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Introduction to Enzyme and Coenzyme Chemistry

De
304 pages
Enzyme catalysis is a topic of fundamental importance in organic, bio-organic and medicinal chemistry. This new edition of a very popular textbook provides a concise introduction to the underlying principles and mechanisms of enzyme and coenzyme action from a chemical perspective.

Whilst retaining the overall structure of the first edition – preliminary chapters describe the basic principles of enzyme structure and catalysis moving through to detailed discussions of the major classes of enzyme processes in the later chapters – the book has been thoroughly updated to include information on the most recent advances in our understanding of enzyme action. A major feature of the second edition is the inclusion of two-colour figures of the active sites of enzymes discussed in the text, in order to illustrate the interplay between enzyme structure and function. Problems, with outline answers, at the end of each chapter give the student the chance to the check their understanding of the material.

As a concise but comprehensive account, Introduction to Enzyme and Coenzyme Chemistry will continue to prove invaluable to both undergraduate and postgraduate students of organic, bio-organic and medicinal chemistry.

Tim Bugg is professor of biological chemistry in the Department of Chemistry, University of Warwick, UK.

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Contents
Preface Representation of Protein ThreeDimensional Structures
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2
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4
From Jack Beans to Designer Genes 1.1 Introduction 1.2 The discovery of enzymes 1.3 The discovery of coenzymes 1.4 The commercial importance of enzymes in biosynthesis and biotechnology 1.5 The importance of enzymes as targets for drug discovery All Enzymes are Proteins 2.1 Introduction 2.2 The structures of thelaamino acids 2.3 The primary structure of polypeptides 2.4 Alignment of amino acid sequences 2.5 Secondary structures found in proteins 2.6 The folded tertiary structure of proteins 2.7 Enzyme structure and function 2.8 Metalloenzymes 2.9 Membraneassociated enzymes 2.10 Glycoproteins
Enzymes are Wonderful Catalysts 3.1 Introduction 3.2 A thermodynamic model of catalysis 3.3 Proximity eVects 3.4 The importance of transition state stabilisation 3.5 Acid/base catalysis in enzymatic reactions 3.6 Nucleophilic catalysis in enzymatic reactions 3.7 The use of strain energy in enzyme catalysis 3.8 Catalytic perfection 3.9 The involvement of protein dynamics in enzyme catalysis Methods for Studying Enzymatic Reactions 4.1 Introduction 4.2 Enzyme puriWcation 4.3 Enzyme kinetics 4.4 The stereochemical course of an enzymatic reaction
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1 1 1 3
3 6 8 8 8 10 12 13 16 19 22 23 24
29 29 31 33 36 37 41 45 47 47 51 51 51 54 60
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vi
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6
7
Contents
4.5 4.6 4.7
The existence of intermediates in enzymatic reactions Analysis of transition states in enzymatic reactions Determination of active site catalytic groups
Enzymatic Hydrolysis and Group Transfer Reactions 5.1 Introduction 5.2 The peptidases CASE STUDY: HIV1 protease 5.3 Esterases and lipases 5.4 Acyl transfer reactions in biosynthesis: use of coenzyme A (CoA) 5.5 Enzymatic phosphoryl transfer reactions 0 5.6 Adenosine 5 triphosphate 5.7 Enzymatic glycosyl transfer reactions 5.8 Methyl group transfer: use of Sadenosyl methionine and tetrahydrofolate coenzymes for onecarbon transfers
Enzymatic Redox Chemistry 6.1 Introduction 6.2 Nicotinamide adenine dinucleotidedependent dehydrogenases 6.3 Flavindependent dehydrogenases and oxidases 6.4 Flavindependent monooxygenases 6.5 CASE STUDY: Glutathione and trypanothione reductases 6.6 DeazaXavins and pterins 6.7 Iron–sulphur clusters 6.8 Metaldependent monooxygenases 6.9aKetoglutaratedependent dioxygenases 6.10 Nonhaem irondependent dioxygenases
Enzymatic Carbon–Carbon Bond Formation Introduction Carbon–carbon bond formation via carbanion equivalents Aldolases CASE STUDY: Fructose1,6bisphosphate aldolase Claisen enzymes Assembly of fatty acids and polyketides Carboxylases: use of biotin Ribulose bisphosphate carboxylase/oxygenase (Rubisco) Vitamin Kdependent carboxylase Thiamine pyrophosphatedependent enzymes Carbon–carbon bond formation via carbocation intermediates Terpene cyclases Carbon–carbon bond formation via radical intermediates Phenolic radical couplings
7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 7.10
68 71 75
81 81 82 96 98 99 102 106 109
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121 121 123 129 134 137 141 142 143 147 148
156 156 158 158 158 164 166 170 171 173 176 179 179 183 184
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Contents
Enzymatic Addition/Elimination Reactions 8.1 Introduction 8.2 Hydratases and dehydratases 8.3 Ammonia lyases 8.4 Elimination of phosphate and pyrophosphate 8.5 CASE STUDY: 5Enolpyruvylshikimate3phosphate (EPSP) synthase
Enzymatic Transformations of Amino Acids 9.1 Introduction 0 9.2 Pyridoxal 5 phosphatedependent reactions at theaposition of amino acids 9.3 CASE STUDY: Aspartate aminotransferase 9.4 Reactions atb andgpositions of amino acids 9.5 Serine hydroxymethyltransferase 9.6NPyruvoyldependent amino acid decarboxylases 9.7 Imines and enamines in alkaloid biosynthesis
Isomerases 10.1 Introduction 10.2 Cofactorindependent racemases and epimerases 10.3 Keto–enol tautomerases 10.4 Allylic isomerases 10.5 CASE STUDY: Chorismate mutase
11 Radicals in Enzyme Catalysis 11.1 Introduction 11.2 Vitamin B12dependent rearrangements 11.3 The involvement of protein radicals in enzyme catalysis 11.4 Sadenosyl methioninedependent radical reactions 11.5 Biotin synthase and sulphur insertion reactions 11.6 Oxidised amino acid cofactors and quinoproteins
12 NonEnzymatic Biological Catalysis 12.1 Introduction 12.2 Catalytic RNA 12.3 Catalytic antibodies 12.4 Synthetic enzyme models
Appendices 1. Cahn–Ingold–Prelog rule for stereochemical nomenclature 2. Amino acid abbreviations 3. A simple demonstration of enzyme catalysis 4. Answers to problems Index
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193 193 194 199 202 204
210 210
211 215 218 220 222 222
227 227 227 230 231 233
240 240 240 244 246 249 250
255 255 255 259 265
272 272 274 275 277 285