The central role of mosquito cytochrome P450 CYP6Zs in insecticide detoxification revealed by functional expression and structural modelling

Autor: Alexia Chandor-Proust, Jessica Roux, Muhammad Asam Riaz, Jean-Philippe David, Jaclyn Bibby, Mark J. I. Paine, Myriam Régent-Kloeckner, Chantal Dauphin-Villemant, Rodolphe Poupardin, Stéphane Reynaud, Emilie Guittard-Crilat
Rok vydání: 2013
Předmět:
cytochrome P450 monooxygenase
0106 biological sciences
Insecticides
Anopheles gambiae
recombinant system
Benzoates
01 natural sciences
Biochemistry
Insecticide Resistance
chemistry.chemical_compound
Cytochrome P-450 Enzyme System
Aedes
7-OH
7-hydroxycoumarin

Pyrethrins
0303 health sciences
Pyrethroid
pyrethroid
Cyt b5
cytochrome b5

Rt
retention time

qPCR
quantitative real-time PCR

Cytochrome P450 reductase
PBA
3-phenoxybenzoic acid

3. Good health
Genetically modified organism
Isoenzymes
Molecular Docking Simulation
qw_52
qx_510
Benzaldehydes
qu_26.5
Inactivation
Metabolic

Insect Proteins
Genetic Engineering
Oxidation-Reduction
Research Article
In silico
mosquito
Saccharomyces cerevisiae
Aedes aegypti
Biology
SRS
substrate recognition site

Microbiology
resistance
TFA
trifluoroacetic acid

03 medical and health sciences
PBAld
3-phenoxybenzaldehyde

qx_600
Anopheles
parasitic diseases
Botany
Escherichia coli
Animals
CPR
NADPH-cytochrome P450-reductase

Aedes/drug effects
Aedes/enzymology
Anopheles gambiae/drug effects
Anopheles gambiae/enzymology
Benzaldehydes/chemistry
Benzaldehydes/metabolism
Benzoates/metabolism
Cytochrome P-450 Enzyme System/chemistry
Cytochrome P-450 Enzyme System/genetics
Escherichia coli/enzymology
Escherichia coli/genetics
Insect Proteins/chemistry
Insect Proteins/genetics
Insect Vectors/drug effects
Insect Vectors/enzymology
Insecticide Resistance/drug effects
Insecticide Resistance/genetics
Insecticides/chemistry
Insecticides/metabolism
Isoenzymes/chemistry
Isoenzymes/genetics
Metabolic Detoxication
Drug

NADPH-Ferrihemoprotein Reductase/chemistry
NADPH-Ferrihemoprotein Reductase/genetics
Pyrethrins/chemistry
Pyrethrins/metabolism
Saccharomyces cerevisiae/drug effects
Saccharomyces cerevisiae/enzymology
Molecular Biology
NADPH-Ferrihemoprotein Reductase
030304 developmental biology
AeCPR
Aedes aegypti CPR

PBAlc
3-phenoxybenzoic alcohol

insecticide
wa_240
Cytochrome P450
Cell Biology
Monooxygenase
biology.organism_classification
Insect Vectors
010602 entomology
chemistry
biology.protein
metabolism
Zdroj: Biochemical Journal
Biochemical Journal, vol. 455, no. 1, pp. 75-85
Biochemical Journal; Vol 455
ISSN: 1470-8728
0264-6021
DOI: 10.1042/bj20130577
Popis: 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.
The key role of mosquito cytochrome P450 monooxygenases from the CYP6Z subfamily in the resistance of mosquitoes to insecticides was revealed. By using functional expression and in silico modelling, the capacity of CYP6Zs to degrade insecticide metabolites produced by esterase-mediated hydrolysis was demonstrated.
Databáze: OpenAIRE