{"product_id":"enzymes-9781119793250","title":"Enzymes","description":"\u003cb\u003eBook Synopsis\u003c\/b\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cb\u003eTable of Contents\u003c\/b\u003e\u003cbr\u003e\u003cp\u003ePreface to the Third Edition xvii\u003c\/p\u003e \u003cp\u003ePreface to the Second Edition xix\u003c\/p\u003e \u003cp\u003ePreface to the First Edition xxi\u003c\/p\u003e \u003cp\u003eAcknowledgments xxiii\u003c\/p\u003e \u003cp\u003e\u003cb\u003e1 A Brief History of Enzymology 1\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eKey Learning Points 1\u003c\/p\u003e \u003cp\u003e1.1 Enzymes in Antiquity 2\u003c\/p\u003e \u003cp\u003e1.2 Early Enzymology 3\u003c\/p\u003e \u003cp\u003e1.3 The Development of Mechanistic Enzymology 4\u003c\/p\u003e \u003cp\u003e1.4 Studies of Enzyme Structure 5\u003c\/p\u003e \u003cp\u003e1.5 Enzymology Today 7\u003c\/p\u003e \u003cp\u003e1.6 Summary 9\u003c\/p\u003e \u003cp\u003eReferences and Further Reading 9\u003c\/p\u003e \u003cp\u003e\u003cb\u003e2 Chemical Bonds and Reactions in Biochemistry 11\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eKey Learning Points 11\u003c\/p\u003e \u003cp\u003e2.1 Atomic and Molecular Orbitals 12\u003c\/p\u003e \u003cp\u003e2.1.1 Atomic Orbitals 12\u003c\/p\u003e \u003cp\u003e2.1.2 Molecular Orbitals 15\u003c\/p\u003e \u003cp\u003e2.1.3 Hybrid Orbitals 16\u003c\/p\u003e \u003cp\u003e2.1.4 Resonance and Aromaticity 18\u003c\/p\u003e \u003cp\u003e2.1.5 Different Electronic Configurations Have Different Potential Energies 20\u003c\/p\u003e \u003cp\u003e2.2 Thermodynamics of Chemical Reactions 22\u003c\/p\u003e \u003cp\u003e2.2.1 The Transition State of Chemical Reactions 24\u003c\/p\u003e \u003cp\u003e2.3 Acid–base Chemistry 27\u003c\/p\u003e \u003cp\u003e2.4 Noncovalent Interactions in Reversible Binding 29\u003c\/p\u003e \u003cp\u003e2.4.1 Electrostatic Interactions 30\u003c\/p\u003e \u003cp\u003e2.4.2 Hydrogen Bonding 30\u003c\/p\u003e \u003cp\u003e2.4.3 Hydrophobic Interactions 31\u003c\/p\u003e \u003cp\u003e2.4.4 Van der Waals Forces 31\u003c\/p\u003e \u003cp\u003e2.5 Rates of Chemical Reactions 33\u003c\/p\u003e \u003cp\u003e2.5.1 Reaction Order 35\u003c\/p\u003e \u003cp\u003e2.5.2 Reversible Chemical Reactions 36\u003c\/p\u003e \u003cp\u003e2.5.3 Measurement of Initial Velocity 37\u003c\/p\u003e \u003cp\u003e2.6 Summary 38\u003c\/p\u003e \u003cp\u003eReferences and Further Reading 38\u003c\/p\u003e \u003cp\u003e\u003cb\u003e3 Structural Components of Enzymes 39\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eKey Learning Points 39\u003c\/p\u003e \u003cp\u003e3.1 The Amino Acids 40\u003c\/p\u003e \u003cp\u003e3.1.1 Properties of Amino-Acid Side Chains 42\u003c\/p\u003e \u003cp\u003e3.1.1.1 Hydrophobicity 42\u003c\/p\u003e \u003cp\u003e3.1.1.2 Hydrogen Bonding 42\u003c\/p\u003e \u003cp\u003e3.1.1.3 Salt-Bridge Formation 43\u003c\/p\u003e \u003cp\u003e3.1.2 Amino Acids as Acids and Bases 44\u003c\/p\u003e \u003cp\u003e3.1.3 Cation and Metal Binding 45\u003c\/p\u003e \u003cp\u003e3.1.4 Anion and Polyanion Binding 46\u003c\/p\u003e \u003cp\u003e3.1.5 Covalent Bond Formation 46\u003c\/p\u003e \u003cp\u003e3.1.5.1 Disulfide Bonds 46\u003c\/p\u003e \u003cp\u003e3.1.5.2 Phosphorylation 46\u003c\/p\u003e \u003cp\u003e3.1.5.3 Glycosylation 47\u003c\/p\u003e \u003cp\u003e3.1.6 Steric Bulk 