Functional importance of a peripheral pocket in mammalian cytochrome P450 2B enzymes

Archives of Biochemistry and Biophysics
Hyun-Hee JangP Ross Wilderman

Abstract

The functional importance of a peripheral pocket found in previously published X-ray crystal structures of CYP2B4 and CYP2B6 was probed using a biophysical approach. Introduction of tryptophan within the pocket of CYP2B4 at F202 or I241 leads to marked impairment of 7-ethoxy-4-(trifluoromethyl)coumarin (7-EFC) or 7-benzyloxyresorufin O-dealkylation efficiency; a similar substitution at F195, near the surface access to the pocket, does not affect these activities. The analogous CYP2B6 F202W mutant is inactive in the 7-EFC O-dealkylation assay. The stoichiometry of 7-EFC deethylation suggested that the decreased activity of F202W and I241W in CYP2B4 and lack of activity of F202W in CYP2B6 coincided with a sharp increase in the flux of reducing equivalents through the oxidase shunt to produce excess water. The results indicate that the chemical identity of residues within this peripheral pocket, but not at the mouth of the pocket, is important in substrate turnover and redox coupling, likely through effects on active site topology.

References

Jul 27, 2001·Current Drug Metabolism·T L Domanski, J R Halpert
Oct 24, 2003·Naunyn-Schmiedeberg's Archives of Pharmacology·Magnus Ingelman-Sundberg
Aug 29, 2006·Biochimica Et Biophysica Acta·Yonghong Zhao, James R Halpert
Dec 17, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Jyothi C TalakadJames R Halpert
May 8, 2010·Antioxidants & Redox Signaling·Thomas C PochapskyMarina Dang
Jan 3, 2012·Current Drug Metabolism·P Ross Wilderman, James R Halpert

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