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Structure and Mechanism in Protein Science: A Guide to Enzyme Catalysis and Protein Folding
SubjectBioscience & Biotechnology
ISBN/SKU0716732688
AuthorAlan Fersht
PublisherFreeman, W. H., Publishers
Publish DateMarch 1999
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Summary
Fourteen years ago when Alan Fersht's Enzyme Structure and Mechanism was published, the field of protein engineering was in its infancy. Since then, spectacular advances in determining biological structure, manipulating genes, engineering proteins, sequencing whole genomes, and computing have led not just to an expansion of protein science, but to its utter transformation. We have entered a new era of protein design, sparked by the convergence of protein folding and enzymology. Fersht's Structure and Mechanism in Protein Science is a defining exploration of this new era, an expert depiction of the core principles of protein structure, activity, and mechanism as understood and applied today. A thorough recasting of Fersht's previous text, the book takes a more general look at mechanisms in protein science, emphasizing the unity of concepts in folding and catalysis and the importance of the relationships between basic chemistry, kinetics, thermodynamics, and structure. By concentrating on fundamental principles and the physical and chemical processes behind them, Structure and Mechanism in Protein Science makes the basic formulas, kinetics, and thermodynamics of protein engineering easier to understand and apply. Up-to-date, authoritative, and full with relevant examples, it provides a solid introduction to a sprawling, still-growing field.
Table of Contents
Structure and Mechanism in Protein Science A Guide to Enzyme Catalysis and Protein Folding Alan Fersht (Cambridge U.) 1. The Three-dimensional Structure of Proteins The primary structure of proteins Methods for determination of three-dimensional structure The three-dimensional structure of proteins Protein diversity Higher levels of organization: Multienzyme complexes The structure of enzyme-substrate complexes Flexibility and conformational mobility of proteins 2. Chemical Catalysis Transition state theory Principles of catalysis Covalent catalysis Structure-activity relationships The principle of microscopic reversibility or detailed balance The principle of kinetic equivalence Kinetic isotope effects Summary of classical factors of enzyme catalysis 3. The Basic Equations of Enzyme Kinetics Steady state kinetics The significance of the Michaelis-Menten parameters Graphical representation of data Inhibition Nonproductive binding kcat/KM = k2/Ks Competing Substrates Reversibility: The Haldene equation Breakdown of the Michaelis-Menten equation Multisubstrate systems Useful kinetic shortcuts Thermodynamic cycles 4. Measurement and Magnitude of Enzymatic Rate Constants Part 1 Methods for measurement: An introduction to pre-steady state kinetics Rapid mixing and sampling techniques Flash photolysis Relaxation methods Analysis of pre-steady state and relaxation kinetics The absolute concentration of enzymes Part 2 The magnitude of rate constants for enzymatic processes Upper limits on rate constants Enzymatic rate constants and rate-determining processes 5. The pH Dependence of Enzyme Catalysis Ionization of simple acids and bases: The basic equations The effect of ionizations of groups in enzymes on kinetics Modifications and breakdown of the simple theory The influence of surface charge on pKa's of groups in enzymes Graphical representation of data Illustrative examples and experimental evidence Direct titration of groups in enzymes The effect of temperature, polarity of solvent, and ionic strength on pKa's Highly perturbed pKa's on enzymes 6. Practical Kinetics Kinetic methods Plotting kinetic data Determination of protein-ligand dissociation constants Plotting binding data Computer fitting of data Statistics, errors of observation of accuracy Appendix: Measurement of protein concentration 7. Detection of Intermediates in Reactions by Kinetics Pre-steady state vs. steady state kinetics Chymotrypsin: Determination of intermediates by stopped-flow spectrophotometry, steady state kinetics, and product partitioning Further examples of detection of intermediates by partition and kinetic experiments Aminoacyl-tRNA synthetases: Detection of intermediates by quenched flow, steady state kinetics, and isotope exchange Detection of conformational changes The future 8. Stereochemistry of Enzymatic Reactions Optical activity and chirality Examples of stereospecific enzyme reactions Detection of intermediates from retention or inversion of configuration at chiral centers The chiral methyl group Chiral phosphate Stereoelectronic control of enzymatic reactions 9. Active-site-directed and Enzyme-activated Irreversible Inhibitors: Affinity Labels and Suicide Inhibitors Chemical modifications of proteins Active-site-directed irreversible inhibitors Enzyme-activated irreversible inhibitors 10. Conformational Change, Allosteric Regulation, Motors, and Work Positive cooperativity Mechanisms of allosteric interactions and cooperativity Negative cooperativity and half-of-the-sites reactivity Quantitative analysis of cooperativity Molecular mechanism of cooperative binding to hemoglobin Regulation of metabolic pathways Phosphofructokinase and control by allosteric feedback Glycogen phosporylase and control by phosphorylation G proteins - molecular switches Motor proteins ATP synthesis by rotary catalysis: ATP synthase and F1-ATPase 11. Forces Between Molecules and Enzyme-Substrate Binding Energies Interactions between nonbonded atoms The binding energies of proteins and ligands Experimental measurements of incremental energies Entropy and binding Enthalpy-entropy compensation Summary 12. Enzyme-substrate Complementarity and the Use of Binding Energies in Catalysis Utilization of enzyme-substrate binding energy in catalysis Experimental evidence for the utilization of binding energy in catalysis and enzyme-transition state complementarity Evolution of the maximum rate: Strong binding of the transition state and weak binding of the substrate Molecular mechanisms for the utilization of binding energy Effects of rate optimization on accumulation of intermediates and internal equilibria in enzymes 13. Specificity and Editing Mechanisms Limits on specificity Editing or proofreading mechanisms The cost of accuracy 14. Recombinant DNA Technology The structure and properties of DNA Cloning enzyme genes for overproduction Site-specific mutagenesis for rational design Random mutagenesis and repertoire selection 15. Case Studies of Enzyme Structure and Mechanism The dehydrogenases The proteases Ribonucleases Lysozyme Some generalizations 16. Protein Engineering Part 1: The Dissection of the structure, activity, and mechanism of an enzyme--the tyrosyl-tRNA synthetase Mechanistic goals The tyrosyl-tRNA synthetase Requirements for systematic site-directed mutagenesis studies Choice of mutation Strategy-free energy profiles and difference energy diagrams Results from difference energy diagrams for the activation of tyrosine Relationship between apparent binding energies from difference energies and incremental binding energies Probing evolution - "reverse genetics" Linear free energy relationships in binding energies Probing the gross structure and symmetry of the enzyme by metagenesis Measuring the free energy of hydrolysis of Tyr-AMP Part 2: Redesigning an enzyme - subtilisin Subtilisin Dissection of the catalytic triad and the oxyanion binding site Redesigning specificity Engineering of stability and other properties 17. Protein Stability Protein denaturation Structure of the denatured state Measurement of changes in stability Energetics of formation of structure Stability-activity trade-off? Prediction of three-dimensional structure from primary structure 18. Kinetics of Protein Folding Kinetics of folding Two-state kinetics Multi-state kinetics Transition state in protein folding Introduction to f-value analysis 1H/2H-exchange methods Folding of peptides 19. Folding Pathways and Energy Landscapes Levinthal's paradox Folding of CI2 The Nucleation-Condensation mechanism Folding of barnase Folding pathway of Barstar at ms resolution Unified folding scheme? Insights from theory Optimization of folding rates Molecular Chaperones

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