47\u003c\/p\u003e \u003cp\u003e3.2 The Peptide Bond 48\u003c\/p\u003e \u003cp\u003e3.3 Amino Acid Sequence or Primary Structure 51\u003c\/p\u003e \u003cp\u003e3.4 Secondary Structure 54\u003c\/p\u003e \u003cp\u003e3.4.1 The Right-Handed \u003ci\u003e𝛼\u003c\/i\u003eHelix 55\u003c\/p\u003e \u003cp\u003e3.4.2 The \u003ci\u003e𝛽\u003c\/i\u003e-Pleated Sheet 56\u003c\/p\u003e \u003cp\u003e3.4.3 \u003ci\u003e𝛽\u003c\/i\u003eTurns 58\u003c\/p\u003e \u003cp\u003e3.4.4 Other Secondary Structures 58\u003c\/p\u003e \u003cp\u003e3.4.5 Supersecondary Structures 59\u003c\/p\u003e \u003cp\u003e3.5 Tertiary Structure 60\u003c\/p\u003e \u003cp\u003e3.5.1 Domains 62\u003c\/p\u003e \u003cp\u003e3.6 Subunits and Quaternary Structure 64\u003c\/p\u003e \u003cp\u003e3.7 Cofactors in Enzymes 67\u003c\/p\u003e \u003cp\u003e3.8 Conformational Dynamics and Enzyme Function 70\u003c\/p\u003e \u003cp\u003e3.9 Methods of Protein Structure Determination 75\u003c\/p\u003e \u003cp\u003e3.9.1 X-ray Crystallography 76\u003c\/p\u003e \u003cp\u003e3.9.2 NMR Spectroscopy 77\u003c\/p\u003e \u003cp\u003e3.9.3 Cryo-Electron Microscopy (Cryo-EM) 78\u003c\/p\u003e \u003cp\u003e3.10 Summary 79\u003c\/p\u003e \u003cp\u003eReferences and Further Reading 80\u003c\/p\u003e \u003cp\u003e\u003cb\u003e4 Protein–Ligand Binding Equilibria 83\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eKey Learnings Points 83\u003c\/p\u003e \u003cp\u003e4.1 The Equilibrium Dissociation Constant, \u003ci\u003eK\u003c\/i\u003e\u003csub\u003ed\u003c\/sub\u003e 84\u003c\/p\u003e \u003cp\u003e4.2 The Kinetic Approach to Equilibrium 86\u003c\/p\u003e \u003cp\u003e4.3 Binding Measurements at Equilibrium 88\u003c\/p\u003e \u003cp\u003e4.3.1 Derivation of the Langmuir Isotherm 88\u003c\/p\u003e \u003cp\u003e4.3.2 Multiple Binding Sites 91\u003c\/p\u003e \u003cp\u003e4.3.2.1 Multiple Equivalent Binding Sites 91\u003c\/p\u003e \u003cp\u003e4.3.2.2 Multiple Nonequivalent Binding Sites 92\u003c\/p\u003e \u003cp\u003e4.3.2.3 Cooperative Interactions Among Multiple Binding Sites 92\u003c\/p\u003e \u003cp\u003e4.3.3 Correction for Nonspecific Binding 93\u003c\/p\u003e \u003cp\u003e4.4 Graphic Analysis of Equilibrium Ligand-Binding Data 94\u003c\/p\u003e \u003cp\u003e4.4.1 Direct Plots on Semilog Scale 94\u003c\/p\u003e \u003cp\u003e4.4.2 Linear Transformations of Binding Data: The Wolff Plots 97\u003c\/p\u003e \u003cp\u003e4.5 Equilibrium Binding with Ligand Depletion (Tight Binding Interactions) 100\u003c\/p\u003e \u003cp\u003e4.6 Competition Among Ligands for a Common Binding Site 101\u003c\/p\u003e \u003cp\u003e4.7 Protein Dynamics in Receptor–Ligand Binding 102\u003c\/p\u003e \u003cp\u003e4.8 Orthosteric and Allosteric Ligand Binding Sites 104\u003c\/p\u003e \u003cp\u003e4.9 Experimental Methods for Measuring Ligand Binding 105\u003c\/p\u003e \u003cp\u003e4.9.1 Methods Based on Mass or Mobility Differences 105\u003c\/p\u003e \u003cp\u003e4.9.1.1 Equilibrium Dialysis 105\u003c\/p\u003e \u003cp\u003e4.9.1.2 Membrane Filtration Methods 107\u003c\/p\u003e \u003cp\u003e4.9.1.3 Size Exclusion Chromatography 109\u003c\/p\u003e \u003cp\u003e4.9.1.4 Microscale Thermophoresis 111\u003c\/p\u003e \u003cp\u003e4.9.2 Spectroscopic Methods 113\u003c\/p\u003e \u003cp\u003e4.9.2.1 Fluorescence Spectroscopy 113\u003c\/p\u003e \u003cp\u003e4.9.2.2 Surface Plasmon Resonance 