesis to begin 831 One strand of DNA is made continuously, whereas the other strand is synthesized in fragments 831 DNA ligase joins ends of DNA in duplex regions 832 The separation of DNA strands requires specific helicases and ATP hydrolysis 832 28.2 DNA Unwinding and Supercoiling Are Controlled by Topoisomerases 833 The linking number of DNA, a topological property, determines the degree of supercoiling 835 Topoisomerases prepare the double helix for unwinding 836 Type I topoisomerases relax supercoiled structures 836 Type II topoisomerases can introduce negative supercoils through coupling to ATP hydrolysis 837 28.3 DNA Replication Is Highly Coordinated 839 DNA replication requires highly processive polymerases 839 The leading and lagging strands are synthesized in a coordinated fashion 840 DNA replication in Escherichia coli begins at a unique site 842 DNA synthesis in eukaryotes is initiated at multiple sites 843 Telomeres are unique structures at the ends of linear chromosomes 844 Telomeres are replicated by telomerase, a specialized polymerase that carries its own RNA template 845 28.4 Many Types of DNA Damage Can Be Repaired 845 Errors can arise in DNA replication 846 Bases can be damaged by oxidizing agents, alkylating agents, and light 846 DNA damage can be detected and repaired by a variety of systems 847 The presence of thymine instead of uracil in DNA permits the repair of deaminated cytosine 849 Some genetic diseases are caused by the expansion of repeats of three nucleotides 850 Many cancers are caused by the defective repair of DNA 850 Many potential carcinogens can be detected by their mutagenic action on bacteria 852 28.5 DNA Recombination Plays Important Roles in Replication, Repair, and Other Processes 852 RecA can initiate recombination by promoting strand invasion 853 Some recombination reactions proceed through Holliday-junction intermediates 854 CHAPTER 29 RNA Synthesis and Processing 859 RNA synthesis comprises three stages: Initiation, elongation, and termination 860 29.1 RNA Polymerases Catalyze Transcription 861 RNA chains are formed de novo and grow in the 59-to-39 direction 862 RNA polymerases backtrack and correct errors 863 RNA polymerase binds to promoter sites on the DNA template to initiate transcription 864 Sigma subunits of RNA polymerase recognize promoter sites 865 RNA polymerases must unwind the template double helix for transcription to take place 865 Elongation takes place at transcription bubbles that move along the DNA template 866 Sequences within the newly transcribed RNA signal termination 866 Some messenger RNAs directly sense metabolite concentrations 867 The rho protein helps to terminate the transcription of some genes 868 Some antibiotics inhibit transcription 869 Precursors of transfer and ribosomal RNA are cleaved and chemically modified after transcription in prokaryotes 870 29.2 Transcription in Eukaryotes Is Highly Regulated 871 Three types of RNA polymerase synthesize RNA in eukaryotic cells 872 Three common elements can be found in the RNA polymerase II promoter region 874 The TFIID protein complex initiates the assembly of the active transcription complex 874 Multiple transcription factors interact with eukaryotic promoters 875 Enhancer sequences can stimulate transcription at start sites thousands of bases away 876 29.3 The Transcription Products of Eukaryotic Polymerases Are Processed 876 RNA polymerase I produces three ribosomal RNAs 877 RNA polymerase III produces transfer RNA 877 The product of RNA polymerase II, the pre-mRNA transcript, acquires a 59 cap and a 39 poly(A) tail 878 Small regulatory RNAs are cleaved from larger precursors 879 RNA editing changes the proteins encoded by mRNA 879 Sequences at the ends of introns specify splice sites in mRNA precursors 880 Splicing consists of two sequential transesterification reactions 881 Small nuclear RNAs in spliceosomes catalyze the splicing of mRNA precursors 882 Transcription and processing of mRNA are coupled 883 Mutations that affect pre-mRNA splicing cause disease 884 Most human pre-mRNAS can be spliced in alternative ways to yield different proteins 885 29.4 The Discovery of Catalytic RNA was Revealing in Regard to Both Mechanism and Evolution 886 CHAPTER 29 RNA S h i d P RNA Synthesis and Processing 859
