From Enzyme Models to Model Enzymes

, by Kirby, Anthony J.; Hollfelder, Florian

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ISBN: 9780854041756 | 0854041753
Cover: Hardcover
Copyright: 10/1/2009

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Designing artificial systems with catalytic efficiencies to rival those of natural enzymes is one of the great challenges facing science today. This introduction to the exciting area of artificial enzymes is suitable for both students and more senior researchers. It starts with a systematic review of the key properties of natural enzymes. This is followed by a summary of the mechanisms involved in the major classes of reactions and a logical progression to the first, rudimentary artificial enzymes catalyzing them. An analysis of the classical design-based approach to catalysis by enzyme mimics leads on to a summary of recent advances in creating and improving catalysts. Key data interpretation skills are introduced in a guided approach that links kinetic measurements with their chemical and biological interpretation.

From Models Through Mimics to Artificial Enzymes	p. 1
Introduction to Enzyme Chemistry	p. 2
Why are Enzymes so Big?	p. 3
Functional Groups Available to Enzymes	p. 4
Principles of Catalysis by Enzymes	p. 6
Dependence on pH	p. 7
General Acid-Base Catalysis	p. 8
Experimental Evidence	p. 8
Mechanisms	p. 9
Kinetic Equivalence	p. 13
Intramolecularity	p. 14
Efficiency of Intramolecular Catalysis	p. 17
Energetics	p. 18
Binding and Recognition	p. 20
Hydrophobic Binding	p. 22
The Special Environment of the Active Site	p. 24
Cofactors	p. 24
Many Enzymes Use the Same Basic Mechanisms	p. 25
Enzyme Models, Mimics and Pretenders	p. 26
Evaluation of Catalytic Efficiency in Enzymes and Enzyme Models	p. 29
Introduction	p. 29
Measurement of Uncatalyzed Rate Constants, k_uncat	p. 30
Characterizing the Catalytic Reactivity of an Enzyme or an Enzyme Model	p. 32
Comparing Catalyzed and Uncatalyzed Rates	p. 34
Calculating Rate Accelerations	p. 35
Catalytic Efficiencies of Representative Enzymes: The Size of the Challenge	p. 41
Constructing Enzyme Models - Building up Complexity	p. 42
Solvents - Catalysis Without Functional Groups?	p. 43
Introducing Catalytic Groups - Without Positioning Them	p. 46
Positioning of Substrate and Catalytic Groups by Covalent Design	p. 47
Binding the Ground State by Noncovalent Interactions	p. 47
Binding the TS More Strongly than the GS by Noncovalent Interactions	p. 50
Existing Enzymes as Catalytic Scaffolds to Accommodate New Functions	p. 52
Enzymes Modified by Addition of Functionality	p. 54
Exploiting Modular Build-Up of Binding and Catalytic Features: Chimeras of Binding Proteins and Reactive Chemical Functionality	p. 54
Noncovalent Introduction of Reactive Cofactors: Transition-Metal Catalysts in a Protein	p. 55
Covalent Derivatization of Active-Site Residues to Introduce Reactive Cofactors	p. 56
Site-Directed Mutants of Enzymes: Minimalist Protein Redesign	p. 56
Exploring Enzyme Promiscuity	p. 57
Enzyme Models Classified by Reaction	p. 61
Acyl Transfer	p. 61
The Serine Proteases. Typical Active Sites	p. 62
The Active-Site Environment…and Mechanism	p. 64
Intramolecular Models	p. 66
Supramolecular Models	p. 69
Cyclodextrins	p. 69
Synthetic Models	p. 72
SH Hydrolases	p. 75
Models	p. 76
Intramolecular Models	p. 78