116\u003c\/p\u003e \u003cp\u003e4.9.3 Ligand-Induced Protein Stabilization 117\u003c\/p\u003e \u003cp\u003e4.9.3.1 Thermal Denaturation of Proteins 118\u003c\/p\u003e \u003cp\u003e4.9.3.2 Chemical Denaturation of Proteins 120\u003c\/p\u003e \u003cp\u003e4.10 Summary 122\u003c\/p\u003e \u003cp\u003eReferences and Further Reading 122\u003c\/p\u003e \u003cp\u003e\u003cb\u003e5 Steady-State Kinetics of Single-Substrate Enzyme Reactions 125\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eKey Learning Points 125\u003c\/p\u003e \u003cp\u003e5.1 The Time Course of Enzymatic Reactions 126\u003c\/p\u003e \u003cp\u003e5.2 Effects of Substrate Concentration on Velocity 127\u003c\/p\u003e \u003cp\u003e5.3 The Rapid Equilibrium Model of Enzyme Kinetics 129\u003c\/p\u003e \u003cp\u003e5.4 The Steady-State Model of Enzyme Kinetics 131\u003c\/p\u003e \u003cp\u003e5.5 The Significance of \u003ci\u003ek\u003c\/i\u003e\u003csub\u003ecat\u003c\/sub\u003e and \u003ci\u003eK\u003c\/i\u003em 134\u003c\/p\u003e \u003cp\u003e5.5.1 \u003ci\u003eK\u003c\/i\u003e\u003csub\u003em\u003c\/sub\u003e 135\u003c\/p\u003e \u003cp\u003e5.5.2 \u003ci\u003ek\u003c\/i\u003e\u003csub\u003ecat\u003c\/sub\u003e 135\u003c\/p\u003e \u003cp\u003e5.5.3 \u003ci\u003ek\u003c\/i\u003e\u003csub\u003ecat\u003c\/sub\u003e\/\u003ci\u003eK\u003c\/i\u003e\u003csub\u003em\u003c\/sub\u003e 136\u003c\/p\u003e \u003cp\u003e5.5.4 Diffusion-Controlled Reactions and Kinetic Perfection 138\u003c\/p\u003e \u003cp\u003e5.6 Experimental Measurement of \u003ci\u003ek\u003c\/i\u003e\u003csub\u003ecat\u003c\/sub\u003e and \u003ci\u003eK\u003c\/i\u003e\u003csub\u003em \u003c\/sub\u003e139\u003c\/p\u003e \u003cp\u003e5.6.1 Graphical Determinations from Untransformed Data 139\u003c\/p\u003e \u003cp\u003e5.6.2 Lineweaver–Burk Plots of Enzyme Kinetics 142\u003c\/p\u003e \u003cp\u003e5.7 Other Linear Transformations of Enzyme Kinetic Data 147\u003c\/p\u003e \u003cp\u003e5.7.1 Eadie–Hofstee Plots 147\u003c\/p\u003e \u003cp\u003e5.7.2 Hanes–Wolff Plots 148\u003c\/p\u003e \u003cp\u003e5.7.3 Eisenthal–Cornish-Bowden Direct Plots 148\u003c\/p\u003e \u003cp\u003e5.8 Measurements at Low Substrate Concentrations 149\u003c\/p\u003e \u003cp\u003e5.9 Deviations From Hyperbolic Kinetics 150\u003c\/p\u003e \u003cp\u003e5.10 Summary 153\u003c\/p\u003e \u003cp\u003eReferences and Further Reading 153\u003c\/p\u003e \u003cp\u003e\u003cb\u003e6 Chemical Mechanisms in Enzyme Catalysis 155\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eKey Learning Points 155\u003c\/p\u003e \u003cp\u003e6.1 Substrate–Active Site Complementarity 156\u003c\/p\u003e \u003cp\u003e6.2 Rate Enhancement Through Transition State Stabilization 159\u003c\/p\u003e \u003cp\u003e6.3 Chemical Mechanisms for Transition State Stabilization 162\u003c\/p\u003e \u003cp\u003e6.3.1 Approximation of Reactants 163\u003c\/p\u003e \u003cp\u003e6.3.2 Covalent Catalysis 166\u003c\/p\u003e \u003cp\u003e6.3.2.1 Nucleophilic Catalysis 167\u003c\/p\u003e \u003cp\u003e6.3.2.2 Electrophilic Catalysis 168\u003c\/p\u003e \u003cp\u003e6.3.3 General Acid\/Base Catalysis 170\u003c\/p\u003e \u003cp\u003e6.3.4 Conformational Distortion 175\u003c\/p\u003e \u003cp\u003e6.3.5 Preorganized Active Site Complementarity to the Transition State 180\u003c\/p\u003e \u003cp\u003e6.4 The Serine Proteases: An Illustrative Example 