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The central role of mosquito cytochrome P450 CYP6Zs in insecticide detoxification revealed by functional expression and structural modelling
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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3778711/ https://www.ncbi.nlm.nih.gov/pubmed/23844938 http://dx.doi.org/10.1042/BJ20130577 |
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author | Chandor-Proust, Alexia Bibby, Jaclyn Régent-Kloeckner, Myriam Roux, Jessica Guittard-Crilat, Emilie Poupardin, Rodolphe Riaz, Muhammad Asam Paine, Mark Dauphin-Villemant, Chantal Reynaud, Stéphane David, Jean-Philippe |
author_facet | Chandor-Proust, Alexia Bibby, Jaclyn Régent-Kloeckner, Myriam Roux, Jessica Guittard-Crilat, Emilie Poupardin, Rodolphe Riaz, Muhammad Asam Paine, Mark Dauphin-Villemant, Chantal Reynaud, Stéphane David, Jean-Philippe |
author_sort | Chandor-Proust, Alexia |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3778711 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-37787112013-09-20 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 Dauphin-Villemant, Chantal Reynaud, Stéphane David, Jean-Philippe Biochem J Research Article 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. Portland Press Ltd. 2013-09-13 2013-10-01 /pmc/articles/PMC3778711/ /pubmed/23844938 http://dx.doi.org/10.1042/BJ20130577 Text en © 2013 The author(s) has paid for this article to be freely available under the terms of the Creative Commons Attribution Licence (CC-BY)(http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Chandor-Proust, Alexia Bibby, Jaclyn Régent-Kloeckner, Myriam Roux, Jessica Guittard-Crilat, Emilie Poupardin, Rodolphe Riaz, Muhammad Asam Paine, Mark Dauphin-Villemant, Chantal Reynaud, Stéphane David, Jean-Philippe The central role of mosquito cytochrome P450 CYP6Zs in insecticide detoxification revealed by functional expression and structural modelling |
title | The central role of mosquito cytochrome P450 CYP6Zs in insecticide detoxification revealed by functional expression and structural modelling |
title_full | The central role of mosquito cytochrome P450 CYP6Zs in insecticide detoxification revealed by functional expression and structural modelling |
title_fullStr | The central role of mosquito cytochrome P450 CYP6Zs in insecticide detoxification revealed by functional expression and structural modelling |
title_full_unstemmed | The central role of mosquito cytochrome P450 CYP6Zs in insecticide detoxification revealed by functional expression and structural modelling |
title_short | The central role of mosquito cytochrome P450 CYP6Zs in insecticide detoxification revealed by functional expression and structural modelling |
title_sort | central role of mosquito cytochrome p450 cyp6zs in insecticide detoxification revealed by functional expression and structural modelling |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3778711/ https://www.ncbi.nlm.nih.gov/pubmed/23844938 http://dx.doi.org/10.1042/BJ20130577 |
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