Single mutations change CYP2F3 from a dehydrogenase of 3-methylindole to an oxygenase.

Biochemistry
Jaya S KarthaGarold S Yost

Abstract

Pulmonary cytochrome P450 2F3 (CYP2F3) catalyzes the dehydrogenation of the pneumotoxin 3-methylindole (3MI) to an electrophilic intermediate, 3-methyleneindolenine, which is responsible for the toxicity of the parent compound. Members of the CYP2F subfamily are the only enzymes known to exclusively dehydrogenate 3MI, without detectable formation of oxygenation products. Thus, CYP2F3 is an attractive model to study dehydrogenation mechanisms. The purpose of this study was to identify specific residues that could facilitate 3MI dehydrogenation. Both single and double mutations were constructed to study the molecular mechanisms that direct dehydrogenation. Double mutations in substrate recognition sites (SRS) 1 produced an inactive enzyme, while double mutants in SRS 4 did not alter 3MI metabolism. However, double mutations in SRS 5 and SRS 6 successfully introduced oxygenase activity to CYP2F3. Single mutations in SRS 5, SRS 6 and near SRS 2 also introduced 3MI oxygenase activity. Mutants S474H and D361T oxygenated 3MI but also increased dehydrogenation rates, while G214L, E215Q and S475I catalyzed 3MI oxygenation exclusively. A homology model of CYP2F3 was precisely consistent with specific dehydrogenation of 3MI via initial hy...Continue Reading

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Citations

Aug 21, 2012·Chemical Research in Toxicology·James B Y H BehrendorffElizabeth M J Gillam
Aug 25, 2009·Toxicological Sciences : an Official Journal of the Society of Toxicology·Jessica M WeemsGarold S Yost
Jul 28, 2012·Chemistry : a European Journal·Rubén Mas-BallestéLawrence Que
Mar 16, 2011·Chembiochem : a European Journal of Chemical Biology·Tianlei YingZhong-Xian Huang
Nov 3, 2009·Chemical Biology & Drug Design·Hao Sun, Dennis O Scott

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