182\u003c\/p\u003e \u003cp\u003e6.5 Enzymatic Reaction Nomenclature 187\u003c\/p\u003e \u003cp\u003e6.6 Summary 191\u003c\/p\u003e \u003cp\u003eReferences and Further Reading 191\u003c\/p\u003e \u003cp\u003e\u003cb\u003e7 Experimental Measures of Steady-State Enzyme Activity 193\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eKey Learning Points 193\u003c\/p\u003e \u003cp\u003e7.1 Initial Velocity Measurements 194\u003c\/p\u003e \u003cp\u003e7.1.1 Direct, Indirect, and Coupled Assays 194\u003c\/p\u003e \u003cp\u003e7.1.2 Analysis of Progress Curves: Measuring True Steady-State Velocity 200\u003c\/p\u003e \u003cp\u003e7.1.3 Continuous Versus End Point Assays 203\u003c\/p\u003e \u003cp\u003e7.1.4 Initiating, Mixing, and Stopping Reactions 204\u003c\/p\u003e \u003cp\u003e7.1.5 The Importance of Running Controls 206\u003c\/p\u003e \u003cp\u003e7.2 Detection Methods 208\u003c\/p\u003e \u003cp\u003e7.2.1 Assays Based on Optical Spectroscopy 208\u003c\/p\u003e \u003cp\u003e7.2.2 Absorption Measurements 208\u003c\/p\u003e \u003cp\u003e7.2.3 Choosing an Analytical Wavelength 210\u003c\/p\u003e \u003cp\u003e7.2.4 Optical Cells 210\u003c\/p\u003e \u003cp\u003e7.2.5 Errors in Absorption Spectroscopy 212\u003c\/p\u003e \u003cp\u003e7.2.6 Fluorescence Measurements 213\u003c\/p\u003e \u003cp\u003e7.2.7 Internal Fluorescence Quenching and Energy Transfer 215\u003c\/p\u003e \u003cp\u003e7.2.8 Errors in Fluorescence Measurements 217\u003c\/p\u003e \u003cp\u003e7.2.9 Radioisotopic Measurements 220\u003c\/p\u003e \u003cp\u003e7.2.10 Errors in Radioactivity Measurements 223\u003c\/p\u003e \u003cp\u003e7.2.11 Other Detection Methods 223\u003c\/p\u003e \u003cp\u003e7.3 Separation Methods in Enzyme Assays 224\u003c\/p\u003e \u003cp\u003e7.3.1 Separation of Proteins from Low Molecular Weight Solutes 224\u003c\/p\u003e \u003cp\u003e7.3.2 Chromatographic Separation Methods 225\u003c\/p\u003e \u003cp\u003e7.3.3 Electrophoretic Methods in Enzyme Assays 230\u003c\/p\u003e \u003cp\u003e7.4 Factors Affecting the Velocity of Enzymatic Reactions 236\u003c\/p\u003e \u003cp\u003e7.4.1 Enzyme Concentration 237\u003c\/p\u003e \u003cp\u003e7.4.2 pH Effects 239\u003c\/p\u003e \u003cp\u003e7.4.3 Temperature Effects 245\u003c\/p\u003e \u003cp\u003e7.4.4 Viscosity Effects 247\u003c\/p\u003e \u003cp\u003e7.4.5 Isotope Effects in Enzyme Kinetics 249\u003c\/p\u003e \u003cp\u003e7.5 Reporting Enzyme Activity Data 252\u003c\/p\u003e \u003cp\u003e7.6 Enzyme Stability 253\u003c\/p\u003e \u003cp\u003e7.6.1 Stabilizing Enzymes During Storage 254\u003c\/p\u003e \u003cp\u003e7.6.2 Enzyme Inactivation During Activity Assays 255\u003c\/p\u003e \u003cp\u003e7.7 Summary 258\u003c\/p\u003e \u003cp\u003eReferences and Further Reading 258\u003c\/p\u003e \u003cp\u003e\u003cb\u003e8 Transient-State Kinetics 261\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eKey Learning Points 261\u003c\/p\u003e \u003cp\u003e8.1 Timescale of Pre-Steady-State Turnover 262\u003c\/p\u003e \u003cp\u003e8.2 Instrumentation for Transient Kinetic Measurements 264\u003c\/p\u003e \u003cp\u003e8.3 Estimating Initial Conditions for Transient Kinetic Measurements 266\u003c\/p\u003e \u003cp\u003e8.4 Examples of Some Common Transient Kinetic Reaction Mechanisms 267\u003c\/p\u003e \u003cp\u003e8.4.1 One Step, Irreversible Binding 267\u003c\/p\u003e \u003cp\u003e8.4.2 One