Inhibition of peptidylglycine alpha-amidating monooxygenase by exploitation of factors affecting the stability and ease of formation of glycyl radicals.
Peptidylglycine alpha-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 alpha-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.
Barratt
Brendon J W
BJ
Research School of Chemistry, Australian National University, Canberra, ACT 0200, Australia.
Easton
Christopher J
CJ
Henry
David J
DJ
Li
Iris H W
IH
Radom
Leo
L
Simpson
Jamie S
JS
D001974:Bromosuccinimide / Q000737:chemistry / Q000378:metabolism; D005609:Free Radicals / Q000737:chemistry / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D006842:Hydrocarbons, Brominated / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013816:Thermodynamics
D005609:Free Radicals; D006842:Hydrocarbons, Brominated; D009097:Multienzyme Complexes; D006899:Mixed Function Oxygenases; C035189:peptidylglycine monooxygenase; D001974:Bromosuccinimide; D005998:Glycine