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Forschungsdatenbank PMU-SQQUID

The central role of mosquito cytochrome P450 CYP6Zs in insecticide detoxification revealed by functional expression and structural modelling.
Chandor-Proust, A; Bibby, J; Régent-Kloeckner, M; Roux, J; Guittard-Crilat, E; Poupardin, R; Riaz, MA; Paine, M; Dauphin-Villemant, C; Reynaud, S; David, JP;
Biochem J. 2013; 455(1):7-85
Originalarbeiten (Zeitschrift)

PMU-Autor/inn/en

Poupardin Rodolphe

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.


Useful keywords (using NLM MeSH Indexing)

Aedes/drug effects*

Aedes/enzymology

Animals

Anopheles/drug effects*

Anopheles/enzymology

Benzaldehydes/chemistry

Benzaldehydes/metabolism

Benzaldehydes/pharmacology

Benzoates/metabolism

Cytochrome P-450 Enzyme System/chemistry

Cytochrome P-450 Enzyme System/genetics

Cytochrome P-450 Enzyme System/metabolism*

Escherichia coli/enzymology

Escherichia coli/genetics

Genetic Engineering

Inactivation, Metabolic

Insect Proteins/chemistry

Insect Proteins/genetics

Insect Proteins/metabolism*

Insect Vectors/drug effects*

Insect Vectors/enzymology

Insecticide Resistance/drug effects

Insecticide Resistance/genetics

Insecticides/chemistry

Insecticides/metabolism*

Insecticides/pharmacology

Isoenzymes/chemistry

Isoenzymes/genetics

Isoenzymes/metabolism

Molecular Docking Simulation

NADPH-Ferrihemoprotein Reductase/chemistry

NADPH-Ferrihemoprotein Reductase/genetics

NADPH-Ferrihemoprotein Reductase/metabolism*

Oxidation-Reduction

Pyrethrins/chemistry

Pyrethrins/metabolism

Pyrethrins/pharmacology

Saccharomyces cerevisiae/drug effects

Saccharomyces cerevisiae/enzymology

Saccharomyces cerevisiae/genetics


Find related publications in this database (Keywords)

cytochrome P450 monooxygenase
insecticide
metabolism
mosquito
pyrethroid
recombinant system
resistance