From enzyme models to model enzymes /
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作 者：Anthony J. Kirby, Florian Hollfelder.
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ISBN：9780854041756
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简介
"Designing artificial systems with catalytic efficiencies to rival those of natural enzymes is one of the great challenges facing science today. Our current level of understanding fails the basic, practical test - designing and making artificial systems with catalytic efficiencies to rival those of natural enzymes. Chemists and bio-scientists are well aware of this problem, and 'artificial enzymes' have been a 'hot topic' for many years. However, until now, there has been no book devoted specifically to this subject. This is the first book to provide a critical introduction to, and overview of, this exciting area. It is aimed at students and more senior researchers with specialist or general interests in the field. The book starts with a systematic overview of the most important properties of natural enzymes, with special emphasis on mechanisms and efficiency of catalysis. This is followed by a summary of the mechanisms involved in the major classes of reaction they catalyze, and spells out the logical progression from simple mechanistic models for particular reactions to the first, rudimentary artificial enzymes catalyzing them. Catalytic efficiency is the key criterion for inclusion. An analysis of the strengths and limitations of the classical design-based approach to catalysis by enzyme mimics leads on to a discussion of recent advances which use selection methods coupled with iterative techniques for creating and improving catalysts by natural methods. The comparison of natural and artificial catalysts requires a quantitative understanding based on the interpretation of kinetic measurements. Key skills in data interpretation are introduced in a guided approach that connects the formal treatment of kinetic measurements with their chemical and biological interpretation."--Publisher's description.
目录
Chapter 1 From Models Through Mimics to Artificial Enzymes p. 1
1.1 Introduction to Enzyme Chemistry p. 2
1.1.1 Why are Enzymes so Big? p. 3
1.1.2 Functional Groups Available to Enzymes p. 4
1.2 Principles of Catalysis by Enzymes p. 6
1.2.1 Dependence on pH p. 7
1.3 General Acid-Base Catalysis p. 8
1.3.1 Experimental Evidence p. 8
1.3.2 Mechanisms p. 9
1.3.3 Kinetic Equivalence p. 13
1.4 Intramolecularity p. 14
1.4.1 Efficiency of Intramolecular Catalysis p. 17
1.5 Energetics p. 18
1.6 Binding and Recognition p. 20
1.6.1 Hydrophobic Binding p. 22
1.6.2 The Special Environment of the Active Site p. 24
1.7 Cofactors p. 24
1.8 Many Enzymes Use the Same Basic Mechanisms p. 25
1.9 Enzyme Models, Mimics and Pretenders p. 26
Chapter 2 Evaluation of Catalytic Efficiency in Enzymes and Enzyme Models p. 29
2.1 Introduction p. 29
2.2 Measurement of Uncatalyzed Rate Constants, k uncat p. 30
