Publication: Homology modeling of mosquito cytochrome P450 enzymes involved in pyrethroid metabolism: insights into differences in substrate selectivity
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Issued Date
2011
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eng
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Mahidol University
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BioMed Central
Bibliographic Citation
BMC Research Notes. Vol. 4, (2011), 321
Suggested Citation
Panida Lertkiatmongkol, Ekachai Jenwitheesuk, Pornpimol Rongnoparut Homology modeling of mosquito cytochrome P450 enzymes involved in pyrethroid metabolism: insights into differences in substrate selectivity. BMC Research Notes. Vol. 4, (2011), 321. doi:10.1186/1756-0500-4-321 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/2723
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Title
Homology modeling of mosquito cytochrome P450 enzymes involved in pyrethroid metabolism: insights into differences in substrate selectivity
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Abstract
Background: Cytochrome P450 enzymes (P450s) have been implicated in insecticide resistance. Anopheles
minumus mosquito P450 isoforms CYP6AA3 and CYP6P7 are capable of metabolizing pyrethroid insecticides,
however CYP6P8 lacks activity against this class of compounds.
Findings: Homology models of the three An. minimus P450 enzymes were constructed using the multiple
template alignment method. The predicted enzyme model structures were compared and used for molecular
docking with insecticides and compared with results of in vitro enzymatic assays. The three model structures
comprise common P450 folds but differences in geometry of their active-site cavities and substrate access
channels are prominent. The CYP6AA3 model has a large active site allowing it to accommodate multiple
conformations of pyrethroids. The predicted CYP6P7 active site is more constrained and less accessible to binding
of pyrethroids. Moreover the predicted hydrophobic interface in the active-site cavities of CYP6AA3 and CYP6P7
may contribute to their substrate selectivity. The absence of CYP6P8 activity toward pyrethroids appears to be due
to its small substrate access channel and the presence of R114 and R216 that may prevent access of pyrethroids to
the enzyme heme center.
Conclusions: Differences in active site topologies among CYPAA3, CYP6P7, and CYP6P8 enzymes may impact
substrate binding and selectivity. Information obtained using homology models has the potential to enhance the
understanding of pyrethroid metabolism and detoxification mediated by P450 enzymes.