Supramolecular Models	p. 79
Aspartic Proteinases	p. 79
Intramolecular Models	p. 80
Metallopeptidases/Amide Hydrolases	p. 83
Enzymes	p. 86
Model Systems with One Metal Centre	p. 86
Intramolecular Reactions	p. 88
Supramolecular Metalloprotease/Peptidase Models	p. 88
Model Systems with Two Metal Centres	p. 90
Aminopeptidase and Lactamase Models	p. 92
Phosphoryl Transfer	p. 95
Phosphoryl Group Transfer from Monoesters	p. 96
Enzymes I. Phosphoryl Transfer Without Metals: PTPases	p. 98
Models	p. 100
Intramolecular Models	p. 100
Supramolecular Models	p. 101
Enzymes II. Metalloenzymes	p. 102
Models	p. 102
Phosphoryl Group Transfer from Phosphodiesters	p. 105
Intramolecular Reactions	p. 106
Intramolecular Attack by OH	p. 108
Enzymes I. Phosphoryl Group Transfer Without Metals	p. 111
Transfer to Neighbouring OH	p. 113
Supramolecular Models	p. 114
Enzymes II. Metalloenzymes	p. 117
Supramolecular Models: RNA Cleavage	p. 118
Supramolecular Models: DNA-Cleavage	p. 122
Glycosyl Transfer	p. 126
Simple Models	p. 129
Enzymes	p. 132
Glycoside Hydrolases	p. 133
Glycoside Transferases	p. 135
Intramolecular Models	p. 138
Enzyme Mimics	p. 142
Hydrogen Transfer	p. 145
Introduction	p. 145
Enolization: Proton Transfer from Carbon	p. 146
Simple Models	p. 148
Intramolecular Models	p. 149
Catalysis by Metal Ions	p. 151
Enzymes Catalyzing Enolization	p. 152
Triose Phosphate Isomerase	p. 152
Citrate Synthase	p. 155
The Enolase Superfamily	p. 155
Mandelate Racemase	p. 157
Models	p. 157
Hydride Transfer	p. 159
Uridine Diphosphate-galaclose-4-epimerase	p. 160
Dehydrogenases	p. 161
Models	p. 161
Intramolecular Models	p. 165
Hydrogen-Atom Transfer	p. 165
Radical Reactions	p. 168
Coenzyme Initiators Based on Adenosylcobalamin	p. 168
Radicals in Enzyme-Active Sites	p. 171
Pyruvate-formate Lyase	p. 171
Ribonucleotide Reductases	p. 172
Models	p. 174
Initiation Stages	p. 176
Hydrogen-Atom Transfers	p. 176
Pericyclic Reactions	p. 180
Chorismate Mutase	p. 181
Models: Catalysis by Antibodies	p. 182
Antibodies Catalyzing the Diels-Alder Reaction	p. 185
Supramolecular Catalysis of the Diels-Alder Reaction	p. 187
Catalysis by RNA	p. 191
Design vs. Iterative Methods - Mimicking the Way Nature Generates Catalysts	p. 195
Introduction	p. 195
Catalytic Polymers	p. 197
Synzymes	p. 199
Dendrimers	p. 202
Peptide Dendrimers	p. 204
Molecular Imprinting	p. 209
Catalytic Antibodies	p. 212
Other Approaches	p. 214
Proton Transfer from Carbon	p. 216
Conclusions	p. 219
Nucleic Acids as Catalysts	p. 220
Mechanisms of Nucleic-acid Catalysis	p. 220
Selection as an Alternative to Design Strategies	p. 225
Access to New Catalysts Using SELEX	p. 227
Changing the Catalyst Backbone: DNAzymes	p. 228
Nucleic-Acid Catalysis of Other Reactions	p. 229
Improving Protein Enzymes	p. 231
Challenges in Exploring Protein Catalysts	p. 231
What Fraction of Diversity Space is Practically Accessible?	p. 233
Mapping Enzyme Function in the Proteome: Protein Superfamilies as a Basis for Understanding Functional Links	p. 236
The Enolase Superfamily	p. 236
The Alkaline Phosphatase Superfamily	p. 238
Challenging Chance by Design and Directed Evolution	p. 243
References	p. 248
Subject Index	p. 266
Table of Contents provided by Ingram. All Rights Reserved.

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From Enzyme Models to Model Enzymes

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