Calmodulin-dependent nitric-oxide synthase. Mechanism of inhibition by imidazole and phenylimidazoles
Calmodulin-dependent nitric-oxide synthase from bovine brain and GH3 pituitary cells is inhibited by imidazole, 1-phenylimidazole, 2-phenylimidazole, and 4-phenylimidazole, with half-maximal inhibition occurring at 200, 25, 160, and 600 microM concentrations of inhibitor, respectively. Imidazole inh...
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Published in | The Journal of biological chemistry Vol. 268; no. 13; pp. 9425 - 9429 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
American Society for Biochemistry and Molecular Biology
05.05.1993
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Subjects | |
Online Access | Get full text |
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Summary: | Calmodulin-dependent nitric-oxide synthase from bovine brain and GH3 pituitary cells is inhibited by imidazole, 1-phenylimidazole,
2-phenylimidazole, and 4-phenylimidazole, with half-maximal inhibition occurring at 200, 25, 160, and 600 microM concentrations
of inhibitor, respectively. Imidazole inhibits the maximal velocity of citrulline formation by the enzyme, but does not alter
the concentration of arginine, calmodulin, or (6R)-5,6,7,8,-tetrahydro-L-biopterin required for expression of half-maximal
activity. Imidazole, 1-phenylimidazole, 2-phenylimidazole, and 4-phenylimidazole had no effect on calmodulin-dependent reduction
of cytochrome c by the enzyme at concentrations up to 50-fold higher than those that inhibited citrulline formation. Imidazole
inhibited calmodulin-dependent NADPH consumption by the enzyme with dissolved oxygen as the sole electron acceptor, with half-maximal
inhibition occurring at a concentration of 225 microM. These observations are consistent with the proposal that imidazole
and phenylimidazoles inhibit citrulline formation and oxygen reduction by acting as a sixth coordination ligand of the heme
iron. This interaction prevents the formation of the activated reduced species of oxygen necessary for the formation of citrulline. |
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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)98368-7 |