Mechanism of selenium-glutathione peroxidase and its inhibition by mercaptocarboxylic acids and other mercaptans.

Abstract

In a systematic search for effectors of glutathione peroxidase, a number of mercaptocarboxylic acids and tertiary mercaptans were found to be strong and specific inhibitors of the enzyme glutathione peroxidase. Assessment of various models was made by linear and nonlinear least squares fitting techniques. The results support the formation of reversible enzyme-inhibitor complexes. The active site selenium is trapped by the rapid binding of the inhibitor in competition with GSH. Data are consistent with the formation of thioselenenate adducts of the active site. The kinetic model which best describes the observed inhibition by the very strong inhibitor mercaptosuccinate implies that a selenenic acid with a kinetically significant lifetime is not formed when hydroperoxide is reduced. A noncovalent binding site for GSH or the presence of a cysteine residue at the active site of the enzyme provides a mechanistic rationale for the observed kinetics. Three of the most potent inhibitors found in this study, mercaptosuccinate, penicillamine, and alpha-mercaptopropionylglycine, are currently used as slow-acting drugs in the treatment of rheumatoid arthritis. Overall, the evidence suggests that glutathione peroxidase may be involved in the etiology of this disease.