Structural model and functional characterization of the Bemisia tabaci CYP6CM1vQ, a cytochrome P450 associated with high levels of imidacloprid resistance

Iris Karunker; Evangelia Morou; Dimitra Nikou; Ralf Nauen; Rotem Sertchook; Bradley J. Stevenson; Mark J.I. Paine; Shai Morin; John Vontas

doi:10.1016/j.ibmb.2009.08.006

Structural model and functional characterization of the Bemisia tabaci CYP6CM1vQ, a cytochrome P450 associated with high levels of imidacloprid resistance

Iris Karunker, Evangelia Morou, Dimitra Nikou, Ralf Nauen, Rotem Sertchook, Bradley J. Stevenson, Mark J.I. Paine, Shai Morin^*, John Vontas

^*Corresponding author for this work

Department of Entomology

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

187 Scopus citations

Abstract

The neonicotinoid imidacloprid is one of the most important insecticides worldwide. It is used extensively against the whitefly Bemisia tabaci (Hemiptera: Aleyrodidae), an insect pest of eminent importance globally, which was also the first pest to develop high levels of resistance against imidacloprid and other neonicotinoids in the field. Recent reports indicated that in both the B and Q biotypes of B. tabaci, the resistant phenotype is associated with over-expression of the cytochrome P450 gene CYP6CM1. In this study, molecular docking and dynamic simulations were used to analyze interactions of imidacloprid with the biotype Q variant of the CYP6CM1 enzyme (CYP6CM1vQ). The binding mode with the lowest energy in the enzyme active site, the key amino acids involved (i.e. Phe-130 and Phe-226), and the putative hydroxylation site (lowest distance to carbon 5 of the imidazolidine ring system of imidacloprid) were predicted. Heterologous expression of the CYP6CM1vQ confirmed the accuracy of our predictions and demonstrated that the enzyme catalyses the hydroxylation of imidacloprid to its less toxic 5-hydroxy form (K_cat = 3.2 pmol/min/pmol P450, K_m = 36 μM). The data identify CYP6CM1vQ as a principle target for inhibitor design, aimed at inactivating insecticide-metabolizing P450s in natural insect pest populations.

Original language	English
Pages (from-to)	697-706
Number of pages	10
Journal	Insect Biochemistry and Molecular Biology
Volume	39
Issue number	10
DOIs	https://doi.org/10.1016/j.ibmb.2009.08.006
State	Published - Oct 2009

Bibliographical note

Funding Information:
This research was supported by grants from the Israel Science Foundation (grant No. 971/04 and 848/08) to Shai Morin, and Bayer Crop Science to John Vontas. Evangelia Morou, Dimitra Nikou, Bradley Stevenson, and Mark Paine were supported by the Innovative Vector Control Consortium. We would like to thank Dr. Hilary Ranson (LSTM, Liverpool), Dr. Michael Beck (Bayer CropScience, Monheim) and Dr. Martin Kaussmann (Bayer CropScience, Monheim) for their critical reading of this manuscript.

Keywords

Bemisia tabaci
Cytochrome P450 CYP6CM1vQ
Heterologous expression
Imidacloprid
Metabolic resistance
Molecular modeling
Neonicotinoid insecticide

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10.1016/j.ibmb.2009.08.006

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Karunker, I., Morou, E., Nikou, D., Nauen, R., Sertchook, R., Stevenson, B. J., Paine, M. J. I., Morin, S., & Vontas, J. (2009). Structural model and functional characterization of the Bemisia tabaci CYP6CM1vQ, a cytochrome P450 associated with high levels of imidacloprid resistance. Insect Biochemistry and Molecular Biology, 39(10), 697-706. https://doi.org/10.1016/j.ibmb.2009.08.006

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title = "Structural model and functional characterization of the Bemisia tabaci CYP6CM1vQ, a cytochrome P450 associated with high levels of imidacloprid resistance",

abstract = "The neonicotinoid imidacloprid is one of the most important insecticides worldwide. It is used extensively against the whitefly Bemisia tabaci (Hemiptera: Aleyrodidae), an insect pest of eminent importance globally, which was also the first pest to develop high levels of resistance against imidacloprid and other neonicotinoids in the field. Recent reports indicated that in both the B and Q biotypes of B. tabaci, the resistant phenotype is associated with over-expression of the cytochrome P450 gene CYP6CM1. In this study, molecular docking and dynamic simulations were used to analyze interactions of imidacloprid with the biotype Q variant of the CYP6CM1 enzyme (CYP6CM1vQ). The binding mode with the lowest energy in the enzyme active site, the key amino acids involved (i.e. Phe-130 and Phe-226), and the putative hydroxylation site (lowest distance to carbon 5 of the imidazolidine ring system of imidacloprid) were predicted. Heterologous expression of the CYP6CM1vQ confirmed the accuracy of our predictions and demonstrated that the enzyme catalyses the hydroxylation of imidacloprid to its less toxic 5-hydroxy form (Kcat = 3.2 pmol/min/pmol P450, Km = 36 μM). The data identify CYP6CM1vQ as a principle target for inhibitor design, aimed at inactivating insecticide-metabolizing P450s in natural insect pest populations.",

keywords = "Bemisia tabaci, Cytochrome P450 CYP6CM1vQ, Heterologous expression, Imidacloprid, Metabolic resistance, Molecular modeling, Neonicotinoid insecticide",