Step, Reversible Binding 268\u003c\/p\u003e \u003cp\u003e8.4.3 Consecutive, Irreversible Reaction 268\u003c\/p\u003e \u003cp\u003e8.4.4 Consecutive, Reversible Reaction with a Fast First Step (Pre-equilibrium Reaction) 269\u003c\/p\u003e \u003cp\u003e8.4.5 Consecutive, Reversible Reaction with a Fast Second Step (Enzyme Pre-isomerization) 271\u003c\/p\u003e \u003cp\u003e8.5 Examples of Transient Kinetic Studies from the Literature 272\u003c\/p\u003e \u003cp\u003e8.5.1 Study of Substrate and Inhibitor Interactions with the Alzheimer’s Disease β-Site Amyloid Precursor Protein-Cleaving Enzyme (BACE) 272\u003c\/p\u003e \u003cp\u003e8.5.2 Study of the Mechanism of Time-Dependent Inhibition of Staphylococcus aureusPolypeptide Deformylase 275\u003c\/p\u003e \u003cp\u003e8.6 Summary 277\u003c\/p\u003e \u003cp\u003eReferences and Further Reading 278\u003c\/p\u003e \u003cp\u003e\u003cb\u003e9 Enzyme Regulation 279\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eKey Learning Points 279\u003c\/p\u003e \u003cp\u003e9.1 Active and Inactive Conformational States 280\u003c\/p\u003e \u003cp\u003e9.2 Post-Translational Modifications 281\u003c\/p\u003e \u003cp\u003e9.2.1 Proteolytic Processing 282\u003c\/p\u003e \u003cp\u003e9.2.2 Covalent Modification of Amino Acid Side Chains 288\u003c\/p\u003e \u003cp\u003e9.3 Enzyme Regulation Through Protein–Protein Interactions 294\u003c\/p\u003e \u003cp\u003e9.4 Small-Molecule Allosteric Ligands 297\u003c\/p\u003e \u003cp\u003e9.4.1 Homotropic and Heterotropic Allostery 298\u003c\/p\u003e \u003cp\u003e9.4.2 Intramolecular and Intermolecular Allostery 298\u003c\/p\u003e \u003cp\u003e9.5 Quantitative Measurements of Enzyme Activation and Inhibition 302\u003c\/p\u003e \u003cp\u003e9.5.1 Thermodynamic Measurement of Activator–Enzyme Interactions 303\u003c\/p\u003e \u003cp\u003e9.5.2 Kinetic Measurement of Enzyme Activation by PTM 306\u003c\/p\u003e \u003cp\u003e9.6 Regulation of Protein Kinases 308\u003c\/p\u003e \u003cp\u003e9.6.1 Kinase Activation by PTM 308\u003c\/p\u003e \u003cp\u003e9.6.2 Kinase Regulation by Protein Association 311\u003c\/p\u003e \u003cp\u003e9.6.3 Kinase Activation by Oligomerization 312\u003c\/p\u003e \u003cp\u003e9.6.4 Kinase Regulation by Small-Molecule Binding 313\u003c\/p\u003e \u003cp\u003e9.6.5 Small-Molecule Mimicry of Intramolecular Allostery 313\u003c\/p\u003e \u003cp\u003e9.7 Summary 314\u003c\/p\u003e \u003cp\u003eReferences and Further Reading 315\u003c\/p\u003e \u003cp\u003e\u003cb\u003e10 Reversible Inhibitors 317\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eKey Learning Points 317\u003c\/p\u003e \u003cp\u003e10.1 Equilibrium Treatment of Reversible Inhibition 319\u003c\/p\u003e \u003cp\u003e10.2 Thermodynamic Modes of Reversible Inhibition 321\u003c\/p\u003e \u003cp\u003e10.2.1 Pure Competitive Inhibition, Exclusive Binding to Free Enzyme (E): \u003ci\u003e𝛼\u003c\/i\u003e=∞ 321\u003c\/p\u003e \u003cp\u003e10.2.2 Mixed or Noncompetitive Inhibition 322\u003c\/p\u003e \u003cp\u003e10.2.2.1 Mixed Inhibitors That Bind Preferentially to the Free Enzyme (E): \u003ci\u003e𝛼\u003c\/i\u003e\u003ci\u003e \u0026gt;\u003c\/i\u003e1 322\u003c\/p\u003e \u003cp\u003e10.2.2.2 Mixed Inhibitors That Bind Equipotently to E and ES: \u003ci\u003e𝛼\u003c\/i\u003e=1 322\u003c\/p\u003e \u003cp\u003e10.2.2.3 Mixed Inhibitors That Bind Preferentially