Journal of Chemical Ecology

, Volume 39, Issue 9, pp 1232–1245 | Cite as

Structure and Function of Cytochrome P450S in Insect Adaptation to Natural and Synthetic Toxins: Insights Gained from Molecular Modeling

  • Mary A. Schuler
  • May R. Berenbaum
Review Article


Over evolutionary time, insect herbivores have adapted to the presence of natural toxins and more recently to synthetic insecticides in or on the plants they consume. Biochemical analyses and molecular modeling of the cytochrome P450 monooxygenases (P450s) that metabolize these compounds have provided insight into the many variations affecting their catalytic activity. Phylogenetically distinct P450s may metabolize similar substrates, and phylogenetically similar P450s may metabolize different substrates; as well, some P450s process broad arrays of both phytochemicals and synthetic insecticides, while closely related P450s are restricted to a narrow range of phytochemicals. Mapped on the predicted three-dimensional structures of insect P450s developed from available mammalian P450 crystal structures, differences in multiple regions of the insect proteins reveal the evolutionary processes occurring as P450 genes have duplicated and diverged. Analyses of site-directed mutants in select lepidopteran and dipteran P450s demonstrate that slight changes in the catalytic site, the putative product release channel, and the proximal surface (interacting with electron transfer partners such as cytochrome P450 reductase and cytochrome b5) yield pronounced activity differences. Additionally, changes in the catalytic site and in the linker region preceding the proline-hinge influence P450 folding. With predicted structures available for many mammalian P450s involved in metabolism of xenobiotics, it is possible to record allelic variation relative to catalytically important regions in the overall P450 structure and to predict functionally critical differences. Together with information on the relative levels of allelic variant transcripts, comprehensive characterization of the mechanisms that modulate metabolism of natural and synthetic xenobiotics in insects can yield insights into plant-insect coevolution and into novel approaches for chemical pest management.


Cytochrome P450 monooxygenases (P450s) Detoxification Insecticide metabolism Insect-plant interactions Molecular modeling Phytochemical metabolism 



Cytochrome P450 monooxygenase


Cytochrome P450 reductase

cyt b5

Cytochrome b5


Substrate recognition site


Miniature inverted-repeat transposable element



The authors are grateful for funding in the area of insect P450s from the National Institutes of Health, National Science Foundation, and United States Department of Agriculture; USDA Agriculture and Food Research Initiative 2010–03760 supported the preparation of this review. We also thank Dr. John Romeo for extending an invitation to contribute this review, Dr. Sanjeewa Rupasinghe, Dr. Wenfu Mao, and Mr. Brendan Colon for their modeling efforts, Dr. Mark Paine and Dr. Jacyln Bibby for providing the CYP6M2 figure, and Katherine Noble and Linus Gog for helpful comments on the manuscript.


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Cell and Developmental BiologyUniversity of IllinoisUrbanaUSA
  2. 2.Department of BiochemistryUniversity of IllinoisUrbanaUSA
  3. 3.Department of Plant BiologyUniversity of IllinoisUrbanaUSA
  4. 4.Department of EntomologyUniversity of IllinoisUrbanaUSA

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