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  • Much is known about FPPS structure and function with over

    2022-06-24

    Much is known about FPPS structure and function, with over 120 FPPS crystal structures being currently available. This wealth of information is largely the consequence of human FPPS serving as a drug target for the treatment and/or prevention of pathologies such as osteoporosis, hypercalcemia and Paget's disease, and more recently for the treatment of certain cancers. In addition, FPPS from several human parasites are being investigated as targets of inhibitors that could prevent the survival of organisms such as Trypanosoma cruzi, the causal agent for Chagas disease (Gabelli et al., 2006). FPPS inhibition is most commonly achieved using bisphosphonates (BPs). The structure of these compounds is characterized by the presence of a central carbon bound to two phosphonate [PO(OH)2] or phosphonate ester [PO(OR)2] groups. The bisphosphonate moiety is designed to mimic the diphosphate group found in natural FPPS substrates, where the central oxygen monobenzone sale is replaced by a carbon to provide chemical stability towards diphosphate hydrolysis. Many BPs have been synthesized and evaluated in clinical trials for the treatment of specific medical conditions. BPs tested for FPPS inhibition usually contain a basic nitrogen atom that is protonated under physiological conditions or is alkylated to mimic the putative allylic carbocation intermediate formed during the rate-determining step (Martin et al., 1999). Sen et al. (2015) synthesized and tested a series of compounds aimed at disrupting insect growth and metabolism through the inhibition of isoprenoid biosynthesis. BPs were chosen as the core structure so as to enhance selectivity towards FPPS. Because homologous allylic substrates such as HDMAPP and bis-homogeranyl diphosphate (BHGPP, precursor to JH0 and JH1) contain C-3 alkyl substituents that are larger than in DMAPP and GPP, and because C-3 alkyl analogs of DMAPP were shown to be readily accommodated by the prenyltransferase of M. sexta CA (Sen et al., 2006), it was hypothesized that appropriately N-alkylated BPs would provide selective binding to the C-3 binding region of lepidopteran FPPS2. After docking potential structures into the active site of a homology model of spruce budworm (Choristoneura fumiferana) FPPS2 ligated to HBGPP, a series of N-alkylated ortho-substituted pyridinium bisphosphonates (PyrBPs) were chosen as candidates for selective inhibition of FPPS2. The inhibitory effect of these N-alkylated PyrBPs (1c-1e, Fig. 2) on the coupling of GPP to IPP by pig liver, fly and moth FPPSs, was shown to be more selective towards the lepidopteran protein. These results are consistent with the notion that there is greater steric latitude in the active site of lepidopteran FPPS (Sen et al., 2015). Here, we report on the crystal structure of type-II FPPS from C. fumiferana (CfFPPS2), in its apo form, as well as in a binary or ternary complex with two PyrBP inhibitors.
    Material and methods
    Results and discussion
    Conclusions We present here the first structural study of a lepidopteran type II FPPS. Close examination of several CfFPPS2 structures, including apo and ligand-bound structures containing ortho-substituted inhibitors and IPP, reveal subtle differences from other FPPSs. In contrast to our docking-based predictions (Sen et al., 2015), the ortho-substituted inhibitors bound to the allylic site in an orientation that positioned their alkyl groups towards the homoallylic binding site, with the bulkier N-propyl 1d occupying a portion of the IPP binding pocket, thereby precluding IPP binding. Unlike most other FPPSs, IPP is not required for the final rigidification and closure of the C-terminal tail of CfFPPS2. A comparison of the insect and human proteins has provided insight into the structural determinants conferring unique substrate specificity to CfFPPS2, with residues that are −3 and −4 to the FARM being important for homologous substrate binding. Collectively, this work provides novel insights into the structure and inhibition of lepidopteran type II FPPS and provides new strategies for inhibitor design.