2.3 Characterizing the Catalytic Reactivity of an Enzyme or an Enzyme Model p. 32
2.3.1 Comparing Catalyzed and Uncatalyzed Rates p. 34
2.3.2 Calculating Rate Accelerations p. 35
2.4 Catalytic Efficiencies of Representative Enzymes: The Size of the Challenge p. 41
Chapter 3 Constructing Enzyme Models - Building up Complexity p. 42
3.1 Solvents - Catalysis Without Functional Groups? p. 43
3.2 Introducing Catalytic Groups - Without Positioning Them p. 46
3.3 Positioning of Substrate and Catalytic Groups by Covalent Design p. 47
3.4 Binding the Ground State by Noncovalent Interactions p. 47
3.5 Binding the TS More Strongly than the GS by Noncovalent Interactions p. 50
3.6 Existing Enzymes as Catalytic Scaffolds to Accommodate New Functions p. 52
3.6.1 Enzymes Modified by Addition of Functionality p. 54
3.6.1.1 Exploiting Modular Build-Up of Binding and Catalytic Features: Chimeras of Binding Proteins and Reactive Chemical Functionality p. 54
3.6.1.2 Noncovalent Introduction of Reactive Cofactors: Transition-Metal Catalysts in a Protein p. 55
3.6.1.3 Covalent Derivatization of Active-Site Residues to Introduce Reactive Cofactors p. 56
3.6.2 Site-Directed Mutants of Enzymes: Minimalist Protein Redesign p. 56
3.6.3 Exploring Enzyme Promiscuity p. 57
Chapter 4 Enzyme Models Classified by Reaction p. 61
4.1 Acyl Transfer p. 61
4.1.1 The Serine Proteases. Typical Active Sites p. 62
4.1.1.1 The Active-Site Environment...and Mechanism p. 64
4.1.1.2 Intramolecular Models p. 66
4.1.1.3 Supramolecular Models p. 69
4.1.1.3.1 Cyclodextrins p. 69
4.1.1.3.2 Synthetic Models p. 72
4.1.2 SH Hydrolases p. 75
4.1.2.1 Models p. 76
4.1.2.2 Intramolecular Models p. 78
4.1.2.3 Supramolecular Models p. 79
4.1.3 Aspartic Proteinases p. 79
4.1.3.1 Intramolecular Models p. 80
4.1.4 Metallopeptidases/Amide Hydrolases p. 83
4.1.4.1 Enzymes p. 86
4.1.4.2 Model Systems with One Metal Centre p. 86
4.1.4.2.1 Intramolecular Reactions p. 88
4.1.4.2.2 Supramolecular Metalloprotease/Peptidase Models p. 88
4.1.4.3 Model Systems with Two Metal Centres p. 90
4.1.4.3.1 Aminopeptidase and Lactamase Models p. 92
4.2 Phosphoryl Transfer p. 95
4.2.1 Phosphoryl Group Transfer from Monoesters p. 96
4.2.1.1 Enzymes I. Phosphoryl Transfer Without Metals: PTPases p. 98
4.2.1.1.1 Models p. 100
4.2.1.1.2 Intramolecular Models p. 100
4.2.1.1.3 Supramolecular Models p. 101
4.2.1.2 Enzymes II. Metalloenzymes p. 102
4.2.1.2.1 Models p. 102
4.2.2 Phosphoryl Group Transfer from Phosphodiesters p. 105
4.2.2.1 Intramolecular Reactions p. 106
4.2.2.1.1 Intramolecular Attack by OH p. 108
4.2.2.2 Enzymes I. Phosphoryl Group Transfer Without Metals p. 111
4.2.2.2.1 Transfer to Neighbouring OH p. 113
4.2.2.2.2 Supramolecular Models p. 114
4.2.2.3 Enzymes II. Metalloenzymes p. 117
4.2.2.3.1 Supramolecular Models: RNA Cleavage p. 118
4.2.2.3.2 Supramolecular Models: DNA-Cleavage p. 122
4.3 Glycosyl Transfer p. 126
4.3.1 Simple Models p. 129
4.3.2 Enzymes p. 132
