Common active site architecture and binding strategy of four phenylpropanoid P450s from Arabidopsis thaliana as revealed by molecular modeling

Rupasinghe, Sanjeewa G.; Baudry, Jérôme; Schuler, Mary A.

doi:10.1093/protein/gzg094

Cited by 60 publications

(63 citation statements)

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“…7B). CYP75B1 encodes an enzyme that mediates synthesis of phenylpropanoid; CYP71A22 is associated with synthesis of furanocoumarins; and CYP82C4 is related to transport of iron ion (Rupasinghe et al, 2003;Murgia et al, 2011;Chen et al, 2014). Overexpression of CYP82C4 and CYP75B1 enhance salt tolerance in soybean plants with transgenic hairy roots (Fig.…”

Section: Discussionmentioning

confidence: 99%

A Histone Code Reader and a Transcriptional Activator Interact to Regulate Genes for Salt Tolerance

et al. 2017

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Section: Discussionmentioning

confidence: 99%

A Histone Code Reader and a Transcriptional Activator Interact to Regulate Genes for Salt Tolerance

et al. 2017

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“…The choice of CYP102 as template over rabbit CYP2C5 is based on the fact that CYP102, CYP6B1, and CYP6B8 are functionally related in their ability to metabolize xanthotoxin, whereas CYP2C5 cannot metabolize this compound. In addition, several high-energy regions in the CYP2C5 crystal structure (19) were reported to strongly bias the predicted binding sites geometry in several P450s (20). Ten models were generated and subjected to a coarse energy minimization for each target protein, with the explicit inclusion of the heme coordinates in all steps of the homology model generation.…”

Section: Materials and Methods Homology Modeling And Molecular Dynamimentioning

confidence: 99%

Structural and functional divergence of insect CYP6B proteins: From specialist to generalist cytochrome P450

Baudry

Berenbaum

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

256

221

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How polyphagous herbivores cope with the diversity and unpredictability of plant defenses remains largely unknown at both the genetic and molecular levels. To examine whether generalist counterdefense enzymes are structurally more flexible and functionally more diverse, two counterdefensive allelochemical-metabolizing cytochrome P450 proteins, CYP6B1 from the specialist Papilio polyxenes, feeding on furanocoumarin-containing plants, and CYP6B8 from the generalist Helicoverpa zea, feeding on hundreds of host plant species, are compared structurally and functionally. Molecular modeling indicates that CYP6B8 has more flexible overall folding, a more elastic catalytic pocket, and one more substrate access channel than CYP6B1. Baculovirus-mediated expression of the CYP6B8 and CYP6B1 proteins demonstrates that CYP6B8 metabolizes six biosynthetically diverse plant allelochemicals (xanthotoxin, quercetin, flavone, chlorogenic acid, indole-3-carbinol, and rutin) and three insecticides (diazinon, cypermethrin, and aldrin), whereas CYP6B1 metabolizes only two allelochemicals (xanthotoxin and flavone) and one insecticide (diazinon) of those tested. These results indicate that generalist counterdefense proteins are capable of accepting a more structurally diverse array of compounds compared with specialist counterdefense proteins. T he majority of herbivorous insects are oligophagous, i.e., specialized on a relatively narrow range of host plants (three or fewer plant families) (1, 2). Such specialization is thought to reduce competition for food from other herbivores and to lower predation͞parasitoid risk from generalist enemies (3). Because of the diversification of plant chemical defenses, however, this strategy may compromise a specialist's ability to make use of alternative food sources. A small proportion of insect herbivores, including some of the world's most important agricultural pests, are polyphagous, i.e., feed on a wide range of plant families. Although polyphagous species may have fewer limitations with respect to food availability, the toxicological challenge of generalized feeding is considerable in view of the tremendous diversity of plant defense compounds (allelochemicals). Because these compounds tend to be taxonomically limited in distribution, a polyphagous diet exposes an insect herbivore to a broad and unpredictable array of plant defenses. In fact, biochemical adaptation to a relatively narrow range of plant defense compounds may explain why the majority of herbivorous insects are specialists.How generalists cope with the diversity and unpredictability of plant defenses remains largely unknown at both the genetic and molecular levels. One possibility is that counterdefense genes of generalists have multiple functions; in the case of detoxificative genes such as cytochrome P450 monooxygenases (4), individual proteins from generalists may have a much wider substrate spectrum. Greater functional flexibility could in theory allow generalists to cope with the unpredictability of plant defense (1).Only a f...

