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Cytochrome P450 6M2 from the malaria vector Anopheles gambiae metabolizes pyrethroids: sequential metabolism of deltamethrin revealed

Stevenson, B. J. and Bibby, J. and Pignatelli, P. and Muangnoicharoen, S. and O'Neill P. M., and Lian, L. Y. and Müller, P. and Nikou, D. and Steven, A. and Hemingway, J. and Sutcliffe, M. J. and Paine, M. J. I.. (2011) Cytochrome P450 6M2 from the malaria vector Anopheles gambiae metabolizes pyrethroids: sequential metabolism of deltamethrin revealed. Insect biochemistry and molecular biology, Vol. 41, H. 7. pp. 492-502.

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Official URL: http://edoc.unibas.ch/dok/A6002157

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Abstract

Resistance to pyrethroid insecticides in the malaria vector Anopheles gambiae is a major threat to malaria control programmes. Cytochome P450-mediated detoxification is an important resistance mechanism. CYP6M2 is over-expressed in wild populations of permethrin resistant A. gambiae but its role in detoxification is not clear. CYP6M2 was expressed in Escherichia coli and a structural model was produced to examine its role in pyrethroid metabolism. Both permethrin and deltamethrin were metabolized. Rates were enhanced by A. gambiae cytochrome b(5) with kinetic parameters of K(M)=12+/-4muM and k(cat)=6+/-1 per min for permethrin (1:1 cis-trans) and K(M)=2.1+/-0.2muM and k(cat)=1.2+/-0.1 per min for deltamethrin. Mass spectrometry and NMR analysis identified 4'-hydroxy deltamethrin and hydroxymethyl deltamethrin as major and minor deltamethrin metabolites respectively. Secondary breakdown products included cyano(3-hydroxyphenyl)methyl deltamethrate and deltamethric acid. CYP6M2 was most highly transcribed in the midgut and Malpighian tubules of adult A. gambiae, consistent with a role in detoxification. Our data indicates that CYP6M2 plays an important role in metabolic resistance to pyrethroids and thus an important target for the design of new tools to combat malaria
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Health Interventions > Vector Control (Müller)
UniBasel Contributors:Müller, Pie
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Pergamon Press
ISSN:0965-1748
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:08 Nov 2012 16:22
Deposited On:08 Nov 2012 16:12

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