Format

Send to

Choose Destination
Arch Biochem Biophys. 2006 May 15;449(1-2):115-29. Epub 2006 Mar 2.

Heteroactivator effects on the coupling and spin state equilibrium of CYP2C9.

Author information

1
University of Minnesota, Department of Experimental and Clinical Pharmacology, USA.

Abstract

The cytochromes P450 are capable of oxidizing a variety of xenobiotics. Binding of a small molecule heteroactivator to a P450 can alter the coupling of substrate oxidation during P450 catalysis, but the degree to which coupling or shunting via one of the three catalytic cycle branch points is linked to the heteroactivator-modified position of bound substrate is unknown. Using reconstituted CYP2C9, stoichiometric measurements were gathered with three substrates and two classes of heteroactivators to further understand the mechanisms involved in heteroactivation. Heteroactivation of P450 metabolism appeared to involve, but not require, changes in coupling and that increased uncoupling to a specific byproduct like H(2)O(2) does not necessarily correlate to the degree of coupling. In addition, spectroscopy demonstrated that every heteroactivator tested influenced the spin equilibrium of the heme iron even in the presence of saturating substrate suggesting that both substrate proximity and the ability to desolvate the heme can be involved in heteroactivation.

PMID:
16545770
DOI:
10.1016/j.abb.2006.02.004
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center