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

Chandor‑Proust, Alexia, Bibby, Jaclyn, Régent‑Kloeckner, Myriam, Roux, Jessica, Guittard‑Crilat, Emilie, Poupardin, Rodolphe, Riaz, Muhammad Asam, Paine, Mark ORCID: https://orcid.org/0000-0003-2061-7713, Dauphin‑Villemant, Chantal, Reynaud, Stéphane and David, Jean‑Philippe (2013) 'The central role of mosquito cytochrome P450 CYP6Zs in insecticide detoxification revealed by functional expression and structural modelling'. Biochemical Journal, Vol 455, Issue 1, pp. 75-85.

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Abstract

The key role of mosquito cytochrome P450 monooxygenases from the CYP6Z subfamily in the resistance of mosquitoes to insecticides was revealed. By using functional expression and in silico modelling, the capacity of CYP6Zs to degrade insecticide metabolites produced by esterase-mediated hydrolysis was demonstrated.

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.

Item Type:	Article
Subjects:	QU Biochemistry > QU 26.5 Informatics. Automatic data processing. Computers QW Microbiology and Immunology > QW 52 Physiology and chemistry of microorganisms. Metabolism. QX Parasitology > Insects. Other Parasites > QX 510 Mosquitoes QX Parasitology > Insects. Other Parasites > QX 600 Insect control. Tick control WA Public Health > Preventive Medicine > WA 240 Disinfection. Disinfestation. Pesticides (including diseases caused by)
Faculty: Department:	Biological Sciences > Vector Biology Department
Digital Object Identifer (DOI):	https://doi.org/10.1042/bj20130577
Depositing User:	Lynn Roberts-Maloney
Date Deposited:	16 Feb 2015 15:44
Last Modified:	06 Feb 2018 13:09
URI:	https://archive.lstmed.ac.uk/id/eprint/4910

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