Mechanism-based inhibition of lactoperoxidase by thiocarbamide goitrogens. Identification of turnover and inactivation pathways.
Direct evidence is presented in support of mechanism-based (suicide) inactivation of lactoperoxidase by thiocarbamide thyroid inhibitors. The turnover of 1-methylbenzimidazolidine-2-thione was demonstrated by identifying the inhibitor-derived products 1-methylbenzimidazole and bisulfite ion that are formed concurrent to enzyme inactivation. The turnover of a hydroperoxide cosubstrate, 5-phenyl-4-pentenyl hydroperoxide, was quantitated from formation of the corresponding alcohol during enzyme inactivation. A specific inactivation pathway is suggested by the covalent binding of 1 mol of 14C- and 35S-labeled benzimidazolidine-2-thione and 1-methylbenzimidazolidine-2-thione per mole of inactivated lactoperoxidase. These results are explained by partitioning of inhibitor-derived S-oxygenated intermediates between turnover and inactivation pathways. The properties of the inactivation process are unique among thiono-sulfur compounds and suggest that benzimidazolinesulfenic acids are the reactive intermediates.
Doerge
D R
DR
Department of Agricultural Biochemistry, University of Hawaii, Honolulu 96822.
D013956:Antithyroid Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D007700:Kinetics; D007784:Lactoperoxidase / Q000037:antagonists & inhibitors*; D009574:Nitro Compounds / Q000494:pharmacology; D010544:Peroxidases / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D013329:Structure-Activity Relationship
D013956:Antithyroid Agents; D001562:Benzimidazoles; D009574:Nitro Compounds; D007784:Lactoperoxidase; D010544:Peroxidases