xxx Contents CHAPTER 30 Protein Synthesis 893 a9 894 APTER 31 The Control of Gene Expression in Prokaryotes 925 mon design 31.1 Many DNA-Binding Proteins Recoanize Some transfer RNA molecules recognize more than Specific DNA Sequences 926 one codon because of wobble in base-pairing 30.2 Amir ad the ynhetase ng pr 927 g Pro 927 Aminoacul-+RNA sunther have highly discriminating amino acid act tion sites protein-encoding genes 928 no 900 929 Ligand binding can induce structural changesin A m 901 can be divided into 930 % 30.3 The Ribosome Is the Site of Protein Synthesis 902 931 uits Can Result in Switching in protein s 903 ene the 30s and 50s subunits RNA-binding sites that bridge Cro form 933 905 tiated by cCmioalsignalstha formylmethionyl Biofilms are complex communities of prokaryotes 934 902 31.4 Gene Expression Can Be Controlled at Elon Posttranscriptional Levels gation factors deliver aminoacyil-trna to the 935 90% RNA secondary structure 935 GTP. g09 CHAPTER 32 The Control of Gene Expression in Fuk 941 910 32.1 Eukaryotic DNA Is Organized into Chromatin 943 ation 943 Initiation 911 around histone octamers to form 943 itio 913 3221 Factors Bind DNA and Regulate otics and Toxins Can 945 913 rotcin synthesis 91 ing prot Dipht thesis in 914 Ricin fatally modifies 28S ribosomal RNA 915 egulatory regions ancers can stimulate transcription in specific mbrane 946 915 erated by odu 916 947 916 32.3 The C nrol of Gene Expression Can Require 948
xxx Contents CHAPTER 30 Protein Synthesis 893 30.1 Protein Synthesis Requires the Translation of Nucleotide Sequences into Amino Acid Sequences 894 The synthesis of long proteins requires a low error frequency 894 Transfer RNA molecules have a common design 895 Some transfer RNA molecules recognize more than one codon because of wobble in base-pairing 897 30.2 Aminoacyl Transfer RNA Synthetases Read the Genetic Code 898 Amino acids are first activated by adenylation 898 Aminoacyl-tRNA synthetases have highly discriminating amino acid activation sites 899 Proofreading by aminoacyl-tRNA synthetases increases the fidelity of protein synthesis 900 Synthetases recognize various features of transfer RNA molecules 901 Aminoacyl-tRNA synthetases can be divided into two classes 901 30.3 The Ribosome Is the Site of Protein Synthesis 902 Ribosomal RNAs (5S, 16S, and 23S rRNA) play a central role in protein synthesis 903 Ribosomes have three tRNA-binding sites that bridge the 30s and 50s subunits 905 The start signal is usually AUG preceded by several bases that pair with 16S rRNA 905 Bacterial protein synthesis is initiated by formylmethionyl transfer RNA 906 Formylmethionyl-tRNAf is placed in the P site of the ribosome in the formation of the 70S initiation complex 907 Elongation factors deliver aminoacyl-tRNA to the ribosome 907 Peptidyl transferase catalyzes peptide-bond synthesis 908 The formation of a peptide bond is followed by the GTPdriven translocation of tRNAs and mRNA 909 Protein synthesis is terminated by release factors that read stop codons 910 30.4 Eukaryotic Protein Synthesis Differs from Bacterial Protein Synthesis Primarily in Translation Initiation 911 Mutations in initiation factor 2 cause a curious pathological condition 913 30.5 A Variety of Antibiotics and Toxins Can Inhibit Protein Synthesis 913 Some antibiotics inhibit protein synthesis 914 Diphtheria toxin blocks protein synthesis in eukaryotes by inhibiting translocation 914 Ricin fatally modifies 28S ribosomal RNA 915 30.6 Ribosomes Bound to the Endoplasmic Reticulum Manufacture Secretory and Membrane Proteins 915 Protein synthesis begins on ribosomes that are free in the cytoplasm 916 Signal sequences mark proteins for translocation across the endoplasmic reticulum membrane 916 Transport vesicles carry cargo proteins to their final destination 