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Vol. 290, Issue 1, 445-451, July 1999
Department of Pharmacology and Toxicology, University of Texas
Medical Branch, Galveston, Texas (S.M.S., Y.Q.H., J.R.H.); Department
of Basic Pharmaceutical Sciences, West Virginia University, Morgantown,
West Virginia (G.D.S.); Department of Chemistry, Xavier University, New
Orleans, Louisiana (M.F.); Department of Chemistry, Tulane University,
New Orleans, Louisiana (W.L.A.); Department of Chemistry and
Biochemistry, University of Detroit Mercy, Detroit, Michigan (E.S.R.);
and Department of Pharmacology, University of Michigan, Ann Arbor,
Michigan (P.F.H.)
Rabbit cytochromes P-450 (P-450) 2B4 and 2B5 differ by only 12 amino
acid residues yet they exhibit unique steroid hydroxylation profiles.
Previous studies have led to the identification of active site residues
that are determinants of these specificities. In this study,
mechanism-based inactivators were identified that discriminate between
the closely related 2B4 and 2B5 enzymes. A previously characterized
inhibitor, 2-ethynylnaphthalene (2EN), was found to be selective for
2B4 inactivation. As inhibitor metabolism and the partition ratio
affect susceptibility, molecular dynamics simulations were performed to
assess the stability of the productive binding orientation of 2EN
within 2B4 and 2B5 three-dimensional models. Although 2EN was
stable within the 2B4 model, it exhibited substantial movement away
from the heme moiety in the 2B5 model. However, heterologously
expressed 2B5 was found to catalyze the oxidation of 2EN to the stable
product 2-naphthylacetic acid. Thus, the increased mobility of 2EN may
result in reduced susceptibility of 2B5 by increasing the probability
that the reactive ketene intermediate hydrolyzes with water instead of
reacting with active site residues. Another compound, 1-adamantyl
propargyl ether (1APE), selectively inactivated 2B5. The structural
basis for 2EN and 1APE susceptibility was assessed using active site
mutants. Interconversion of 2EN susceptibility was observed for 2B4 or
2B5 mutants containing a single alteration at residue 363. Single
substitutions in 2B4 also conferred susceptibility to 1APE; however,
multiple alterations were required to reduce the susceptibility of 2B5.
These alterations may influence inhibitor susceptibility by affecting
the stability of the productive binding orientation.
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