Cytochromes P450 are a superfamily of isoenzymes present in a wide variety of life-forms including animals, plants, fungi and microorganisms.
First discovered in 1955 in rat liver microsomes, P450 is
characterised by an intense absorption band at 450nm in the presence
of carbon monoxide an example of which can be seen in Figure
5.1. Members of this family have since been identified in
mitochondria and microsomes from numerous different tissues as well as
in microorganisms such as yeast and bacteria. In particular some
bacterial P450s were found to be water soluble, leading to the
successful purification and crystallisation of a camphor-hydroxylating
P450 of Pseaudomonas Pudita (
, CYP101) in 1970
[24] [25] and the determination of its 3-dimensional
structure (See Figure 5.2) in 1985 [26]. Recently
the structure of two other P450s, 
[27]
and 
[28] have been determined,
allowing comparative analysis of the structures of P450 isoenzymes
[29]. At present however, no human P450s have been
crystallised due to the insolubility of membrane bound P450s.
Figure 5.2: The overall structure of 
.
The widespread interest in P450 is justified by the enormous range of physiological processes which involve enzymes from this family. These include, but are not limited to, steroid metabolism, drug deactivation, procarcinogen activation and xenobiotic detoxification.
This chapter outlines a course of investigation of P450 using ab initio quantum mechanical calculations. The aim of this effort is the development of techniques for prediction of the outcome of an interaction between a substrate molecule and a member of the P450 family. This work will be undertaken in collaboration with Professor G. T. Tucker and Dr. S. W. Ellis of the Department of Medicine and Pharmacology of the Royal Hallamshire Hospital.
The remaining sections of this chapter may be summarised as follows
