Enzymatic Reaction Mechanisms

by Perry A. Frey, Adrian D. Hegeman

Overview

Books dealing with the mechanisms of enzymatic reactions were written a generation ago. They included volumes entitled Bioorganic Mechanisms, I and II by T.C. Bruice and S.J. Benkovic, published in 1965, the volume entitled Catalysis in Chemistry and Enzymology by W.P. Jencks in 1969, and the volume entitled Enzymatic Reaction Mechanisms by C.T. Walsh in 1979. The Walsh book was based on the course taught by W.P. Jencks and R.H. Abeles at Brandeis University in the 1960's and 1970's. By the late 1970's, much more could be included about the structures of enzymes and the kinetics and mechanisms of enzymatic reactions themselves, and less emphasis was placed on chemical models. Walshs book was widely used in courses on enzymatic mechanisms for many years. Much has happened in the field of mechanistic enzymology in the past 15 to 20 years. Walshs book is both out-of-date and out-of-focus in todays world of enzymatic mechanisms. There is no longer a single volume or a small collection of volumes to which students can be directed to obtain a clear understanding of the state of knowledge regarding the chemicals mechanisms by which enzymes catalyze biological reactions. There is no single volume to which medicinal chemists and biotechnologists can refer on the subject of enzymatic mechanisms. Practitioners in the field have recognized a need for a new book on enzymatic mechanisms for more than ten years, and several, including Walsh, have considered undertaking to modernize Walshs book. However, these good intentions have been abandoned for one reason or another. The great size of the knowledge base in mechanistic enzymology has been a deterrent. It seems too large a subject for a single author, and it is difficult for several authors to coordinate their work to mutual satisfaction. This text by Perry A. Frey and Adrian D. Hegeman accomplishes this feat, producing the long-awaited replacement for Walshs classic text.

Product Details

ISBN-13:	9780199880744
Publisher:	Oxford University Press
Publication date:	01/27/2007
Sold by:	Barnes & Noble
Format:	eBook
File size:	60 MB
Note:	This product may take a few minutes to download.

