Covalent Catalysis by Enzymes

Some years ago one of my students and I reported that the acetate kinase reaction is mediated by a phosphorylated form of the enzyme [R. S. Anthony and L. B. Spector, lBe 245, 6739 (1970)]. The reversible reaction between ATP and acetate to give acetyl phosphate and ADP had hitherto been thought to proceed by direct transfer of a phosphoryl group from A TP to acetate in a single-displacement reaction. But now it became clear that acetate kinase was one of that substantial number of enzymes whose mech anism is that of the double displacement. For some reason, I began to wonder about the possibility that all enzymes, like acetate kinase, are double displacement enzymes, and do their work by covalent catalysis. For one thing, I could not think of a single instance of an enzyme for which single displacement catalysis had been proved, and inquiries on this point among knowledgeable friends elicited the same negative response. Moreover, it was long known that the two other kinds of chemical catalysis~homo geneous and heterogeneous~occur through the intermediary formation of a covalent bond between catalyst and reactant. I began to feel confident that chemical catalysis by enzymes must happen the same way. 1 The Thesis.- Nonenzymic Chemical Catalysis: Its Resemblance to Enzymic Catalysis.- Enzymic Catalysis.- Steric Inversion and Covalent Catalysis.- Why Covalent Catalysis Is Favored Over Single- Displacement Catalysis.- Is Covalent Catalysis a Means of Stabilizing Very Reactive (Hypothetical) Intermediates?.- Enzymes as Phase Transfer Catalysts and Energy Transducers.- A Definition of Catalysis.- Enzymes as Transferases.- 2 Oxidoreductases.- Flavoenzymes.- NAD Enzymes.- Copper Enzymes.- Copper-Heme Enzymes.- Heme Enzymes.- Disulfide Enzymes.- Summary.- 3 Transferases.- Methionine Synthase [EC 2.1.1.13].- N-Methylglutamate Synthase [EC 2.1.1.21].- Serine Hydroxymethyltransferase [EC 2.1.2.1].- Transcarboxylase [EC 2.1.3.1].- Glycine Amidinotransferase [EC 2.1.4.1].- Transketolase [EC 2.2.1.1].- Transaldolase [EC 2.2.1.2].- Arylamine Acetyltransferase [EC 2.3.1.5].- Acetyl-CoA Acetyltransferase [EC 2.3.1.9].- [Acyl-Carrier-Protein] Malonyltransferase [EC 2.3.1.39].- Transglutaminase [EC 2.3.2.13].- Sucrose Phosphorylase [EC 2.4.1.7].- Adenine Phosphoribosyltransferase [EC 2.4.2.7].- Thiaminase [EC 2.5.1.2].- Aspartate Aminotransferase [EC 2.6.1.1].- Hexokinase [EC 2.7.1.1].- Pyruvate Kinase [EC 2.7.1.40].- Acetate Kinase [EC 2.7.2.1].- Phosphoglycerate Kinase [EC 2.7.2.3].- Nucleosidediphosphate Kinase [EC 2.7.4.6].- Phosphoglucomutase [EC 2.7.5.1].- Galactose-1-Phosphate Uridylyltransferase [EC 2.7.7.10].- Pyruvate, Orthophosphate Dikinase [EC 2.7.9.1].- Rhodanese [EC 2.8.1.1].- 3-Ketoacid CoA-Transferase [EC 2.8.3.5].- 4 Hydrolases.- Carboxylesterase [EC 3.1.1.1].- Alkaline Phosphatase [EC 3.1.3.1].- Acid Phosphatase [EC 3.1.3.2].- Glucose-6-Phosphatase [EC 3.1.3.9].- 5'-Nucleotide Phosphodiesterase [EC 3.1.4.1].- Arylsulfatase [EC 3.1.6.1].- ?-Galactosidase [EC 3.2.1.23].- NADase [EC 3.2.2.5].- Carboxypeptidase A [EC 3.4.17.1].- Chymotrypsin [EC 3.4.21.1].- Papain [EC 3.4.22.2].- Pepsin [EC 3.4.23.1].- Glutaminase [EC 3.5.1.2].- Inorganic Pyrophosphatase [EC 3.6.1.1].- Adenosine Triphosphatase [EC 3.6.1.3].- 5 Lyases.- Pyruvate Decarboxylase [EC 4.1.1.1].- Acetoacetate Decarboxylase [EC 4.1.1.4].- Glutamate Decarboxylase [EC 4.1.1.15].- Histidine Decarboxylase [EC 4.1.1.22].- Phosphoenolpyruvate Carboxykinase [EC 4.1.1.32].- Fructose Diphosphate Aldolase [EC 4.1.2.13].- 3-Hydroxy-3-Methylglutaryl-Coenzyme A Synthase [EC 4.1.3.5].- Citrate Lyase [EC 4.1.3.6].- ATP Citrate Lyase [EC 4.1.3.8].- Tryptophanase [EC 4.1.99.1].- Carbonic Anhydrase [EC 4.2.1.1].- Dehydroquinase [EC 4.2.1.10].- Enolase [EC 4.2.1.11].- Propanediol Dehydrase [EC 4.2.1.28].- Phenylalanine Ammonia-Lyase [EC 4.3.1.5].- 6 Isomerases.- Alanine Racemase [EC 5.1.1.1].- Proline Racemase [EC 5.1.1.4].- Phenylalanine Racemase [EC 5.1.1.11].- Mandelate Racemase [EC 5.1.2.2].- Uridine Diphosphoglucose Epimerase [EC 5.1.3.2].- Triosephosphate Isomerase [EC 5.3.1.1].- Steroid ?-Isomerase [EC 5.3.3.1].- Phosphoglycerate Mutase [EC 5.4.2.1].- DNA Topoisomerase [EC 5.4.2.-].- D-?-Lysine Mutase [EC 5.4.3.4].- 7 Ligases.- Tryptophanyl-tRNA Synthetase [EC 6.1.1.2].- Phenylalanyl-tRNA Synthetase [EC 6.1.1.20].- Carnosine Synthetase [EC 6.3.2.11].- Acetyl-CoA Synthetase [EC 6.2.1.1].- Succinyl-CoA Synthetase [EC 6.2.1.5].- Long-Chain Fatty Acyl-CoA Synthetase [EC 6.2.1.3].- Pyruvate Carboxylate [EC 6.4.1.1].- DNA Ligase (NAD) [EC 6.5.1.2].- 8 Summary.- Key to Numbering and Classification of Enzymes.