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“…To predict whether DDT and/or carbaryl might be substrates for CYP6Z1 and CYP6Z2, these insecticides were docked within each predicted catalytic site by using DOCK function within MOE after attaching a singlet oxygen to the heme plane using parameter assignments specified by Rupasinghe et al (30). After their initial placement above the heme plane, docking simulations were run by using the MMFF94s force field (31)(32)(33)(34)(35)(36) and the simulated annealing conformation search method of the DOCK function.…”

Section: Docking Of Prospective Substrates Into the Cyp6z1 And Cyp6z2mentioning

confidence: 99%

Comparative molecular modeling of Anopheles gambiae CYP6Z1, a mosquito P450 capable of metabolizing DDT

Chiu

Wen

Rupasinghe

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

170

138

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One of the challenges faced in malarial control is the acquisition of insecticide resistance that has developed in mosquitoes that are vectors for this disease. Anopheles gambiae, which has been the major mosquito vector of the malaria parasite Plasmodium falciparum in Africa, has over the years developed resistance to insecticides including dieldrin, 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), and pyrethroids. Previous microarray studies using fragments of 230 An. gambiae genes identified five P450 loci, including CYP4C27, CYP4H15, CYP6Z1, CYP6Z2, and CYP12F1, that showed significantly higher expression in the DDT-resistant ZAN/U strain compared with the DDT-susceptible Kisumu strain. To predict whether either of the CYP6Z1 and CYP6Z2 proteins might potentially metabolize DDT, we generated and compared molecular models of these two proteins with and without DDT docked in their catalytic sites. This comparison indicated that, although these two CYP6Z proteins share high sequence identity, their metabolic profiles were likely to differ dramatically from the larger catalytic site of CYP6Z1, potentially involved in DDT metabolism, and the more constrained catalytic site of CYP6Z2, not likely to metabolize DDT. Heterologous expressions of these proteins have corroborated these predictions: only CYP6Z1 is capable of metabolizing DDT. Overlays of these models indicate that slight differences in the backbone of SRS1 and variations of side chains in SRS2 and SRS4 account for the significant differences in their catalytic site volumes and DDT-metabolic capacities. These data identify CYP6Z1 as one important target for inhibitor design aimed at inactivating insecticide-metabolizing P450s in natural populations of this malarial mosquito.cytochrome P450 monooxygenases ͉ insecticides ͉ plant allelochemicals I n 2004, the World Health Organization reported that up to 2.7 million people die of malaria every year with 80-90% of these deaths occurring in Africa (ref. 1 and www.africanfront.com/ AIDS1.php). Many prevention and treatment strategies have been developed to tackle this life-threatening disease from the side of the mosquito vector and that of the human host (2, 3). These range from antimalarial drugs to indoor spraying of insecticides and use of bed nets treated with pyrethroid insecticides. Although these practices have helped reduce human mortality, various issues have emerged with mosquito vectors developing insecticide resistance and parasites developing drug resistance. Both of these significantly reduce the efficacy of current malarial prevention and treatment practices (2, 4-8).The development of insecticide resistance in mosquito vectors is illustrated by Anopheles gambiae, which has been the major mosquito vector of the malaria parasite Plasmodium falciparum in Africa (4, 6). Throughout the years, people have reported Anopheles resistance (albeit low-level resistance) to various insecticides including dieldrin (a cyclodiene-type insecticide), 1,1-bis(pchlorophenyl)-2,2,2-trichloroethane (DDT), and pe...

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Common active site architecture and binding strategy of four phenylpropanoid P450s from Arabidopsis thaliana as revealed by molecular modeling

Cited by 60 publications

References 0 publications

A Histone Code Reader and a Transcriptional Activator Interact to Regulate Genes for Salt Tolerance

A Histone Code Reader and a Transcriptional Activator Interact to Regulate Genes for Salt Tolerance

Structural and functional divergence of insect CYP6B proteins: From specialist to generalist cytochrome P450

Comparative molecular modeling of Anopheles gambiae CYP6Z1, a mosquito P450 capable of metabolizing DDT

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