Thiorphan, tiopronin, and related analogs as substrates and inhibitors of peptidylglycine alpha-amidating monooxygenase (PAM)

摘要

Peptidyglycine alpha-amidating monooxygenase is a copper- and zinc-dependent, bifunctional enzyme that catalyzes the cleavage of glycine-extended peptides or N-acylglycines to the corresponding amides and glyoxylate. This reaction is a key step in the biosynthesis of bioactive a-amidated peptides and, perhaps, the primary fatty acids amides also. Two clinically useful N-acylglycines are thiorphan and tiopronin, each with a thiol moiety attached to the acyl group. We report here that thiorphan and tiopronin are substrates for PAM, exhibiting relatively low K-M,K-app and V-MAX,V-app values. The low V-MAX,V-app values result, most likely, from a decrease in active PAM(.)2Cu(II) as the enzyme competes ineffectively with thiorphan and tiopronin for free copper. (c) 2005 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.