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Vol. 26, Issue 12, 1179-1184, December 1998
Department of Pharmacology and Toxicology, University of
Texas Medical Branch at Galveston (J.R.H.), and
Department of Basic
Pharmaceutical Sciences, West Virginia University (G.D.S.)
Three-dimensional homology models of cytochromes P450
(P450) 2B1 and P450 3A4 have been utilized along with
site-directed mutagenesis to elucidate the molecular determinants of
substrate specificity. Most of the key residues identified in 2B
enzymes fall within five substrate recognition sites (SRSs) and have
counterparts in bacterial P450 residues that regulate substrate binding
or access. Docking of inhibitors into 2B models has provided a
plausible explanation for changes in susceptibility to mechanism-based
inactivation that accompany particular amino acid side-chain
replacements. These studies provide a basis for predicting drug
interactions due to P450 inhibition and for rational inhibitor design.
In addition, the location of P450 3A4 residues capable of influencing
homotropic stimulation by substrates and heterotropic stimulation by
flavonoids has been identified. Steroid hydroxylation by the wild-type
enzyme exhibits sigmoidal kinetics, indicative of positive
cooperativity. Based on the 3A4 model and single-site mutants, a double
mutant in SRS-2 has been constructed that exhibits normal
Michaelis-Menten kinetics. Results of modeling and mutagenesis studies
suggest that the substrate and effector bind at adjacent sites within a
single large cavity in P450 3A4. A thorough understanding of the
location and structural requirements of the substrate-binding and
effector sites in cytochrome P450 3A4 should prove valuable in
rationalizing and predicting interactions among the multitude of drugs
and other compounds that bind to the enzyme.
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