The role of phenylalanine 483 in cytochrome P450 2D6 is strongly substrate dependent

B.M.A. Lussenburg, P.H.J. Keizers, C. de Graaf, M. Hidestrand, M. Ingelman-Sundberg, N.P.E. Vermeulen, J.N.M. Commandeur

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

The polymorphic cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of 30% of the drugs currently prescribed, and is thus clinically relevant. Typical CYP2D6 substrates generally contain a basic nitrogen atom and an aromatic moiety adjacent to the site of metabolism. Recently, we demonstrated the importance of active site residue F120 in substrate binding and catalysis in CYP2D6. On the basis of protein homology models, it is claimed that another active site phenylalanine, F483, may also play an important role in the interaction with the aromatic moiety of CYP2D6 substrates. Experimental data to support this hypothesis, however, is not yet available. In fact, in the only study performed, mutation of F483 to isoleucine or tryptophan did not affect the 1′-hydroxylation of bufuralol at all [Smith G, Modi S, Pillai I, Lian LY, Sutcliffe MJ, Pritchard MP, et al., Determinants of the substrate specificity of human cytochrome P-450 CYP2D6: design and construction of a mutant with testosterone hydroxylase activity. Biochem J 1998;331:783-92]. In the present study, the role of F483 in ligand binding and metabolism by CYP2D6 was examined experimentally using site-directed mutagenesis. Replacement of F483 by alanine resulted in a 30-fold lower V
Original languageEnglish
Pages (from-to)1253-61
JournalBiochemical Pharmacology
Volume70
Issue number8
DOIs
Publication statusPublished - 2005

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