4.3.2.1 Glycoside Hydrolases p. 133
4.3.2.2 Glycoside Transferases p. 135
4.3.3 Intramolecular Models p. 138
4.3.4 Enzyme Mimics p. 142
4.4 Hydrogen Transfer p. 145
Introduction p. 145
4.4.1 Enolization: Proton Transfer from Carbon p. 146
4.4.1.1 Simple Models p. 148
4.4.1.2 Intramolecular Models p. 149
4.4.1.3 Catalysis by Metal Ions p. 151
4.4.1.4 Enzymes Catalyzing Enolization p. 152
4.4.1.4.1 Triose Phosphate Isomerase p. 152
4.4.1.4.2 Citrate Synthase p. 155
4.4.1.4.3 The Enolase Superfamily p. 155
4.4.1.4.4 Mandelate Racemase p. 157
4.4.1.4.5 Models p. 157
4.4.2 Hydride Transfer p. 159
4.4.2.1 Uridine Diphosphate-galaclose-4-epimerase p. 160
4.4.2.2 Dehydrogenases p. 161
4.4.2.3 Models p. 161
4.4.2.4 Intramolecular Models p. 165
4.4.3 Hydrogen-Atom Transfer p. 165
4.5 Radical Reactions p. 168
4.5.1 Coenzyme Initiators Based on Adenosylcobalamin p. 168
4.5.2 Radicals in Enzyme-Active Sites p. 171
4.5.2.1 Pyruvate-formate Lyase p. 171
4.5.2.2 Ribonucleotide Reductases p. 172
4.5.3 Models p. 174
4.5.3.1 Initiation Stages p. 176
4.5.3.2 Hydrogen-Atom Transfers p. 176
4.6 Pericyclic Reactions p. 180
4.6.1 Chorismate Mutase p. 181
4.6.1.1 Models: Catalysis by Antibodies p. 182
4.6.2 Antibodies Catalyzing the Diels-Alder Reaction p. 185
4.6.2.1 Supramolecular Catalysis of the Diels-Alder Reaction p. 187
4.6.3 Catalysis by RNA p. 191
Chapter 5 Design vs. Iterative Methods - Mimicking the Way Nature Generates Catalysts p. 195
Introduction p. 195
5.1 Catalytic Polymers p. 197
5.1.1 Synzymes p. 199
5.1.2 Dendrimers p. 202
5.1.2.1 Peptide Dendrimers p. 204
5.1.3 Molecular Imprinting p. 209
5.2 Catalytic Antibodies p. 212
5.2.1 Other Approaches p. 214
5.2.2 Proton Transfer from Carbon p. 216
5.2.3 Conclusions p. 219
5.3 Nucleic Acids as Catalysts p. 220
5.3.1 Mechanisms of Nucleic-acid Catalysis p. 220
5.3.2 Selection as an Alternative to Design Strategies p. 225
5.3.3 Access to New Catalysts Using SELEX p. 227
5.3.4 Changing the Catalyst Backbone: DNAzymes p. 228
5.3.5 Nucleic-Acid Catalysis of Other Reactions p. 229
5.4 Improving Protein Enzymes p. 231
5.4.1 Challenges in Exploring Protein Catalysts p. 231
5.4.2 What Fraction of Diversity Space is Practically Accessible? p. 233
5.4.3 Mapping Enzyme Function in the Proteome: Protein Superfamilies as a Basis for Understanding Functional Links p. 236
5.4.3.1 The Enolase Superfamily p. 236
5.4.3.2 The Alkaline Phosphatase Superfamily p. 238
5.4.4 Challenging Chance by Design and Directed Evolution p. 243
References p. 248
Subject Index p. 266
1.1 Introduction to Enzyme Chemistry p. 2
1.1.1 Why are Enzymes so Big? p. 3
1.1.2 Functional Groups Available to Enzymes p. 4
1.2 Principles of Catalysis by Enzymes p. 6
1.2.1 Dependence on pH p. 7
1.3 General Acid-Base Catalysis p. 8
1.3.1 Experimental Evidence p. 8
1.3.2 Mechanisms p. 9
1.3.3 Kinetic Equivalence p. 13
1.4 Intramolecularity p. 14
1.4.1 Efficiency of Intramolecular Catalysis p. 17
1.5 Energetics p. 18
1.6 Binding and Recognition p. 20