918 CHAPTER 31 The Control of Gene Expression in Prokaryotes 925 31.1 Many DNA-Binding Proteins Recognize Specific DNA Sequences 926 The helix-turn-helix motif is common to many prokaryotic DNA-binding proteins 927 31.2 Prokaryotic DNA-Binding Proteins Bind Specifically to Regulatory Sites in Operons 927 An operon consists of regulatory elements and protein-encoding genes 928 The lac repressor protein in the absence of lactose binds to the operator and blocks transcription 929 Ligand binding can induce structural changes in regulatory proteins 930 The operon is a common regulatory unit in prokaryotes 930 Transcription can be stimulated by proteins that contact RNA polymerase 931 31.3 Regulatory Circuits Can Result in Switching Between Patterns of Gene Expression 932 The l repressor regulates its own expression 932 A circuit based on the l repressor and Cro forms a genetic switch 933 Many prokaryotic cells release chemical signals that regulate gene expression in other cells 933 Biofilms are complex communities of prokaryotes 934 31.4 Gene Expression Can Be Controlled at Posttranscriptional Levels 935 Attenuation is a prokaryotic mechanism for regulating transcription through the modulation of nascent RNA secondary structure 935 CHAPTER 32 The Control of Gene Expression in Eukaryotes 941 32.1 Eukaryotic DNA Is Organized into Chromatin 943 Nucleosomes are complexes of DNA and histones 943 DNA wraps around histone octamers to form nucleosomes 943 32.2 Transcription Factors Bind DNA and Regulate Transcription Initiation 945 A range of DNA-binding structures are employed by eukaryotic DNA-binding proteins 945 Activation domains interact with other proteins 946 Multiple transcription factors interact with eukaryotic regulatory regions 946 Enhancers can stimulate transcription in specific cell types 946 Induced pluripotent stem cells can be generated by introducing four transcription factors into differentiated cells 947 32.3 The Control of Gene Expression Can Require Chromatin Remodeling 948 CHAPTER 30 P iS hrotein Synthesis 893 CHAPTER 31 The Control of Gene Expression in Prokaryotes 925 CHAPTER 32 The Control of Gene Expression in Eukaryotes 941
Contents xxxi The methylation of DNA can alter pattems of gene 949 g76 949 977 950 sing 951 977 Chro ismodulated through covalent CHAPTER 34 The Immune System 981 952 te to transcriptional g8 32.4 Eukary ssion Can Be 954 984 Genes asatedithro metabolism are transaioly egula 954 986 ulate the expression of many ype 988 s of a bet -sandwich frameworkwith hypervariable loops 988 X-ray analyses have revealed how antibodies bind 989 CHAPTER 33 Sensory Systems 961 tigens bind antibodicswith numero interactions 990 34.3 Diversity Is Generated by Gene 962 Rearrangements 991 Olfactior nous family of J)(diversity) 991 Odorants are decoded by a combinatorial mechanism 96 han 10s antibodi 33.2 Taste Is a Combination of Senses That 992 Function by Different Mechanisms 966 erization of antibodi o the discovery ion 993 of anti d hy the A heterodimeric 7TM receptor responds to sweet hopping of VH genes 994 34.4 Major-Histocc mpatibility-Complex Proteins ell Surfaces for by a heterodimeric rece 969 ns on c ion by 995 d pr rily by the passage of 969 soccupy a deep 996 (acids)on channels 33.3 Photoreceptor Molecules in the Eve Detect CD8 on toxic T s in concert with T-cell Visible Light 970 receptors 998 t display foreign 970 1000 Ligh HelperTcells rely on the T-cell r and CD4 t 971 ognize foreign peptides on antigen-presenting cells Light-induced wering of the calium level coordinates HC proteins a 100 972 Color vision is mediated by three one receptors that the mmne 1003 are homologs of rhodopsin 973 34.5 The Immune System Contributes to the 974 Prevention and the Development of Huma 1004 s on the Speedy Detection of 975 1004 Autoimmune diseases result from the generation of 975 mmune responses against self-antigen 100