author = "Iris Karunker and Evangelia Morou and Dimitra Nikou and Ralf Nauen and Rotem Sertchook and Stevenson, {Bradley J.} and Paine, {Mark J.I.} and Shai Morin and John Vontas",

note = "Funding Information: This research was supported by grants from the Israel Science Foundation (grant No. 971/04 and 848/08) to Shai Morin, and Bayer Crop Science to John Vontas. Evangelia Morou, Dimitra Nikou, Bradley Stevenson, and Mark Paine were supported by the Innovative Vector Control Consortium. We would like to thank Dr. Hilary Ranson (LSTM, Liverpool), Dr. Michael Beck (Bayer CropScience, Monheim) and Dr. Martin Kaussmann (Bayer CropScience, Monheim) for their critical reading of this manuscript. ",

year = "2009",

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doi = "10.1016/j.ibmb.2009.08.006",

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journal = "Insect Biochemistry and Molecular Biology",

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Karunker, I, Morou, E, Nikou, D, Nauen, R, Sertchook, R, Stevenson, BJ, Paine, MJI, Morin, S & Vontas, J 2009, 'Structural model and functional characterization of the Bemisia tabaci CYP6CM1vQ, a cytochrome P450 associated with high levels of imidacloprid resistance', Insect Biochemistry and Molecular Biology, vol. 39, no. 10, pp. 697-706. https://doi.org/10.1016/j.ibmb.2009.08.006

TY - JOUR

T1 - Structural model and functional characterization of the Bemisia tabaci CYP6CM1vQ, a cytochrome P450 associated with high levels of imidacloprid resistance

AU - Karunker, Iris

AU - Morou, Evangelia

AU - Nikou, Dimitra

AU - Nauen, Ralf

AU - Sertchook, Rotem

AU - Stevenson, Bradley J.

AU - Paine, Mark J.I.

AU - Morin, Shai

AU - Vontas, John

N1 - Funding Information: This research was supported by grants from the Israel Science Foundation (grant No. 971/04 and 848/08) to Shai Morin, and Bayer Crop Science to John Vontas. Evangelia Morou, Dimitra Nikou, Bradley Stevenson, and Mark Paine were supported by the Innovative Vector Control Consortium. We would like to thank Dr. Hilary Ranson (LSTM, Liverpool), Dr. Michael Beck (Bayer CropScience, Monheim) and Dr. Martin Kaussmann (Bayer CropScience, Monheim) for their critical reading of this manuscript.

PY - 2009/10

Y1 - 2009/10

N2 - The neonicotinoid imidacloprid is one of the most important insecticides worldwide. It is used extensively against the whitefly Bemisia tabaci (Hemiptera: Aleyrodidae), an insect pest of eminent importance globally, which was also the first pest to develop high levels of resistance against imidacloprid and other neonicotinoids in the field. Recent reports indicated that in both the B and Q biotypes of B. tabaci, the resistant phenotype is associated with over-expression of the cytochrome P450 gene CYP6CM1. In this study, molecular docking and dynamic simulations were used to analyze interactions of imidacloprid with the biotype Q variant of the CYP6CM1 enzyme (CYP6CM1vQ). The binding mode with the lowest energy in the enzyme active site, the key amino acids involved (i.e. Phe-130 and Phe-226), and the putative hydroxylation site (lowest distance to carbon 5 of the imidazolidine ring system of imidacloprid) were predicted. Heterologous expression of the CYP6CM1vQ confirmed the accuracy of our predictions and demonstrated that the enzyme catalyses the hydroxylation of imidacloprid to its less toxic 5-hydroxy form (Kcat = 3.2 pmol/min/pmol P450, Km = 36 μM). The data identify CYP6CM1vQ as a principle target for inhibitor design, aimed at inactivating insecticide-metabolizing P450s in natural insect pest populations.

AB - The neonicotinoid imidacloprid is one of the most important insecticides worldwide. It is used extensively against the whitefly Bemisia tabaci (Hemiptera: Aleyrodidae), an insect pest of eminent importance globally, which was also the first pest to develop high levels of resistance against imidacloprid and other neonicotinoids in the field. Recent reports indicated that in both the B and Q biotypes of B. tabaci, the resistant phenotype is associated with over-expression of the cytochrome P450 gene CYP6CM1. In this study, molecular docking and dynamic simulations were used to analyze interactions of imidacloprid with the biotype Q variant of the CYP6CM1 enzyme (CYP6CM1vQ). The binding mode with the lowest energy in the enzyme active site, the key amino acids involved (i.e. Phe-130 and Phe-226), and the putative hydroxylation site (lowest distance to carbon 5 of the imidazolidine ring system of imidacloprid) were predicted. Heterologous expression of the CYP6CM1vQ confirmed the accuracy of our predictions and demonstrated that the enzyme catalyses the hydroxylation of imidacloprid to its less toxic 5-hydroxy form (Kcat = 3.2 pmol/min/pmol P450, Km = 36 μM). The data identify CYP6CM1vQ as a principle target for inhibitor design, aimed at inactivating insecticide-metabolizing P450s in natural insect pest populations.

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KW - Cytochrome P450 CYP6CM1vQ

KW - Heterologous expression

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KW - Metabolic resistance

KW - Molecular modeling

KW - Neonicotinoid insecticide

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Structural model and functional characterization of the Bemisia tabaci CYP6CM1vQ, a cytochrome P450 associated with high levels of imidacloprid resistance

Abstract

Bibliographical note

Keywords

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