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Thiorphan, tiopronin, and related analogs as substrates and inhibitors of peptidylglycine α‐amidating monooxygenase (PAM)
Author(s) -
McIntyre Neil R.,
Lowe Edward W.,
Chew Geoffrey H.,
Owen Terrence C.,
Merkler David J.
Publication year - 2006
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2005.12.058
Subject(s) - thiorphan , chemistry , tiopronin , monooxygenase , moiety , biochemistry , enzyme , glycine , stereochemistry , amino acid , enzyme inhibitor , pharmacology , biology , cytochrome p450
Peptidyglycine α‐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 α‐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,app and V MAX,app values. The low V MAX,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.