Exploiting Streptomyces coelicolor A3(2) P450s as a model for application in drug discovery

Abstract

One of the surprising discoveries about the genomics of the cytochrome P450 (CYP) superfamily is the large number of CYPs in the bacterial class of actinomycetes. It had previously been imagined that bacteria have small numbers of CYPs or none at all. Particularly intriguing is that the bacterial genus Streptomyces, which produce a large number of secondary metabolites with important medical application, has a large CYP complement reflecting the ecological niche that the organism finds itself in. In 2001 the first complete Streptomyces species genome (Streptomyces coelicolor A3[2]) was published, revealing the presence of 18 CYP genes. Subsequently, genomes for Streptomyces avermitilis, with 33 CYPs, and Streptomyces peucetius, with 15 CYPs, have been reported. Although a certain number of these CYPs have known functions in secondary metabolism, as identified biochemically or through gene locus organisation, in the vast majority of Streptomyces species, CYP functions are unknown. The first detailed analysis of the CYP complement from a Streptomyces species genome has begun in the laboratories of Waterman etal. The long-term goal of this effort is to identify orphan CYP function, to establish their high resolution structure and to establish a strategy for producing novel secondary metabolites that have new biomedical function. This chapter provides an overview of CYP systems in Streptomyces species and provides a plan of how new drugs might be generated from streptomycetes by modifying the structure of specific CYPs.

Keywords::

• antibiotics
• cytochrome P450
• metabolism
• streptomyces
• xenobiotics

Acknowledgements

This work is supported by National Institutes of Health Grants GM37942 (to M.R.W.), GM69970 (to M.R.W., F.P.G., S.L.K. and D.C.L.), ES00267 (to F.P.G. and M.R.W.) and the Biological and Biotechnology Sciences Research Council (D.C.L. and S.L.K), the Wellcome Trust (D.C.L.) and Society for General Microbiology (D.C.L.).