Cooperative effects on radical recombination in CYP3A4-catalyzed oxidation of the radical clock beta-thujone.
The timing of the beta-thujone radical clock (see scheme) can be specifically altered by an allosteric effector. Progesterone, a well-documented CYP3A4 allosteric effector, was found to increase the yield of the unrearranged, C4-derived product of beta-thujone oxidation at the expense of the combined yields of all the rearranged C4-oxidized metabolites. The results demonstrate that the apparent radical recombination rate in the CYP3A4 hydroxylation of beta-thujone is accelerated by the progesterone heterotropic cooperativity.
Jiang
Yongying
Y
Department of Pharmaceutical Chemistry, University of California-San Francisco, 600 16th Street, San Francisco, CA 94158-2517, USA.
Ortiz de Montellano
Paul R
PR
D000494:Allosteric Regulation / Q000187:drug effects; D000081008:Bicyclic Monoterpenes; D055162:Biocatalysis; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry* / Q000378:metabolism*; D005609:Free Radicals / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D039821:Monoterpenes / Q000737:chemistry* / Q000378:metabolism; D010084:Oxidation-Reduction; D011374:Progesterone / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D000081008:Bicyclic Monoterpenes; D005609:Free Radicals; D039821:Monoterpenes; D011374:Progesterone; C005790:beta-thujone; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human