Evidence for
Stabilisation of Low Spin State of Cytochrome P450 due to
Shortening of the Proximal Haem Bond
Abstract
The cytochrome P450 superfamily of enzymes is ubiquitous, being
responsible for the metabolism of a wide range of endogenous and
xenobiotic compounds. However, the detailed mechanism of the catalytic
cycle of these enzymes is still not fully understood. We describe
results, obtained from first principles molecular simulations, which
indicate that the low spin state of the Fe3+ ion, present in the haem
moiety at the active site of a cytochrome P450 enzyme, may be stabilised
by shortening of the proximal bond of the haem. Calculations
indicate that a bond length of less than approx. 2.05 Angstroms between the
haem Fe3+ ion and the cysteine S, which forms the proximal ligand,
would result in the stabilisation of the low-spin state of the Fe3+,
inhibiting the progress of the P450 catalytic cycle. Our investigation
uses novel first principles modeling techniques which treat the entire
system quantum-mechanically.
A full version of this paper can be downloaded in gzipped postscript. If you wish to receive
a paper copy, please email me.
Matthew Segall (mds21@phy.cam.ac.uk)
Last modified: Thu Jun 25 11:57:22 1998