Contents xxxi The methylation of DNA can alter patterns of gene expression 949 Steroids and related hydrophobic molecules pass through membranes and bind to DNA-binding receptors 949 Nuclear hormone receptors regulate transcription by recruiting coactivators to the transcription complex 950 Steroid-hormone receptors are targets for drugs 951 Chromatin structure is modulated through covalent modifications of histone tails 952 Histone deacetylases contribute to transcriptional repression 953 32.4 Eukaryotic Gene Expression Can Be Controlled at Posttranscriptional Levels 954 Genes associated with iron metabolism are translationally regulated in animals 954 Small RNAs regulate the expression of many eukaryotic genes 956 Part IV RESPONDING TO ENVIRONMENTAL CHANGES CHAPTER 33 Sensory Systems 961 33.1 A Wide Variety of Organic Compounds Are Detected by Olfaction 962 Olfaction is mediated by an enormous family of seven-transmembrane-helix receptors 962 Odorants are decoded by a combinatorial mechanism 964 33.2 Taste Is a Combination of Senses That Function by Different Mechanisms 966 Sequencing of the human genome led to the discovery of a large family of 7TM bitter receptors 967 A heterodimeric 7TM receptor responds to sweet compounds 968 Umami, the taste of glutamate and aspartate, is mediated by a heterodimeric receptor related to the sweet receptor 969 Salty tastes are detected primarily by the passage of sodium ions through channels 969 Sour tastes arise from the effects of hydrogen ions (acids) on channels 969 33.3 Photoreceptor Molecules in the Eye Detect Visible Light 970 Rhodopsin, a specialized 7TM receptor, absorbs visible light 970 Light absorption induces a specific isomerization of bound 11-cis-retinal 971 Light-induced lowering of the calcium level coordinates recovery 972 Color vision is mediated by three cone receptors that are homologs of rhodopsin 973 Rearrangements in the genes for the green and red pigments lead to “color blindness” 974 33.4 Hearing Depends on the Speedy Detection of Mechanical Stimuli 975 Hair cells use a connected bundle of stereocilia to detect tiny motions 975 Mechanosensory channels have been identified in Drosophila and vertebrates 976 33.5 Touch Includes the Sensing of Pressure, Temperature, and Other Factors 977 Studies of capsaicin reveal a receptor for sensing high temperatures and other painful stimuli 977 CHAPTER 34 The Immune System 981 Innate immunity is an evolutionarily ancient defense system 982 The adaptive immune system responds by using the principles of evolution 984 34.1 Antibodies Possess Distinct Antigen-Binding and Effector Units 985 34.2 Antibodies Bind Specific Molecules Through Hypervariable Loops 988 The immunoglobulin fold consists of a beta-sandwich framework with hypervariable loops 988 X-ray analyses have revealed how antibodies bind antigens 989 Large antigens bind antibodies with numerous interactions 990 34.3 Diversity Is Generated by Gene Rearrangements 991 J (joining) genes and D (diversity) genes increase antibody diversity 991 More than 108 antibodies can be formed by combinatorial association and somatic mutation 992 The oligomerization of antibodies expressed on the surfaces of immature B cells triggers antibody secretion 993 Different classes of antibodies are formed by the hopping of VH genes 994 34.4 Major-Histocompatibility-Complex Proteins Present Peptide Antigens on Cell Surfaces for Recognition by T-Cell Receptors 995 Peptides presented by MHC proteins occupy a deep groove flanked by alpha helices 996 T-cell receptors are antibody-like proteins containing variable and constant regions 998 CD8 on cytotoxic T cells acts in concert with T-cell receptors 998 Helper T cells stimulate cells that display foreign peptides bound to class II MHC proteins 1000 Helper T cells rely on the T-cell receptor and CD4 to recognize foreign peptides on antigen-presenting cells 1000 MHC proteins are highly diverse 1002 Human immunodeficiency viruses subvert the immune system by destroying helper T cells 1003 34.5 The Immune System Contributes to the Prevention and the Development of Human Diseases 1004 T cells are subjected to positive and negative selection in the thymus 1004 Autoimmune diseases result from the generation of immune responses against self-antigens 1005 CHAPTER 33 Sensory Systems 961 CHAPTER 34 The Immune System 981