1.6.1 Hydrophobic Binding p. 22
1.6.2 The Special Environment of the Active Site p. 24
1.7 Cofactors p. 24
1.8 Many Enzymes Use the Same Basic Mechanisms p. 25
1.9 Enzyme Models, Mimics and Pretenders p. 26
Chapter 2 Evaluation of Catalytic Efficiency in Enzymes and Enzyme Models p. 29
2.1 Introduction p. 29
2.2 Measurement of Uncatalyzed Rate Constants, k uncat p. 30
2.3 Characterizing the Catalytic Reactivity of an Enzyme or an Enzyme Model p. 32
2.3.1 Comparing Catalyzed and Uncatalyzed Rates p. 34
2.3.2 Calculating Rate Accelerations p. 35
2.4 Catalytic Efficiencies of Representative Enzymes: The Size of the Challenge p. 41
Chapter 3 Constructing Enzyme Models - Building up Complexity p. 42
3.1 Solvents - Catalysis Without Functional Groups? p. 43
3.2 Introducing Catalytic Groups - Without Positioning Them p. 46
3.3 Positioning of Substrate and Catalytic Groups by Covalent Design p. 47
3.4 Binding the Ground State by Noncovalent Interactions p. 47
3.5 Binding the TS More Strongly than the GS by Noncovalent Interactions p. 50
3.6 Existing Enzymes as Catalytic Scaffolds to Accommodate New Functions p. 52
3.6.1 Enzymes Modified by Addition of Functionality p. 54
3.6.1.1 Exploiting Modular Build-Up of Binding and Catalytic Features: Chimeras of Binding Proteins and Reactive Chemical Functionality p. 54
3.6.1.2 Noncovalent Introduction of Reactive Cofactors: Transition-Metal Catalysts in a Protein p. 55
3.6.1.3 Covalent Derivatization of Active-Site Residues to Introduce Reactive Cofactors p. 56
3.6.2 Site-Directed Mutants of Enzymes: Minimalist Protein Redesign p. 56
3.6.3 Exploring Enzyme Promiscuity p. 57
Chapter 4 Enzyme Models Classified by Reaction p. 61
4.1 Acyl Transfer p. 61
4.1.1 The Serine Proteases. Typical Active Sites p. 62
4.1.1.1 The Active-Site Environment...and Mechanism p. 64
4.1.1.2 Intramolecular Models p. 66
4.1.1.3 Supramolecular Models p. 69
4.1.1.3.1 Cyclodextrins p. 69
4.1.1.3.2 Synthetic Models p. 72
4.1.2 SH Hydrolases p. 75
4.1.2.1 Models p. 76
4.1.2.2 Intramolecular Models p. 78
4.1.2.3 Supramolecular Models p. 79
4.1.3 Aspartic Proteinases p. 79
4.1.3.1 Intramolecular Models p. 80
4.1.4 Metallopeptidases/Amide Hydrolases p. 83
4.1.4.1 Enzymes p. 86
4.1.4.2 Model Systems with One Metal Centre p. 86
4.1.4.2.1 Intramolecular Reactions p. 88
4.1.4.2.2 Supramolecular Metalloprotease/Peptidase Models p. 88
4.1.4.3 Model Systems with Two Metal Centres p. 90
4.1.4.3.1 Aminopeptidase and Lactamase Models p. 92
4.2 Phosphoryl Transfer p. 95
4.2.1 Phosphoryl Group Transfer from Monoesters p. 96
4.2.1.1 Enzymes I. Phosphoryl Transfer Without Metals: PTPases p. 98
4.2.1.1.1 Models p. 100
4.2.1.1.2 Intramolecular Models p. 100
4.2.1.1.3 Supramolecular Models p. 101
4.2.1.2 Enzymes II. Metalloenzymes p. 102
4.2.1.2.1 Models p. 102
4.2.2 Phosphoryl Group Transfer from Phosphodiesters p. 105
4.2.2.1 Intramolecular Reactions p. 106
4.2.2.1.1 Intramolecular Attack by OH p. 108
