The central role of mosquito cytochrome P450 CYP6Zs in insecticide detoxification revealed by functional expression and structural modelling.

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Version: Final published version
Serval ID
serval:BIB_3BD092DD43F6
Type
Article: article from journal or magazin.
Collection
Publications
Title
The central role of mosquito cytochrome P450 CYP6Zs in insecticide detoxification revealed by functional expression and structural modelling.
Journal
Biochemical Journal
Author(s)
Chandor-Proust A., Bibby J., Régent-Kloeckner M., Roux J., Guittard-Crilat E., Poupardin R., Riaz M.A., Paine M., Dauphin-Villemant C., Reynaud S., David J.P.
ISSN
1470-8728 (Electronic)
ISSN-L
0264-6021
Publication state
Published
Issued date
2013
Volume
455
Number
1
Pages
75-85
Language
english
Abstract
The resistance of mosquitoes to chemical insecticides is threatening vector control programmes worldwide. Cytochrome P450 monooxygenases (CYPs) are known to play a major role in insecticide resistance, allowing resistant insects to metabolize insecticides at a higher rate. Among them, members of the mosquito CYP6Z subfamily, like Aedes aegypti CYP6Z8 and its Anopheles gambiae orthologue CYP6Z2, have been frequently associated with pyrethroid resistance. However, their role in the pyrethroid degradation pathway remains unclear. In the present study, we created a genetically modified yeast strain overexpressing Ae. aegypti cytochrome P450 reductase and CYP6Z8, thereby producing the first mosquito P450-CPR (NADPH-cytochrome P450-reductase) complex in a yeast recombinant system. The results of the present study show that: (i) CYP6Z8 metabolizes PBAlc (3-phenoxybenzoic alcohol) and PBAld (3-phenoxybenzaldehyde), common pyrethroid metabolites produced by carboxylesterases, producing PBA (3-phenoxybenzoic acid); (ii) CYP6Z8 transcription is induced by PBAlc, PBAld and PBA; (iii) An. gambiae CYP6Z2 metabolizes PBAlc and PBAld in the same way; (iv) PBA is the major metabolite produced in vivo and is excreted without further modification; and (v) in silico modelling of substrate-enzyme interactions supports a similar role of other mosquito CYP6Zs in pyrethroid degradation. By playing a pivotal role in the degradation of pyrethroid insecticides, mosquito CYP6Zs thus represent good targets for mosquito-resistance management strategies.
Keywords
Aedes/drug effects, Aedes/enzymology, Animals, Anopheles gambiae/drug effects, Anopheles gambiae/enzymology, Benzaldehydes/chemistry, Benzaldehydes/metabolism, Benzoates/metabolism, Cytochrome P-450 Enzyme System/chemistry, Cytochrome P-450 Enzyme System/genetics, Escherichia coli/enzymology, Escherichia coli/genetics, Genetic Engineering, Insect Proteins/chemistry, Insect Proteins/genetics, Insect Vectors/drug effects, Insect Vectors/enzymology, Insecticide Resistance/drug effects, Insecticide Resistance/genetics, Insecticides/chemistry, Insecticides/metabolism, Isoenzymes/chemistry, Isoenzymes/genetics, Metabolic Detoxication, Drug, Molecular Docking Simulation, NADPH-Ferrihemoprotein Reductase/chemistry, NADPH-Ferrihemoprotein Reductase/genetics, Oxidation-Reduction, Pyrethrins/chemistry, Pyrethrins/metabolism, Saccharomyces cerevisiae/drug effects, Saccharomyces cerevisiae/enzymology
Pubmed
Web of science
Open Access
Yes
Create date
12/02/2014 14:08
Last modification date
20/08/2019 14:31
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