xxxii Contents 1005 1036 1006 Toxicity can limit drug effectiveness 1040 36.2 Drug Candidates Can Be Discovered by CHAPTER 35 Molecular Motors 1011 Serendipity.Screening.or Design 1041 35.1 Most Molecular-Motor Proteins Are Members iippimiobsernvationseamdnredhag of the P-Loop NTPase Superfamily 1012 oducts area valuable sour of drugs and poin drug leads 1043 n exte structur 1012 ounds an be de 1044 1014 35.2 Myosins Move Along Actin Filaments 1016 1046 Actinisapolar,self-assembling.dynamic polymer 1016 Myosin head domains bind to actin filaments 1018 2Ag828a6nmthHoepom8e 1048 Moiprote be directly 1018 1048 stroke 1049 The length of the leverarm determines motor velocity 1022 targets can be identified in the genomes of 1050 35.3 Kinesin and Dynein Move Along Microtubules 1022 Microtubules are hollow cylindrical polymers 102 Genetic differences influence individual responses 1024 1050 Kinesin motion is highly processive 35 4 A Rotary Motor Drives Bacterial Motion 102日 36.4Th 1051 Bacteria swim by rotating their flagella 1026 are time consuming and Proton flow drives bacterial flagellar rotation 1026 expensive 1052 1028 The evol otogtneentheuti 1053 CHAPTER 36 Drug Development 1033 Answers to Problems 9 Selected Readings 1034 st be potent and selective 1035 Index
xxxii Contents The immune system plays a role in cancer prevention 1005 Vaccines are a powerful means to prevent and eradicate disease 1006 CHAPTER 35 Molecular Motors 1011 35.1 Most Molecular-Motor Proteins Are Members of the P-Loop NTPase Superfamily 1012 Molecular motors are generally oligomeric proteins with an ATPase core and an extended structure 1012 ATP binding and hydrolysis induce changes in the conformation and binding affinity of motor proteins 1014 35.2 Myosins Move Along Actin Filaments 1016 Actin is a polar, self-assembling, dynamic polymer 1016 Myosin head domains bind to actin filaments 1018 Motions of single motor proteins can be directly observed 1018 Phosphate release triggers the myosin power stroke 1019 Muscle is a complex of myosin and actin 1019 The length of the lever arm determines motor velocity 1022 35.3 Kinesin and Dynein Move Along Microtubules 1022 Microtubules are hollow cylindrical polymers 1022 Kinesin motion is highly processive 1024 35.4 A Rotary Motor Drives Bacterial Motion 1026 Bacteria swim by rotating their flagella 1026 Proton flow drives bacterial flagellar rotation 1026 Bacterial chemotaxis depends on reversal of the direction of flagellar rotation 1028 CHAPTER 36 Drug Development 1033 36.1 The Development of Drugs Presents Huge Challenges 1034 Drug candidates must be potent and selective modulators of their targets 1035 Drugs must have suitable properties to reach their targets 1036 Toxicity can limit drug effectiveness 1040 36.2 Drug Candidates Can Be Discovered by Serendipity, Screening, or Design 1041 Serendipitous observations can drive drug development 1041 Natural products are a valuable source of drugs and drug leads 1043 Screening libraries of synthetic compounds expands the opportunity for identification of drug leads 1044 Drugs can be designed on the basis of three-dimensional structural information about their targets 1046 36.3 Analyses of Genomes Hold Great Promise for Drug Discovery 1048 Potential targets can be identified in the human proteome 1048 Animal models can be developed to test the validity of potential drug targets 1049 Potential targets can be identified in the genomes of pathogens 1050 Genetic differences influence individual responses to drugs 1050 36.4 The Clinical Development of Drugs Proceeds Through Several Phases 1051 Clinical trials are time consuming and expensive 1052 The evolution of drug resistance can limit the utility of drugs for infectious agents and cancer 1053 Answers to Problems A1 Selected Readings B1 Index C1 CHAPTER 35 Molecular Motors 1011 CHAPTER 36 Drug Development 1033