Abstract
Carbon-carbon bond cleavage reactions are catalyzed by, among others, lanosterol 14-demethylase (CYP51), cholesterol side-chain cleavage enzyme (CYP11), sterol 17β-lyase (CYP17), and aromatase (CYP19). Because of the high substrate specificities of these enzymes and the complex nature of their substrates, these reactions have been difficult to characterize. A CYP1A2-catalyzed carbon-carbon bond cleavage reaction is required for conversion of the prodrug nabumetone to its active form, 6-methoxy-2-naphthylacetic acid (6-MNA). Despite worldwide use of nabumetone as an anti-inflammatory agent, the mechanism of its carbon-carbon bond cleavage reaction remains obscure. With the help of authentic synthetic standards, we report here that the reaction involves 3-hydroxylation, carbon-carbon cleavage to the aldehyde, and oxidation of the aldehyde to the acid, all catalyzed by CYP1A2 or, less effectively, by other P450 enzymes. The data indicate that the carbon-carbon bond cleavage is mediated by the ferric peroxo anion rather than the ferryl species in the P450 catalytic cycle. CYP1A2 also catalyzes O-demethylation and alcohol to ketone transformations of nabumetone and its analogs.
Footnotes
- Received January 9, 2014.
- Accepted February 28, 2014.
This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01 GM25515] (to P.R.O.M.) and the Australian Research Council [Grant DP110104455] (to J.D.V.). H.P. was supported by the National Research Foundation of Korea [Grant 2011-0016509].
An earlier account of this work was presented by Paul R. Ortiz de Montellano at the 18th International Conference on Cytochrome P450 Biochemistry, Biophysics and Biotechnology, Seattle, Washington, June 19, 2013.
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- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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