Reduction of the active-site iron by potent inhibitors of lipoxygenases

Lipoxygenases are non-heme iron dioxygenases that catalyze the oxygenation of polyunsaturated fatty acids. Using soybean lipoxygenase-1 as a model, we have shown that two classes of lipoxygenase inhibitors currently in development as potential antiinflammatory agents obtain a significant amount of t...

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Bibliographic Details
Published in:	The Journal of biological chemistry Vol. 266; no. 13; pp. 8225 - 8229
Main Authors:	Nelson, M.J, Batt, D.G, Thompson, J.S, Wright, S.W
Format:	Journal Article
Language:	English
Published:	Bethesda, MD American Society for Biochemistry and Molecular Biology 05-05-1991
Subjects:	Analytical, structural and metabolic biochemistry Binding Sites Biological and medical sciences Electron Spin Resonance Spectroscopy enzyme activity enzyme inhibitors Enzymes and enzyme inhibitors Fundamental and applied biological sciences. Psychology Glycine max Glycine max - enzymology Hydroxamic Acids - pharmacology iron Iron - metabolism lipoxygenase Lipoxygenase Inhibitors Naphthols - pharmacology Oxidation-Reduction Oxidoreductases Active site EPR spectrometry Enzyme inhibitor Iron Inflammation Models NMR spectrometry Soybean Lipoxygenase Mechanism of action Fatty acids
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Summary:	Lipoxygenases are non-heme iron dioxygenases that catalyze the oxygenation of polyunsaturated fatty acids. Using soybean lipoxygenase-1 as a model, we have shown that two classes of lipoxygenase inhibitors currently in development as potential antiinflammatory agents obtain a significant amount of their potency by reducing the lipoxygenase active-site iron from the active ferric state to the inactive ferrous state. It is not surprising that the members of the first of these classes, the 2-benzyl-1-naphthols, are reducing agents. The members of the second class, the N-alkyl-hydroxamic acids, were not anticipated to be sufficiently strong reducing agents to be oxidized by the lipoxygenase ferric center; that they are provides additional evidence for that iron having a high reduction potential. This brings to (at least) five the number of classes of lipoxygenase inhibitors that are capable of reducing the active-site ferric ion and suggests the generality of this approach in the rational design of lipoxygenase inhibitors.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0021-9258 1083-351X
DOI:	10.1016/s0021-9258(18)92965-0