Involvement of phenyl radicals in iodonium inhibition of flavoenzymes.
Iodonium inhibition of the flavoenzymes neutrophil NADPH oxidase and cytochrome P450 reductase has been suggested to require reductive metabolism of the inhibitor to a phenyl radical. Inhibition would ultimately result from covalent attachment of phenyl radicals to either the flavin cofactor or adjacent amino acid side chains important in catalysis. In this paper we provide evidence, using EPR techniques, that phenyl radicals are formed during reaction of iodonium diphenyl with reduced free flavin (FMN) and protein-bound (cytochrome P450 reductase or xanthine oxidase) flavin. Kinetic analysis indicated iodonium diphenyl to be an uncompetitive inhibitor of xanthine oxidase, suggesting the need for reduced enzyme for inhibition. A study of the catalytic and structural properties of different flavoenzymes suggested that only enzymes containing flavins that function in one-electron transfer are targets for iodonium inhibition.
O'Donnell
V B
VB
Division of Biochemical Sciences, Rowett Research Institute, Aberdeen, UK.
Smith
G C
GC
Jones
O T
OT
D000818:Animals; D001713:Biphenyl Compounds / Q000378:metabolism / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D007700:Kinetics; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D019255:NADPH Oxidases; D009251:NADPH-Ferrihemoprotein Reductase / Q000037:antagonists & inhibitors*; D009861:Onium Compounds / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits
D001713:Biphenyl Compounds; D005609:Free Radicals; D009861:Onium Compounds; C031291:diphenyliodonium; D009247:NADH, NADPH Oxidoreductases; D009251:NADPH-Ferrihemoprotein Reductase; D019255:NADPH Oxidases