4.2.2.2 Enzymes I. Phosphoryl Group Transfer Without Metals p. 111
4.2.2.2.1 Transfer to Neighbouring OH p. 113
4.2.2.2.2 Supramolecular Models p. 114
4.2.2.3 Enzymes II. Metalloenzymes p. 117
4.2.2.3.1 Supramolecular Models: RNA Cleavage p. 118
4.2.2.3.2 Supramolecular Models: DNA-Cleavage p. 122
4.3 Glycosyl Transfer p. 126
4.3.1 Simple Models p. 129
4.3.2 Enzymes p. 132
4.3.2.1 Glycoside Hydrolases p. 133
4.3.2.2 Glycoside Transferases p. 135
4.3.3 Intramolecular Models p. 138
4.3.4 Enzyme Mimics p. 142
4.4 Hydrogen Transfer p. 145
Introduction p. 145
4.4.1 Enolization: Proton Transfer from Carbon p. 146
4.4.1.1 Simple Models p. 148
4.4.1.2 Intramolecular Models p. 149
4.4.1.3 Catalysis by Metal Ions p. 151
4.4.1.4 Enzymes Catalyzing Enolization p. 152
4.4.1.4.1 Triose Phosphate Isomerase p. 152
4.4.1.4.2 Citrate Synthase p. 155
4.4.1.4.3 The Enolase Superfamily p. 155
4.4.1.4.4 Mandelate Racemase p. 157
4.4.1.4.5 Models p. 157
4.4.2 Hydride Transfer p. 159
4.4.2.1 Uridine Diphosphate-galaclose-4-epimerase p. 160
4.4.2.2 Dehydrogenases p. 161
4.4.2.3 Models p. 161
4.4.2.4 Intramolecular Models p. 165
4.4.3 Hydrogen-Atom Transfer p. 165
4.5 Radical Reactions p. 168
4.5.1 Coenzyme Initiators Based on Adenosylcobalamin p. 168
4.5.2 Radicals in Enzyme-Active Sites p. 171
4.5.2.1 Pyruvate-formate Lyase p. 171
4.5.2.2 Ribonucleotide Reductases p. 172
4.5.3 Models p. 174
4.5.3.1 Initiation Stages p. 176
4.5.3.2 Hydrogen-Atom Transfers p. 176
4.6 Pericyclic Reactions p. 180
4.6.1 Chorismate Mutase p. 181
4.6.1.1 Models: Catalysis by Antibodies p. 182
4.6.2 Antibodies Catalyzing the Diels-Alder Reaction p. 185
4.6.2.1 Supramolecular Catalysis of the Diels-Alder Reaction p. 187
4.6.3 Catalysis by RNA p. 191
Chapter 5 Design vs. Iterative Methods - Mimicking the Way Nature Generates Catalysts p. 195
Introduction p. 195
5.1 Catalytic Polymers p. 197
5.1.1 Synzymes p. 199
5.1.2 Dendrimers p. 202
5.1.2.1 Peptide Dendrimers p. 204
5.1.3 Molecular Imprinting p. 209
5.2 Catalytic Antibodies p. 212
5.2.1 Other Approaches p. 214
5.2.2 Proton Transfer from Carbon p. 216
5.2.3 Conclusions p. 219
5.3 Nucleic Acids as Catalysts p. 220
5.3.1 Mechanisms of Nucleic-acid Catalysis p. 220
5.3.2 Selection as an Alternative to Design Strategies p. 225
5.3.3 Access to New Catalysts Using SELEX p. 227
5.3.4 Changing the Catalyst Backbone: DNAzymes p. 228
5.3.5 Nucleic-Acid Catalysis of Other Reactions p. 229
5.4 Improving Protein Enzymes p. 231
5.4.1 Challenges in Exploring Protein Catalysts p. 231
5.4.2 What Fraction of Diversity Space is Practically Accessible? p. 233
5.4.3 Mapping Enzyme Function in the Proteome: Protein Superfamilies as a Basis for Understanding Functional Links p. 236
5.4.3.1 The Enolase Superfamily p. 236
5.4.3.2 The Alkaline Phosphatase Superfamily p. 238
5.4.4 Challenging Chance by Design and Directed Evolution p. 243
References p. 248
Subject Index p. 266
From enzyme models to model enzymes /
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