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Publication Detail

Title: Steroid bioconjugation to a CYP3A4 allosteric site and its effect on substrate binding and coupling efficiency.

Authors: Polic, Vanja; Sevrioukova, Irina F; Auclair, Karine

Published In Arch Biochem Biophys, (2018 09 01)

Abstract: Human cytochrome P450 3A4 (CYP3A4) is an important drug metabolizing enzyme involved in a number of drug-drug and food-drug interactions. As such, much effort has been devoted into investigating its mechanism of interaction with ligands. CYP3A4 has one of the highest levels of substrate promiscuity for an enzyme, and can even bind multiple ligands simultaneously. The location and orientation of these ligands depend on the chemical structure and stoichiometry, and are generally poorly understood. In the case of the steroid testosterone, up to three copies of the molecule can associate with the enzyme at once, likely two in the active site and one at a postulated allosteric site. Recently, we demonstrated that steroid bioconjugation at the allosteric site results in an increase in activity of CYP3A4 toward testosterone and 7-benzyloxy-4-trifluoromethylcoumarin oxidation. Here, using the established bioconjugation methodology, we show how steroid bioconjugation at the allosteric site affects the heme spin state, the binding affinity (KS) of CYP3A4 for testosterone, as well as the enzyme coupling efficiency.

PubMed ID: 29958895 Exiting the NIEHS site

MeSH Terms: Allosteric Site; Chromatography, High Pressure Liquid; Coumarins/metabolism; Cytochrome P-450 CYP3A/metabolism*; Humans; Kinetics; Ligands; Oxidation-Reduction; Progesterone/metabolism*; Spectrophotometry, Ultraviolet; Substrate Specificity; Testosterone/metabolism*

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