Canadian Forest Service Publications

Structural characterization of a lepidopteran type-II farnesyl diphosphate synthase from the spruce budworm, Choristoneura fumiferana: Implications for inhibitor design. 2018. Picard, M.-È.; Nisole, A.; Béliveau, C.; Sen, S.; Barbar, A.; Shi, R.; Cusson, M. Insect Biochem. Mol. Biol. 92: 84-92.

Year: 2018

Available from: Laurentian Forestry Centre

Catalog ID: 38984

Language: English

CFS Availability: PDF (request by e-mail)

Available from the Journal's Web site.
DOI: 10.1016/j.ibmb.2017.11.011

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Abstract

Farnesyl diphosphate synthase (FPPS) is an enzyme from the class of short chain (E)-prenyltransferases that catalyzes the condensation of two molecules of isopentenyl diphosphate (IPP, C5) with dimethylallyl diphosphate (DMAPP, C5) to generate the C15 product FPP. In insects, FPPS plays a key role in the biosynthesis of the morphogenetic and gonadotropic “juvenile hormone” (JH). Lepidopteran genomes encode two very distinct FPPS paralogs, one of which (“type-II”) is expressed almost exclusively in the JH-producing glands, the corpora allata. This paralog has been hypothesized to display structural features that enable the binding of the bulkier precursors required for the biosynthesis of lepidopteran ethyl-branched JHs. Here, we report on the first crystal structures of an insect FPPS solved to date. Apo, ligand-bound, and inhibitor-bound structures of type-II FPPS (FPPS2) from the spruce budworm, Choristoneura fumiferana (Order: Lepidoptera), were obtained. Comparison of apo and inhibitor-bound enzymes revealed differences in both inhibitor binding and structural plasticity of CfFPPS2 compared to other FPPSs. Our data showed that IPP is not essential to the closure of the C-terminal tail. Ortho-substituted pyridinium bisphosphonates, previously shown to inhibit CfFPPS2, bound to the allylic site, as predicted; however, their alkyl groups were oriented towards the homoallylic binding site, with the bulkier propyl-substituted inhibitor penetrating deeply into the IPP binding pocket. The current study sheds light on the structural basis of substrate specificity of type-II FPPS of the spruce budworm. Through a comparison with other inhibitor-bound FPPSs, we propose several approaches to improve inhibitor selectivity and potency.

Plain Language Summary

In this study, the researchers identified the three-dimensional structure of the type-II farnesyl diphosphate synthase (FPPS) enzyme for the first time in a moth. This enzyme plays a key role in juvenile hormone production in insects. Juvenile hormone production is essential for the development and reproduction of insects, making it an attractive target for the development of insecticides. The study of enzymes involved in the synthesis of this hormone is a major step in insect pest control, especially against the spruce budworm.

Funding programs

  • Genomics Research and Development Initiative
Structural characterization of a lepidopteran type-II farnesyl diphosphate synthase from the spruce budworm, _Choristoneura fumiferana_: Implications for inhibitor design
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