Volume 17, Issue 2 p. 125-135

Characterization of inhibitors and substrates of Anopheles gambiae CYP6Z2

L. A. Mclaughlin

L. A. Mclaughlin

Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom;

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U. Niazi

U. Niazi

Manchester Interdisciplinary Biocentre & School of Chemical Engineering and Analytical Science, University of Manchester, Manchester, United Kingdom;

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J. Bibby

J. Bibby

Manchester Interdisciplinary Biocentre & School of Chemical Engineering and Analytical Science, University of Manchester, Manchester, United Kingdom;

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J.-P. David

J.-P. David

Laboratoire d’Ecologie Alpine, UMR 5553 Université Joseph Fourier – CNRS, Grenoble, France;

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J. Vontas

J. Vontas

Laboratory of Pesticide Science, Agricultural University of Athens, Greece; and

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J. Hemingway

J. Hemingway

Liverpool School of Tropical Medicine, Liverpool, United Kingdom

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H. Ranson

H. Ranson

Liverpool School of Tropical Medicine, Liverpool, United Kingdom

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M. J. Sutcliffe

M. J. Sutcliffe

Manchester Interdisciplinary Biocentre & School of Chemical Engineering and Analytical Science, University of Manchester, Manchester, United Kingdom;

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M. J. I. Paine

M. J. I. Paine

Liverpool School of Tropical Medicine, Liverpool, United Kingdom

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First published: 15 February 2008
Citations: 85
Mark J. I. Paine, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, United Kingdom. Tel.: +44 (0)151 705 3310; fax: +44 (0)151 705 3370; e-mail: [email protected]

Abstract

Three CYP6Z genes are linked to a major pyrethroid resistance locus in the mosquito Anopheles gambiae. We have expressed CYP6Z2 in Escherichia coli and produced a structural model in order to examine its role in detoxification. E. coli membranes co-expressing CYP6Z2 and An. gambiae P450 reductase (AgCPR) catalysed the dealkylation of benzyloxyresorufin with kinetic parameters Km = 0.13 µM; Kcat = 1.5 min-1. The IC50 values of a wide range of compounds were measured. Pyrethroids cypermethrin and permethrin produced low IC50 values, but were not metabolized. Plant flavanoids were the most potent inhibitors. Several compounds were shown to be substrates, suggesting that CYP6Z2 has broad substrate specificity and plays an important chemo-protective role during the herbivorous phase of the life-cycle.