From ‘reactive C 2 units’ to acetyl coenzyme A: a long trail with an acetyl phosphate detour

Abstract

Discovery of CoA and acetyl CoA diminished interest in acetyl phosphate, but it has a role in many bacterial fermentations. It is formed from acetate and ATP by the action of acetate kinase (EC 2.7.2.1) and by three other enzymatic reactions. Acetate kinase, when named systematically, is ATP:acetate phosphotransferase – hence, in the direction of ATP synthesis this enzyme uses acetyl phosphate in Lipmann’s second splitting mode16xDevelopment of the acetylation problem, a personal account. Lipmann, F. Science. 1954; 120: 855–865Crossref | PubMedSee all References, 17xSee all References as a phosphate donor. This transfer is a major route for ATP formation in some bacteria.Acetate kinase, together with adenosine kinase and adenylate kinase, has been used in an ingenious, large-scale synthesis of ATP from ADP with acetyl phosphate as phosphate donor28xLarge-scale enzyme-catalysed synthesis of ATP from adenosine and acetyl phosphate. Regeneration of ATP from ADP. Baughn, R.L. et al. J. Am. Chem. Soc. 1978; 100: 304–306CrossrefSee all References28. The sum of three separate reactions is as follows: adenosine + 3 acetyl phosphate = ATP + 3 acetate. The acetyl phosphate, required in large amounts, was obtained (as diammonium salt) by the keten reaction19xA new synthesis of acetyl dihydrogen phosphate. Bentley, R. J. Am. Chem. Soc. 1948; 70: 2183–2185Crossref | PubMedSee all References19.After the discoveries of CoA and acetyl CoA, progress was rapid. Acetyl CoA was found to play a crucial role in the tricarboxylic acid cycle by reaction with oxaloacetate to form citrate. Another carrier for acyl groups, acyl carrier protein (ACP) was discovered; it contains the same pantetheine moiety as CoA. Both CoA and ACP activate a variety of acids, for example, in fatty acid anabolism. In this process, it was established that the extending C2 units derive from malonyl CoA; this further CoA derivative was formed from acetyl CoA by the biotin-dependent acetyl CoA carboxylase (EC 6.4.1.2). The trail from ‘activated acetate’ to acetyl CoA provided a truly bountiful harvest of information. Moreover, four Nobel Prizes had involved work with CoA in one way or another!