to the Enzyme–Substrate Complex (ES): \u003ci\u003e𝛼\u003c\/i\u003e\u003ci\u003e \u0026lt;\u003c\/i\u003e1 322\u003c\/p\u003e \u003cp\u003e10.2.3 Pure Uncompetitive Inhibitors, Exclusive Binding to the Enzyme-Substrate Complex (ES): \u003ci\u003e𝛼≪\u003c\/i\u003e1 323\u003c\/p\u003e \u003cp\u003e10.2.4 Partial Inhibitors 323\u003c\/p\u003e \u003cp\u003e10.3 Effects of Inhibitors on Steady-State Parameters 324\u003c\/p\u003e \u003cp\u003e10.3.1 Competitive Inhibitors 325\u003c\/p\u003e \u003cp\u003e10.3.2 Noncompetitive Inhibitors 329\u003c\/p\u003e \u003cp\u003e10.3.3 Uncompetitive Inhibitors 330\u003c\/p\u003e \u003cp\u003e10.3.4 Fitting of Untransformed Data 332\u003c\/p\u003e \u003cp\u003e10.4 Concentration-Response Plots of Enzyme Inhibition 333\u003c\/p\u003e \u003cp\u003e10.4.1 Concentration-Response Plots for Partial Inhibition 336\u003c\/p\u003e \u003cp\u003e10.5 Effects of Substrate Concentration on Inhibitor Concentration–Response Curves 337\u003c\/p\u003e \u003cp\u003e10.6 Mutually Exclusive Binding of Two Inhibitors 340\u003c\/p\u003e \u003cp\u003e10.7 Structure–Activity Relationships and Inhibitor Design 343\u003c\/p\u003e \u003cp\u003e10.7.1 SAR in the Absence of Enzyme Structural Information 343\u003c\/p\u003e \u003cp\u003e10.7.2 Inhibitor Design Based on Enzyme Structure 350\u003c\/p\u003e \u003cp\u003e10.8 Summary 353\u003c\/p\u003e \u003cp\u003eReferences and Further Reading 354\u003c\/p\u003e \u003cp\u003e\u003cb\u003e11 Tight-Binding Inhibitors 357\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eKey Learning Points 357\u003c\/p\u003e \u003cp\u003e11.1 Identifying Tight-Binding Inhibition 358\u003c\/p\u003e \u003cp\u003e11.2 Distinguishing Inhibitor Type for Tight-Binding Inhibitors 359\u003c\/p\u003e \u003cp\u003e11.3 Determining \u003ci\u003eK\u003c\/i\u003ei for Tight-Binding Inhibitors 362\u003c\/p\u003e \u003cp\u003e11.4 Use of Tight-Binding Inhibitors to Determine Active Enzyme Concentration 365\u003c\/p\u003e \u003cp\u003e11.5 Summary 368 References and Further Reading 368\u003c\/p\u003e \u003cp\u003e\u003cb\u003e12 Time-Dependent Inhibition 371\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eKey Learning Points 371\u003c\/p\u003e \u003cp\u003e12.1 Progress Curves for Slow-Binding Inhibitors 375\u003c\/p\u003e \u003cp\u003e12.2 Distinguishing Between Slow-Binding Schemes 378\u003c\/p\u003e \u003cp\u003e12.2.1 Scheme B 379\u003c\/p\u003e \u003cp\u003e12.2.2 Scheme C 379\u003c\/p\u003e \u003cp\u003e12.2.3 Scheme D 380\u003c\/p\u003e \u003cp\u003e12.3 Distinguishing Between Modes of Inhibitor Interaction with Enzyme 382\u003c\/p\u003e \u003cp\u003e12.4 Determining Reversibility 384\u003c\/p\u003e \u003cp\u003e12.4.1 Enzyme-Inhibitor Residence Time 385\u003c\/p\u003e \u003cp\u003e12.5 Examples of Slow-Binding Enzyme Inhibitors 386\u003c\/p\u003e \u003cp\u003e12.5.1 Serine Proteases 386\u003c\/p\u003e \u003cp\u003e12.5.2 Prostaglandin G\/H Synthase 387\u003c\/p\u003e \u003cp\u003e12.5.3 Chemical Modification as Probes of Enzyme Structure and Mechanism 391\u003c\/p\u003e \u003cp\u003e12.5.3.1 Amino Acid Selective Chemical Modification 392\u003c\/p\u003e \u003cp\u003e12.5.3.2 Substrate Protection Experiments 394\u003c\/p\u003e \u003cp\u003e12.5.3.3 Affinity Labels 396\u003c\/p\u003e \u003cp\u003e12.6 Summary 398\u003c\/p\u003e \u003cp\u003eReferences