About the Author

University of Wisconsin at Madison

University of Wisconsin at Madison

Table of Contents

Enzymes and Catalytic Mechanisms     1
Catalysis and the Active Site     1
Rate Enhancement in Enzymatic Catalysis     3
Conformational Mobility in Catalysis     5
Substrate-Induced Conformational Changes     5
Catalysis of Multistep Reactions     6
Structural Mobility in Enzymes     6
Acid-Base Catalysis     9
Acids and Bases     9
Acid- and Base-Catalyzed Reactions     11
Nucleophilic Catalysis     16
Electrophilic Catalysis     21
Catalysis of Enolization     21
Imine Formation by Lysine     23
Catalysis by Metal Ions     26
Hydrogen Bonding     30
Strong and Weak Hydrogen Bonds     30
Hydrogen Bonding in Catalysis     32
Binding Energy in Catalysis     34
Binding and Activation Energy     34
The Active Site as an Entropy Trap     36
Dissecting the Binding Effect in Enzymatic Action     40
Stabilization of the Transition State     41
Binding the Near Attack Conformation     46
Destabilization of Ground States     48
Rate Enhancement through Binding of Remote Groups     48
Characterization of Active Sites     53
Competitive Inhibitors: Analogs of Substrates     53
Group-Selective Chemical Modification     53
Site-Directed Mutagenesis     57
Affinity Labeling     59
Why Are Enzymes Large Molecules?     62
Sizes of Enzymatic Binding Domains     62
Catalytic Antibodies     63
Kinetics of Enzymatic Reactions     69
Steady-State Kinetics     69
One-Substrate Reactions     70
Two-Substrate Reactions     74
Three-Substrate Reactions     89
Isotope Effects     91
Classes of Isotope Effects     91
Measurement of Isotope Effects     95
Transient-Phase Kinetics     101
Reaction Characteristics     101
Transient Methods     102
pH-Rate Profiles     111
Profile Interpretation     111
Measurements of pH-Rate Profiles     111
Allosteric Regulation     117
Theory     118
Binding Equations for Cooperative Systems     120
Aspartate Transcarbamoylase     123
Coenzymes I: Organic Coenzymes     129
Nicotinamide Coenzymes      129
Structures and Functions of Nicotinamide Coenzymes     129
Stereospecificity of Hydride Transfer     132
NAD[superscript +] as a Coenzyme     134
Thiamine Pyrophosphate     141
Structure     141
Reaction Mechanism     141
[alpha]-Lipoamide     147
Pyridoxal-5[prime]-Phosphate     148
Enzymatic Reactions Facilitated by Pyridoxal-5[prime]-Phosphate     149
Pyridoxal-5[prime]-Phosphate-Stabilized Amino Acid Carbanions     149
Mechanisms of Pyridoxal-5[prime]-Phosphate-Dependent Reactions     151
Flavin Coenzymes     158
Structures of Flavin Coenzymes     158
Mechanisms of Flavin Catalysis     159
Biotin     163
Structure and Role as a Carboxyl Carrier     163
Chemistry of Biotin and N[superscript 1]-Carboxybiotin     164
Mechanism of Biotin-Dependent Carboxylation     164
Phosphopantetheine Coenzymes     165
Structures of Phosphopantetheine Coenzymes     165
Mechanism of Phosphopantetheine Action     165
Folate Compounds     167
Folate Compounds of One-Carbon Metabolism     168
Enzymes in Tetrahydrofolate Metabolism      170
Biological Importance of Folate     171
Amino Acid-Based Coenzymes     172
Pyruvoyl Decarboxylases     172
Methylidene Imidazolinone-Dependent Deaminases     173
Quinoproteins     174
Coenzymes II: Metallic Coenzymes     189
Vitamin B[subscript 12] Coenzymes     190
Chemistry of B[subscript 12] Coenzymes     190
Adenosylcobalamin-Dependent Enzymes     193
Methylcobalamin-Dependent Enzymes     199
Heme Coenzymes     201
Chemistry of Oxygen and Heme     201
Heme Enzymes     204
Oxygen Binding and Electron Transfer     209
Mononuclear Nonheme Iron     210
Monooxygenases     210
Dioxygenases     217
Oxo-Fe[subscript 2] Complexes     217
Structures     218
Reactions of Di-iron Enzymes     219
Metallopterin Enzymes     222
Molybdopterin and Tungstopterin     222
Iron-Sulfur Centers     227
Structures     227
Catalytic Functions     230
S-Adenosylmethionine and Iron-Sulfur Centers     234
Catalytic Action of S-Adenosylmethionine and [4Fe-4S] Centers      234
Stoichiometric Reactions of S-Adenosylmethionine and [4Fe-4S] Centers     236
Divalent Metal Ions     237
Electrostatic Activation of Coordinated Water     237
Electrostatic Activation of Enolization     238
Copper as a Cofactor     240
Copper Proteins     240
Other Copper Enzymes     241
Nickel Coenzymes     243
Nickel in Methanogenesis     243
Other Nickel Coenzymes     245
Long-Range Electron Transfer     247
Biological Electron Transfer     247
Marcus Theory     248
Enzyme Inhibition     253
Two-Substrate Analogs     254
Inhibition and Binding     254
PALA and Aspartate Transcarbamylase     254
Suicide Inactivation     255
Thymidylate Synthase     255
[beta]-Hydroxydecanoyl Thioester Dehydratase     260
[gamma]-Aminobutyrate Aminotransferase     262
Kinetics of Slow-Binding and Tight-Binding Inhibition     268
Slow Binding     268
Tight Binding     269
Slow-Binding Inhibition     270
Dihydrofolate Reductase     271
Prostaglandin H Synthase      274
Tight-Binding Inhibition     280
HMG-CoA Reductase     280
Alanine Racemase     285
5-Enolpyruvoylshikimate-3-Phosphate Synthase     289
Acetylcholinesterase     291
Acyl Group Transfer: Proteases and Esterases     297
Chemistry of Acyl Transfer     297
Serine Proteases     300
Chymotrypsin     301
Subtilisin     311
Cysteine Proteases     314
Papain     315
Caspases     317
Aspartic Proteases     317
Molecular Properties     318
Mechanism of Action     320
Metalloproteases     323
Carboxypeptidase A     324
Thermolysin     327
Esterases     328
Structure and Function     328
Phospholipase A[subscript 2]     329
Isomerization     333
Aldose and Ketose Isomerases     333
Chemistry     333
