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Introduction

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

  1. Mechanism of Interaction. The accepted mechanism for the interaction of a P450 enzyme with a substrate is outlined.

  2. Proposed Course of Investigation. The path it is anticipated the investigation will follow is detailed.

  3. Conclusion. A summary of this chapter is given and conclusions are drawn.



next up previous contents
Next: Mechanism of Interaction Up: Proposed Investigation of Previous: Proposed Investigation of



Mr. Matthew D. Segall
Fri Jul 21 15:33:30 BST 1995