Roles of Residues F206 and V367 in Human CYP2B6: Effects of Mutations on Androgen Hydroxylation, Mechanism-Based Inactivation, and Reversible Inhibition

The crystal structures of human CYP2B6 indicate that Phe206 and Val367 are in close proximity to the substrate binding site and suggest that both residues may play important roles in substrate metabolism and inhibitor binding. To test this hypothesis, we investigated the effects of mutating these re...

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Bibliographic Details
Published in:Drug metabolism and disposition 2016-11, Vol.44 (11), p.1771-1779
Main Authors: Lin, Hsia-Lien, Zhang, Haoming, Kenaan, Cesar, Hollenberg, Paul F
Format: Article
Language:English
Subjects:
Androgens - metabolism
Androstenedione - metabolism
Binding Sites - drug effects
Binding Sites - genetics
Cytochrome P-450 CYP2B6 - genetics
Cytochrome P-450 CYP2B6 - metabolism
Enzyme Inhibitors - pharmacology
Humans
Hydroxylation
Kinetics
Mutation
Substrate Specificity - drug effects
Substrate Specificity - genetics
Testosterone - metabolism
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Summary:The crystal structures of human CYP2B6 indicate that Phe206 and Val367 are in close proximity to the substrate binding site and suggest that both residues may play important roles in substrate metabolism and inhibitor binding. To test this hypothesis, we investigated the effects of mutating these residues to Ala on the regiospecificity of CYP2B6 for the metabolism of testosterone and androstenedione. For testosterone metabolism, 16β-OH-testosterone formation by the F206A mutant was
ISSN:0090-9556
1521-009X
DOI:10.1124/dmd.116.071662