and Further Reading 398\u003c\/p\u003e \u003cp\u003e\u003cb\u003e13 Enzyme Reactions with Multiple Substrates 401\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eKey Learning Points 401\u003c\/p\u003e \u003cp\u003e13.1 Reaction Nomenclature 402\u003c\/p\u003e \u003cp\u003e13.2 Bi–Bi Reaction Mechanisms 403\u003c\/p\u003e \u003cp\u003e13.2.1 Random Ordered Bi–Bi Reactions 403\u003c\/p\u003e \u003cp\u003e13.2.2 Compulsory-Ordered Bi–Bi Reactions 404\u003c\/p\u003e \u003cp\u003e13.2.3 Double Displacement or Ping–Pong Bi–Bi Reactions 406\u003c\/p\u003e \u003cp\u003e13.3 Distinguishing Between Random and Compulsory-Ordered Mechanisms by Inhibition Pattern 407\u003c\/p\u003e \u003cp\u003e13.4 Isotope Exchange Studies for Distinguishing Reaction Mechanisms 409\u003c\/p\u003e \u003cp\u003e13.5 Using the King–Altman Method to Determine Velocity Equations 411\u003c\/p\u003e \u003cp\u003e13.6 Cleland’s Net Rate Constant Method for Determining \u003ci\u003eV\u003c\/i\u003e\u003csub\u003emax \u003c\/sub\u003eand \u003ci\u003eV\u003c\/i\u003e\u003csub\u003emax\u003c\/sub\u003e\/\u003ci\u003eK\u003c\/i\u003e\u003csub\u003em\u003c\/sub\u003e 414\u003c\/p\u003e \u003cp\u003e13.7 Summary 416\u003c\/p\u003e \u003cp\u003eReferences and Further Reading 417\u003c\/p\u003e \u003cp\u003e\u003cb\u003e14 Enzyme–Macromolecule Interactions 419\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eKey Learning Points 419\u003c\/p\u003e \u003cp\u003e14.1 Mutlitprotein Enzyme Complexes 420\u003c\/p\u003e \u003cp\u003e14.2 Enzyme Reactions on Macromolecular Substrates 422\u003c\/p\u003e \u003cp\u003e14.2.1 Differences Between Small Molecule and Protein Substrate Binding to Enzymes 422\u003c\/p\u003e \u003cp\u003e14.2.2 Factors Affecting Protein–Protein Interactions 425\u003c\/p\u003e \u003cp\u003e14.2.3 Separation of Binding and Catalytic Recognition Elements 427\u003c\/p\u003e \u003cp\u003e14.2.4 Noncompetitive Inhibition by Active Site Binding Molecules for Exosite Utilizing Enzymes 429\u003c\/p\u003e \u003cp\u003e14.2.5 Processive and Distributive Mechanisms of Catalysis 430\u003c\/p\u003e \u003cp\u003e14.2.6 Effect of Substrate Conformation on Enzyme Kinetics 434\u003c\/p\u003e \u003cp\u003e14.2.7 Inhibitor Binding to Substrates 434\u003c\/p\u003e \u003cp\u003e14.3 Summary 436\u003c\/p\u003e \u003cp\u003eReferences and Further Reading 436\u003c\/p\u003e \u003cp\u003e\u003cb\u003e15 Cooperativity in Enzyme Catalysis 439\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eKey Learning Points 439\u003c\/p\u003e \u003cp\u003e15.1 Historic Examples of Cooperativity and Allostery in Proteins 441\u003c\/p\u003e \u003cp\u003e15.2 Models of Allosteric Behavior 445\u003c\/p\u003e \u003cp\u003e15.3 Effects of Cooperativity on Velocity Curves 449\u003c\/p\u003e \u003cp\u003e15.4 Sigmoidal Kinetics for Nonallosteric Enzymes 452\u003c\/p\u003e \u003cp\u003e15.5 Summary 453\u003c\/p\u003e \u003cp\u003eReferences and Further Reading 453\u003c\/p\u003e \u003cp\u003e\u003cb\u003e16 Evolution of Enzymes 455\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eKey Learning Points 455\u003c\/p\u003e \u003cp\u003e16.1 Early Earth Conditions 456\u003c\/p\u003e \u003cp\u003e16.2 Natural Selection 456\u003c\/p\u003e \u003cp\u003e16.3 Genetic Alterations 459\u003c\/p\u003e \u003cp\u003e16.3.1 Single Nucleotide Polymorphisms (SNPs) 