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 1991-05, Vol.266 (13), p.8225-8229
Main Authors: Nelson, M.J, Batt, D.G, Thompson, J.S, Wright, S.W
Format: Article
Language:English
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
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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.
ISSN:0021-9258
1083-351X
DOI:10.1016/s0021-9258(18)92965-0