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

Bradley J. Stevenson; Jaclyn Bibby; Patricia Pignatelli; Sant Muangnoicharoen; Paul M. O'Neill; Lu Yun Lian; Pie Müller; Dimitra Nikou; Andrew Steven; Janet Hemingway; Michael J. Sutcliffe; Mark J I Paine

doi:10.1016/j.ibmb.2011.02.003

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

Bradley J. Stevenson, Jaclyn Bibby, Patricia Pignatelli, Sant Muangnoicharoen, Paul M. O'Neill, Lu Yun Lian, Pie Müller, Dimitra Nikou, Andrew Steven, Janet Hemingway, Michael J. Sutcliffe, Mark J I Paine

Research output: Contribution to journal › Article › peer-review

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 b5 with kinetic parameters of KM=11±1μM and kcat=6.1±0.4 per min for permethrin (1:1 cis-trans) and KM=2.0±0.3μM and kcat=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. © 2011.

Original language	English
Pages (from-to)	492-502
Number of pages	10
Journal	Insect Biochemistry and Molecular Biology
Volume	41
Issue number	7
DOIs	https://doi.org/10.1016/j.ibmb.2011.02.003
Publication status	Published - Jul 2011

Keywords

Detoxification
Insecticide resistance
Malaria
Mixed-function oxidase
Mosquito

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ibmb.2011.02.003

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Stevenson, B. J., Bibby, J., Pignatelli, P., Muangnoicharoen, S., O'Neill, P. M., Lian, L. Y., Müller, P., Nikou, D., Steven, A., Hemingway, J., Sutcliffe, M. J., & 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, 41(7), 492-502. https://doi.org/10.1016/j.ibmb.2011.02.003

@article{8567f1a1661d4df19ea8c9965727a5de,

title = "Cytochrome P450 6M2 from the malaria vector Anopheles gambiae metabolizes pyrethroids: Sequential metabolism of deltamethrin revealed",

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 b5 with kinetic parameters of KM=11±1μM and kcat=6.1±0.4 per min for permethrin (1:1 cis-trans) and KM=2.0±0.3μM and kcat=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. {\textcopyright} 2011.",

keywords = "Detoxification, Insecticide resistance, Malaria, Mixed-function oxidase, Mosquito",

author = "Stevenson, {Bradley J.} and Jaclyn Bibby and Patricia Pignatelli and Sant Muangnoicharoen and O'Neill, {Paul M.} and Lian, {Lu Yun} and Pie M{\"u}ller and Dimitra Nikou and Andrew Steven and Janet Hemingway and Sutcliffe, {Michael J.} and Paine, {Mark J I}",

note = "Stevenson, Bradley J. Bibby, Jaclyn Pignatelli, Patricia Muangnoicharoen, Sant O'Neill, Paul M. Lian, Lu-Yun Mueller, Pie Nikou, Dimitra Steven, Andrew Hemingway, Janet Sutcliffe, Michael J. Paine, Mark J. I. Si",

year = "2011",

month = jul,

doi = "10.1016/j.ibmb.2011.02.003",

language = "English",

volume = "41",

pages = "492--502",

journal = "Insect Biochemistry and Molecular Biology",

issn = "0965-1748",

publisher = "Elsevier BV",

number = "7",

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Stevenson, BJ, Bibby, J, Pignatelli, P, Muangnoicharoen, S, O'Neill, PM, Lian, LY, Müller, P, Nikou, D, Steven, A, Hemingway, J, Sutcliffe, MJ & Paine, MJI 2011, 'Cytochrome P450 6M2 from the malaria vector Anopheles gambiae metabolizes pyrethroids: Sequential metabolism of deltamethrin revealed', Insect Biochemistry and Molecular Biology, vol. 41, no. 7, pp. 492-502. https://doi.org/10.1016/j.ibmb.2011.02.003

TY - JOUR

T1 - Cytochrome P450 6M2 from the malaria vector Anopheles gambiae metabolizes pyrethroids: Sequential metabolism of deltamethrin revealed

AU - Stevenson, Bradley J.

AU - Bibby, Jaclyn

AU - Pignatelli, Patricia

AU - Muangnoicharoen, Sant

AU - O'Neill, Paul M.

AU - Lian, Lu Yun

AU - Müller, Pie

AU - Nikou, Dimitra

AU - Steven, Andrew

AU - Hemingway, Janet

AU - Sutcliffe, Michael J.

AU - Paine, Mark J I

N1 - Stevenson, Bradley J. Bibby, Jaclyn Pignatelli, Patricia Muangnoicharoen, Sant O'Neill, Paul M. Lian, Lu-Yun Mueller, Pie Nikou, Dimitra Steven, Andrew Hemingway, Janet Sutcliffe, Michael J. Paine, Mark J. I. Si

PY - 2011/7

Y1 - 2011/7

N2 - 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 b5 with kinetic parameters of KM=11±1μM and kcat=6.1±0.4 per min for permethrin (1:1 cis-trans) and KM=2.0±0.3μM and kcat=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. © 2011.

AB - 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 b5 with kinetic parameters of KM=11±1μM and kcat=6.1±0.4 per min for permethrin (1:1 cis-trans) and KM=2.0±0.3μM and kcat=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. © 2011.

KW - Detoxification

KW - Insecticide resistance

KW - Malaria

KW - Mixed-function oxidase

KW - Mosquito

U2 - 10.1016/j.ibmb.2011.02.003

DO - 10.1016/j.ibmb.2011.02.003

M3 - Article

SN - 0965-1748

VL - 41

SP - 492

EP - 502

JO - Insect Biochemistry and Molecular Biology

JF - Insect Biochemistry and Molecular Biology

IS - 7

ER -

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

Abstract

Keywords

UN SDGs

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