Enzymatic Reaction Mechanisms

by Frey, Perry A.; Hegeman, Adrian D.

• ISBN13: 9780195122589
• ISBN10: 0195122585
• Edition: 1st
• Format: Hardcover
• Copyright: 2007-01-27
• Publisher: Oxford University Press

Summary

The past fifteen years have seen a tremendous surge in knowledge about enzymatic catalysis. This is largely due to the empowerment of this vibrant and mature field by the fruits of methodological advances. Enzymatic Reaction Mechanisms presents the current state of understanding about mechanisms of enzymatic catalysis, focusing on the chemical mechanisms facilitated by enzymes.

Author Biography

Perry A. Frey is Robert H. Ables Professor of Biochemistry at the University of Wisconsin at Madison Adrian D. Hegenen is NIH Postdoctoral Fellow at the University of Wisconsin at Madison

Table of Contents

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