Analysis of Mammalian Cytochrome P450 Structure and Function by Site-Directed Mutagenesis

Authors: Domanski T.L.; Halpert J.R.

Source: Current Drug Metabolism, Volume 2, Number 2, June 2001 , pp. 117-137(21)

Publisher: Bentham Science Publishers

Abstract:

Over the past decade, site-directed mutagenesis has become an essential tool in the study of mammalian cytochrome P450 structure-function relationships. Residues affecting substrate specificity, cooperativity, membrane localization, and interactions with redox partners have been identified using a combination of amino-acid sequence alignments, homology modeling, chimeragenesis, and site-directed mutagenesis. As homology modeling and substrate docking technology continue to improve, the ability to predict more precise functions for specific residues will also advance, making it possible to utilize site-directed mutagenesis to test these predictions. Future studies will employ site-directed mutagenesis to learn more about cytochrome P450 substrate access channels, to define the role of residues that do not lie within substrate recognition sites, to engineer additional soluble forms of microsomal cytochromes P450 for x-ray crystallography, and to engineer more efficient enzymes for drug activation and / or bioremediation.

Keywords: Mammalian Cytochrome P450 Structure; Mutagenesis; Chimeragenesis; Aflatoxin B1; naphthoflavone; Dehydroepiandrosterone

Language: English

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1389200013338612

Publication date: 2001-06-01

• Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:
  
  In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.

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• In this Subject: Anatomy & Physiology ,  Pharmacology
• By this author: Domanski T.L. ;  Halpert J.R.

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