Quantum tunneling in testosterone 6beta-hydroxylation by cytochrome P450: reaction dynamics calculations employing multiconfiguration molecular-mechanical potential energy surfaces.
Testosterone hydroxylation is a prototypical reaction of human cytochrome P450 3A4, which metabolizes about 50% of oral drugs on the market. Reaction dynamics calculations were carried out for the testosterone 6beta-hydrogen abstraction and the 6beta-d(1)-testosterone 6beta-duterium abstraction employing a model that consists of the substrate and the active oxidant compound I. The calculations were performed at the level of canonical variational transition state theory with multidimensional tunneling and were based on a semiglobal full-dimensional potential energy surface generated by the multiconfiguration molecular mechanics technique. The tunneling coefficients were found to be around 3, indicating substantial contributions by quantum tunneling. However, the tunneling made only modest contributions to the kinetic isotope effects. The kinetic isotope effects were computed to be about 2 in the doublet spin state and about 5 in the quartet spin state.
Zhang
Yan
Y
Chemistry Department, University of Colorado Denver, Denver, Colorado 80217-3364, USA.
Lin
Hai
H
D051544:Cytochrome P-450 CYP3A / Q000737:chemistry* / Q000378:metabolism*; D003903:Deuterium / Q000378:metabolism; D004583:Electrons; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D008956:Models, Chemical; D011789:Quantum Theory; D013696:Temperature; D013739:Testosterone / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics
D013739:Testosterone; D003903:Deuterium; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human