Inhibition of peptidylglycine α-amidating monooxygenase by exploitation of factors affecting the stability and ease of formation of glycyl radicals

B.J.W. Barratt; C.J. Easton; D.J. Henry; I.H.W. Li; L. Radom; J.S. Simpson

doi:10.1021/ja046204n

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Inhibition of peptidylglycine α-amidating monooxygenase by exploitation of factors affecting the stability and ease of formation of glycyl radicals

Journal article

Peer reviewed

Inhibition of peptidylglycine α-amidating monooxygenase by exploitation of factors affecting the stability and ease of formation of glycyl radicals

B.J.W. Barratt, C.J. Easton, D.J. Henry, I.H.W. Li, L. Radom and J.S. Simpson

Journal of the American Chemical Society, Vol.126(41), pp.13306-13311

2004

DOI: https://doi.org/10.1021/ja046204n

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Abstract

Peptidylglycine α-amidating monooxygenase catalyzes the biosynthesis of peptide hormones through radical cleavage of the C-terminal glycine residues of the corresponding prohormones. We have correlated ab initio calculations of radical stabilization energies and studies of free radical brominations with the extent of catalysis displayed by peptidylglycine α-amidating monooxygenase, to identify classes of inhibitors of the enzyme. In particular we find that, in closely related systems, the substitution of glycolate for glycine reduces the calculated radical stabilization energy by 34.7 kJ mol -1, decreases the rate of bromination with N-bromosuccinimide at reflux in carbon tetrachloride by a factor of at least 2000, and stops catalysis by the monooxygenase, while maintaining binding to the enzyme.

Details

Title: Inhibition of peptidylglycine α-amidating monooxygenase by exploitation of factors affecting the stability and ease of formation of glycyl radicals
Authors/Creators: B.J.W. Barratt (Author/Creator)
C.J. Easton (Author/Creator)
D.J. Henry (Author/Creator)
I.H.W. Li (Author/Creator)
L. Radom (Author/Creator)
J.S. Simpson (Author/Creator)
Publication Details: Journal of the American Chemical Society, Vol.126(41), pp.13306-13311
Publisher: American Chemical Society
Identifiers: 991005543555407891
Copyright: © 2004 American Chemical Society
Murdoch Affiliation: Murdoch University
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.195 Neuroendocrine & Intestinal Disorders; 1.195.2005 Prohormone Convertases
Web Of Science research areas: Chemistry, Multidisciplinary
ESI research areas: Chemistry