459\u003c\/p\u003e \u003cp\u003e16.3.2 Gene Duplication 460\u003c\/p\u003e \u003cp\u003e16.3.3 Deletions and Insertions 461\u003c\/p\u003e \u003cp\u003e16.3.4 Translocations and Inversions 461\u003c\/p\u003e \u003cp\u003e16.4 Enzyme Families and Superfamilies 463\u003c\/p\u003e \u003cp\u003e16.5 Enzyme Promiscuity as a Springboard of Evolution 467\u003c\/p\u003e \u003cp\u003e16.5.1 Evolution of Enzyme Steady State Parameters 471\u003c\/p\u003e \u003cp\u003e16.6 Protein Dynamics and Conformational Selection in Evolution of Neofunctionality 474\u003c\/p\u003e \u003cp\u003e16.7 Ancestral Enzyme Reconstruction 475\u003c\/p\u003e \u003cp\u003e16.7.1 Mechanism of Drug Selectivity for Gleevec 477\u003c\/p\u003e \u003cp\u003e16.7.2 Overcoming Epistasis to Define the Mechanism of Substrate Specificity 478\u003c\/p\u003e \u003cp\u003e16.7.3 Revealing Generalist to Specialist Evolution 479\u003c\/p\u003e \u003cp\u003e16.7.4 Ancestral Sequence Reconstruction as a Practical Tool 480\u003c\/p\u003e \u003cp\u003e16.8 Contemporary Enzyme Evolution 480\u003c\/p\u003e \u003cp\u003e16.9 Summary 483\u003c\/p\u003e \u003cp\u003eReferences and Further Reading 483\u003c\/p\u003e \u003cp\u003e\u003cb\u003e17 Enzymes in Human Health 487\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eKey Learning Points 487\u003c\/p\u003e \u003cp\u003e17.1 Enzymes as Therapeutic Agents 487\u003c\/p\u003e \u003cp\u003e17.2 Enzyme Inhibitors as Therapeutic Agents 488\u003c\/p\u003e \u003cp\u003e17.2.1 Properties of Small-Molecule Drugs 489\u003c\/p\u003e \u003cp\u003e17.2.2 Enzymes as Drug Targets 489\u003c\/p\u003e \u003cp\u003e17.3 Enzyme Essentiality in Disease 492\u003c\/p\u003e \u003cp\u003e17.3.1 Paralogues with Distinct Physiological Roles 492\u003c\/p\u003e \u003cp\u003e17.3.2 Distinct Orthologues in Infectious Diseases 494\u003c\/p\u003e \u003cp\u003e17.3.3 Diseases of Lifestyle, Environmental, and Aging 497\u003c\/p\u003e \u003cp\u003e17.3.4 Pathogenic Alterations to Enzyme Function 501\u003c\/p\u003e \u003cp\u003e17.3.4.1 Relating Genetic Alterations to Disease Essentiality 502\u003c\/p\u003e \u003cp\u003e17.3.4.2 Enzyme Overexpression 505\u003c\/p\u003e \u003cp\u003e17.3.4.3 Activating Mutations 506\u003c\/p\u003e \u003cp\u003e17.3.4.4 Chromosomal Translocations 515\u003c\/p\u003e \u003cp\u003e17.3.4.5 Synthetic Lethality 518\u003c\/p\u003e \u003cp\u003e17.3.5 Pro-Drug Activation by Enzymes 522\u003c\/p\u003e \u003cp\u003e17.4 Enzyme-Mediated Target Protein Degradation 524\u003c\/p\u003e \u003cp\u003e17.5 The Role of Enzymology in Drug Discovery and Development 527\u003c\/p\u003e \u003cp\u003e17.5.1 Enzyme Selectivity Assessment 529\u003c\/p\u003e \u003cp\u003e17.5.2 Correlating Enzyme Inhibition with Cellular Phenotype 530\u003c\/p\u003e \u003cp\u003e17.5.3 Hepatic Metabolism of Xenobiotics 533\u003c\/p\u003e \u003cp\u003e17.5.4 Mutation-Based Drug Resistance 535\u003c\/p\u003e \u003cp\u003e17.6 Summary 537\u003c\/p\u003e \u003cp\u003eReferences and Further Reading 537\u003c\/p\u003e \u003cp\u003eIndex 543\u003c\/p\u003e","brand":"John Wiley \u0026 Sons Inc","offers":[{"title":"Default Title","offer_id":48738372387159,"sku":"9781119793250","price":146.7,"currency_code":"GBP","in_stock":false}],"url":"https:\/\/bookcurl.com\/products\/enzymes-9781119793250","provider":"Book Curl","version":"1.0","type":"link"}