Phosphoglucose Isomerase     334
Triosephosphate Isomerase     335
Xylose Isomerase     341
Phosphomutases     341
[alpha]-Phosphoglucomutase      341
[beta]-Phosphoglucomutase     343
Phosphoglycerate Mutases     343
Racemases and Epimerases     346
Proline Racemase     346
Glutamate Racemase     350
Mandelate Racemase     352
UDP-Galactose 4-Epimerase     355
Ribulose-5-P 4-Epimerase     360
UDP-N-Acetylglucosamine-2-Epimerase     361
Chorismate Mutase     364
[delta superscript 5]-3-Ketosteroid Isomerase     366
Radical Isomerizations     368
Glutamate Mutase     369
Methylmalonyl CoA Mutase     371
Lysine 2,3-Aminomutase     376
Newer Isomerases     379
UDP-Galactopyranose Mutase     379
Pseudouridine Synthase     379
Decarboxylation and Carboxylation     387
Chemistry of Decarboxylation and Carboxylation     387
Decarboxylases     388
Pyruvate Decarboxylase     389
Amino Acid Decarboxylases     394
Acetoacetate Decarboxylase     403
Mevalonate Pyrophosphate Decarboxylase     405
Radical-Based Decarboxylases     407
Orotidine Monophosphate Decarboxylase     414
Carboxylases      418
Ribulose-1,5-Bisphosphate Carboxylase     419
Phosphoenolpyruvate Carboxylase     425
Vitamin K-Dependent Carboxylase     426
Addition and Elimination     433
[alpha],[beta]-Elimination/Addition Reactions     433
Cofactor-Independent [alpha],[beta]-Elimination/Addition Reactions     434
Cofactor-Dependent [alpha],[beta]-Elimination/Addition Reactions     440
[beta],[alpha]-Elimination/Addition Reactions     456
Methylidene Imidazolone-Dependent Elimination and Addition     456
Carbonic Anhydrase     462
Isomerization and Elimination     465
Catalytic Process     465
Coenzyme B[subscript 12]-Dependent Elimination     466
Phosphotransfer and Nucleotidyltransfer     476
Chemistry of Phosphoryl Group Transfer     476
Phosphomonoesters     476
Phosphodiesters     483
Phosphotriesters     483
Five-Member Ring Phosphoesters     484
Enzymatic Phosphoryl Group Transfer     487
Single and Double Displacements     487
Phosphotransferases     489
Protein Phosphorylation: Protein Kinase A     502
Phosphomonoesterases      509
Enzymatic Nucleotidyl Group Transfer     521
Nucleotidyltransferases     521
Phosphodiesterases     539
ATP-Dependent Synthetases and Ligases     547
Ligation and the Energy of ATP     547
Activation by Phosphorylation     548
Glutamine Synthetase     548
Carbamoyl Phosphate Synthetase     554
Activation by Adenylylation     559
DNA Ligase     559
Aminoacyl-tRNA Synthetases     561
Ubiquitin     566
Glycosyl Group Transferases     569
Chemical Mechanisms     570
Chemistry of Glycoside Hydrolysis     570
Enzymatic Glycosyl Transfer     573
Glycosyltransferases     575
Sucrose Phosphorylase     575
Glycogen Phosphorylase     577
Purine Nucleoside Phosphorylase     584
Glycosidases     587
Families and Structures     587
Lysozyme     589
T4 Lysozyme     595
Nitrogen and Sulfur Transferases     597
Nitrogen Transfer     597
Aspartate Aminotransferase     597
Tyrosine 2,3-Aminomutase     602
Amidotransfer      604
Glutamine:PRPP Amidotransferase     607
Sulfur Transfer     609
Biotin Synthase     611
Lipoyl Synthase     612
Carbon-Carbon Condensation and Cleavage     617
Chemistry     617
Enolization of Acetyl CoA     619
Acetyl CoA in Ester Condensations     619
Citrate Synthase     620
Thiolases     627
Carbanionic Mechanisms     630
Transaldolase     631
Transketolase     634
Serine Hydroxymethyltransferase     639
Carbocationic Mechanisms     645
Farnesyl Pyrophosphate Synthase     645
Squalene Synthase     648
Alkyltransferases     655
Chemistry of Alkylation     655
Biological Alkylations     655
Alkylation Mechanisms     656
Enzymatic Alkylation     657
Protein Farnesyltransferase     657
Catechol O-Methyltransferase     661
S-Adenosylmethionine Synthetase     665
Methionine Synthases     670
Oxidoreductases     679
Pyridine Nucleotide-Dependent Dehydrogenases     680
Alcohol Dehydrogenase      680
Lactate Dehydrogenase     686
Short-Chain Alcohol Dehydrogenases     687
Glyceraldehyde-3-P Dehydrogenase     690
Glutamate Dehydrogenase     693
Disulfide Oxidoreductases     694
Dihydrolipoyl Dehydrogenase     694
Ribonucleotide Reductases     698
Classes of Ribonucleotide Reductases     700
Structural Relationships of Ribonucleotide Reductases     705
Oxidases and Oxygenases     710
Oxidases     710
D-Amino Acid Oxidase     710
Monoamine Oxidases     716
Isopenicillin-N Synthase     718
Urate Oxidase     721
Monooxygenases     722
Lactate Monooxygenase     722
Cytochrome P450 Monooxygenases     722
Iron-Methane Monooxygenase     727
[alpha]-Ketoglutarate-Dependent Oxygenases     732
Dopamine [beta]-Monooxygenase     735
Copper-Methane Monooxygenase     737
Nitric Oxide Synthase     738
Dioxygenases     741
Intradiol Dioxygenases     741
Extradiol Dioxygenases     744
Complex Enzymes     749
Multienzyme Complexes      750
[alpha]-Ketoacid Dehydrogenase Complexes     750
Pyruvate Dehydrogenase Complex     750
Fatty Acid Synthesis     757
Acetyl CoA Carboxylase     757
Fatty Acid Synthases     761
Modular Enzymes     763
Polyketide Synthases     763
Nonribosomal Polypeptide Synthetases     767
Ribosomal Protein Synthesis     768
RNA Polymerase     768
The Ribosome     770
Energy-Coupling Enzymes     777
Nitrogenase     777
Cytochrome c Oxidase     782
ATP Synthase     786
Myosin and Muscle Contraction     792
Appendices     803
Haldane Relationships for Some Kinetic Mechanisms     803
Inhibition Patterns for Three-Substrate Kinetic Mechanisms     804
Equations for Number of Occupied Sites in the Binding of a Ligand to a Multisite Macromolecule     804
Derivation of Steady-State Kinetic Equations by the King-Altman Method     805
Index     809