Inactivation of peptidylglycine α-hydroxylating monooxygenase by cinnamic acid analogs.

Citation data:

Journal of enzyme inhibition and medicinal chemistry, ISSN: 1475-6374, Vol: 31, Issue: 4, Page: 551-62

Publication Year:
2016
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Repository URL:
http://scholarcommons.usf.edu/chm_facpub/33
PMID:
26024288
DOI:
10.3109/14756366.2015.1046064
PMCID:
PMC4801743
Author(s):
McIntyre, Neil R; Lowe, Edward W, Jr; Battistini, Matthew R; Leahy, James W; Merkler, David J
Publisher(s):
Informa UK Limited
Tags:
Pharmacology, Toxicology and Pharmaceutics; Cinnamate; cinnamate–Cu(I) complex; peptidylglycine α-hydroxylating monooxygenase; time-dependent enzyme inactivation; Chemistry
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article description
Peptidylglycine α-amidating monooxygenase (PAM) is a bifunctional enzyme that catalyzes the final reaction in the maturation of α-amidated peptide hormones. Peptidylglycine α-hydroxylating monooxygenase (PHM) is the PAM domain responsible for the copper-, ascorbate- and O2-dependent hydroxylation of a glycine-extended peptide. Peptidylamidoglycolate lyase is the PAM domain responsible for the Zn(II)-dependent dealkylation of the α-hydroxyglycine-containing precursor to the final α-amidated peptide. We report herein that cinnamic acid and cinnamic acid analogs are inhibitors or inactivators of PHM. The inactivation chemistry exhibited by the cinnamates exhibits all the attributes of a suicide-substrate. However, we find no evidence for the formation of an irreversible linkage between cinnamate and PHM in the inactivated enzyme. Our data support the reversible formation of a Michael adduct between an active site nucleophile and cinnamate that leads to inactive enzyme. Our data are of significance given that cinnamates are found in foods, perfumes, cosmetics and pharmaceuticals.