CYP121, CYP51 and associated redox systems in Mycobacterium tuberculosis: Towards deconvoluting enzymology of P450 systems in a human pathogen

K. J. McLean, A. J. Dunford, M. Sabri, R. Neeli, H. M. Girvan, P. R. Balding, D. Leys, H. E. Seward, K. R. Marshall, A. W. Munro

Research output: Contribution to journalConference article

13 Citations (Scopus)

Abstract

An extraordinary array of P450 (cytochrome P450) enzymes are encoded on the genome of the human pathogen Mycobacterium tuberculosis (Mtb) and in related mycobacteria and actinobacteria. These include the first characterized sterol 14α-demethylase P450 (CYP51), a known target for azole and triazole drugs in yeasts and fungi. To date, only two Mtb P450s have been characterized in detail: CYP51 and CYP121. The CYP121 P450 shows structural relationships with P450 enzymes involved in synthesis of polyketide antibiotics. Both P450s exhibit tight binding to a range of azole drugs (e.g. clotrimazole and fluconazole) and the same drugs also have potent effects on growth of mycobacteria (but not of e.g. Escherichia coli). Atomic structures are available for both Mtb CYP51 and CYP121, revealing modes of azole binding and intriguing mechanistic and structural aspects. This paper reviews our current knowledge of these and the other P450 systems in Mtb including recent data relating to the reversible conversion of the CYP51 enzyme between P450 (thiolate-co-ordinated) and P420 (thiol-co-ordinated) species on reduction of the haem iron in the absence of a P450 substrate. The accessory flavoprotein and iron-sulfur proteins required to drive P450 catalysis are also discussed, providing an overview of the current state of knowledge of Mtb P450 redox systems.

Original languageEnglish
Pages (from-to)1178-1182
Number of pages5
JournalBiochemical Society Transactions
Volume34
Issue number6
Early online date25 Oct 2006
DOIs
Publication statusPublished - 1 Dec 2006
Externally publishedYes
Event8th International Symposium on Cytochrome P450 Biodiversity and Biotechnology - Swansea Medical School, Swansea, United Kingdom
Duration: 23 Jul 200627 Jul 2006
Conference number: 8

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