CYP121, CYP51 and associated redox systems in Mycobacterium tuberculosis: towards deconvoluting enzymology of P450 systems in a human pathogen.
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 14alpha-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.
McLean
K J
KJ
Manchester Interdisciplinary Biocentre, School of Chemical Engineering and Analytical Science, University of Manchester, 131 Princess Street, Manchester M1 7ND, UK. Kirsty.McLean@Manchester.ac.uk
Dunford
A J
AJ
Sabri
M
M
Neeli
R
R
Girvan
H M
HM
Balding
P R
PR
Leys
D
D
Seward
H E
HE
Marshall
K R
KR
Munro
A W
AW
D001393:Azoles; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000472:pathogenicity; D010084:Oxidation-Reduction; D011485:Protein Binding; D011487:Protein Conformation
D001393:Azoles; D001426:Bacterial Proteins; C464825:cytochrome P-450 CYP121; D003577:Cytochrome P-450 Enzyme System; C501935:cytochrome P-450 CYP51, Mycobacterium tuberculosis