Farnesyl diphosphate synthase (FPPS) is a short chain (E)-prenyltransferase that catalyzes the condensation of two molecules of isopentenyl diphosphate (IPP) with dimethylallyl diphosphate to generate the C15 product FPP. In insects, FPPS plays a key role in the biosynthesis of juvenile hormone (JH), and in lepidopteran insects, a type-II FPPS (FPPS2) is responsible for the biosynthesis of homologous JH structures. Here, we present crystal structures of apo, ligand-, and inhibitor-bound structures of FPPS2 from the spruce budworm, Choristoneura fumiferana (Order: Lepidoptera). 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, a selective inhibitor of CfFPPS2, penetrating deeply into the IPP binding pocket. These results suggest a new approach for the design of selective anti-JH agents, as inhibition of enzymes involved in JH biosynthesis (such as FPPS) can have a profound impact on insect maturation and viability. Active site analysis of CfFPPS2 was conducted along with a comparison to other inhibitor-bound FPPSs, from which we propose several approaches to improve FPPS2 inhibitor selectivity and potency. The results of these studies will be presented.

Design of selective anti-juvenile hormone agents based on the structural analysis of apo, ligand-, and inhibitor-bound type II FPPS of the spruce budworm

256th National Meeting (2018)

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