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Phenylalanine and Tryptophan Scanning Mutagenesis of CYP3A4 Substrate Recognition Site Residues and Effect on Substrate Oxidation and Cooperativity

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    Phenylalanine and Tryptophan Scanning Mutagenesis of CYP3A4 Substrate Recognition Site Residues and Effect on Substrate Oxidation and Cooperativity†
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    Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555-1031
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    Biochemistry

    Cite this: Biochemistry 2001, 40, 34, 10150–10160
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    https://doi.org/10.1021/bi010758a
    Published August 4, 2001
    Copyright © 2001 American Chemical Society
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    Abstract

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    Phenylalanine and/or tryptophan scanning mutagenesis was performed at 15 sites within CYP3A4 proposed to be involved in substrate specificity or cooperativity. The sites were chosen on the basis of previous studies or from a comparison with the structure of P450eryF containing two molecules of androstenedione. The function of the 25 mutants was assessed in a reconstituted system using progesterone, testosterone, 7-benzyloxy-4-(trifluoromethyl)coumarin (7-BFC), and α-naphthoflavone (ANF) as substrates. CYP3A4 wild type displayed sigmoidal kinetics of ANF 5,6-oxide formation and 7-BFC debenzylation. Analysis of 12 mutants with significant steroid hydroxylase activity showed a lack of positive correlation between ANF oxidation and stimulation of progesterone 6β-hydroxylation by ANF, indicating that ANF binds at two sites within CYP3A4. 7-BFC debenzylation was stimulated by progesterone and ANF, and 7-BFC did not inhibit testosterone or progesterone 6β-hydroxylation. Correlational analysis showed no relationship between 7-BFC debenzylation and either progesterone or testosterone 6β-hydroxylation. These data are difficult to explain with a two-site model of CYP3A4 but suggest that three subpockets exist within the active site. Interestingly, classification of the mutants according to their ability to oxidize the four substrates utilized in this study suggested that substrates do bind at preferred locations in the CYP3A4 binding pocket.

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    †

     Supported by Grant GM54995 (J.R.H.) and Center Grant ES06676 from the National Institutes of Health.

    *

     To whom correspondence should be addressed. Telephone:  (409) 772-9677. Fax:  (409) 772-9642. E-mail:  [email protected].

    ‡

     These authors contributed equally to the work presented in this paper.

    Cited By

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    This article is cited by 117 publications.

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    Cite this: Biochemistry 2001, 40, 34, 10150–10160
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    https://doi.org/10.1021/bi010758a
    Published August 4, 2001
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