title: Irreversible inhibition of phosphotransacetylase by S-dimethylarsino-CoA.
abstract: S-Dimethylarsino-CoA was synthesized by acylation of CoA with dimethylchloroarsine. The new analogue of acetyl-CoA was tested as an active-site-directed irreversible inhibitor of phosphotransacetylase (EC 2.3.1.8), carnitine acetyltransferase (EC 2.3.1.7) and citrate synthase (EC 4.1.3.7). Irreversible inhibition was observed only with phosphotransacetylase, which was derivatized via a simple bimolecular process (k2 = 197 +/- 15 min-1 . M-1). Acetyl-CoA provided complete substrate protection against the inactivation, while phosphate (a substrate) and desulfo-CoA (a competitive inhibitor) provided a partial protection. The inactivation was not reversed by dithiothreitol. The new reagent was a linear competitive inhibitor versus acetyl-CoA with both carnitine acetyltransferase (Ki = 41 microM) and citrate synthase (Ki = 20 microM). Chemical studies showed that S-dimethylarsino-CoA reacts with the thiol of N alpha-acetylcysteine but not with the side-chain functional groups of histidine and lysine. The nature of the chemical modification of cysteine was determined by investigating a model system. Thus the chemical reaction between the thioarsenite linkage of S-dimethylarsinobenzylmercaptan and the thiol of cysteine was shown to involve transesterification of the dimethylarsino group.
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D002332:Carnitine O-Acetyltransferase / Q000037:antagonists & inhibitors; D002950:Citrate (si)-Synthase / Q000037:antagonists & inhibitors; D003013:Clostridium / Q000201:enzymology; D003065:Coenzyme A / Q000031:analogs & derivatives* / Q000494:pharmacology; D010856:Columbidae; D009682:Magnetic Resonance Spectroscopy; D008433:Mathematics; D010709:Phosphate Acetyltransferase / Q000037:antagonists & inhibitors*; D013552:Swine
chemical_list: C039969:S-dimethylarsino-coenzyme A; D000123:Acetyltransferases; D002332:Carnitine O-Acetyltransferase; D010709:Phosphate Acetyltransferase; D002950:Citrate (si)-Synthase; D003065:Coenzyme A