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    • br Introduction Isoprenoid structures play

    2022-09-15


    Introduction Isoprenoid structures play an essential role in biology and over 30,000 natural products of this class are known (Greenhagen et al., 2003). Like other animals, insects require these compounds for many disparate processes, including electron transport (e.g., ubiquinones), protein glycosylation (e.g., dolichols), and membrane association (e.g., prenylated proteins). Isoprenoids are also used in certain unique insect processes, such as pheromone and hormone biosynthesis (e.g., faranal and juvenile hormone, JH). Construction of the terpene carbon backbone requires the coupling of isopentenyl diphosphate (IPP) to several variable sized allylic primers, as catalyzed by a group of enzymes known as isoprenyltransferases (Koyama and Ogura, 1999). The construction of the sesquiterpenoid farnesyl diphosphate (FPP) is catalyzed by the specific prenyltransferase, FPP synthase (FPPS). Because insects are unique in their inability to construct sterols from FPP (Clark, 1959; Santos and Lehmann, 2004a, Santos and Lehmann, 2004b), several steps in isoprenoid biogenesis appear to play a different role in insect metabolism. For example, the sterol regulatory binding protein (SREBP), which normally activates sterol biosynthetic genes in mammalian cells, is activated by phosphatidylethanolamine and is responsible for regulating fatty Spectinomycin hydrochloride hydrate biosynthesis in Drosophila melanogaster (Dobrosotskaya et al., 2002). The mode of FPPS binding and catalysis is derived from a combination of kinetic, site-directed mutagenesis (Kellogg and Poulter, 1997), and crystallographic studies. The structures of unliganded chicken FPPS and of a double mutant resolved in the presence of DMAPP, GPP and FPP, are known (Tarshis et al., 1994; Tarshis et al., 1996). Binding of the non-allylic substrate IPP has also been elucidated through analysis of the crystal structures of Staphylococcus aureus and Escherichia coli FPPSs (Hosfield et al., 2004), X-ray data for Trypanosoma cruzi FPPS (Gabelli et al., 2006), and for human FPPS (Gabelli et al., 2005; Rondeau et al., 2006) have been obtained, providing new insight into the mechanism of the prenyltransfer reaction. Analysis of the D. melanogaster (Dm) genome indicates that FPPS is a single copy gene, located on chromosome 2R (47F1) and comprised of 6 introns that span 2064bp (Fig. 1). A BLAST search of all known Dm ESTs and mRNAs indicates that this organism produces two transcripts, DmFPPS-1a (accession number AJ009963) and DmFPPS-1b (accession number NP_477380), the latter possessing an extension of 39 amino acids at its N-terminus (Fig. 1). Although vertebrate FPPS is believed to be localized in the peroxisomes (Krisans et al., 1994), this does not appear to be the case for Drosophila. Fusion of the DmFPPS-1b N-terminus to green fluorescent protein and subsequent expression in Dm and Spodoptera frugiperda (Sf) cells showed selective localization to the mitochondria, suggesting that this longer transcript encodes a mitochondrial FPPS (Belles et al., 2005; Martin et al., 2007). The functional role of DmFPPS can be inferred from recent complementation studies using the yeast mutant CC25, which has significantly impaired FPPS activity as a result of a single amino acid mutation (Blanchard and Karst, 1993). DmFPPS-1b was shown to fully complement the genetic defect, providing similar growth as that of the mutant grown in the presence of ergosterol (Cusson et al., 2006). Because of its central role in isoprenoid biosynthesis and unique genetics, DmFPPS is likely to be important for insect development. Indeed, Drosophila germ cell specialization and migration requires FPPS function, and several fpps mutations are lethal, presumably due to loss of protein prenylation ability (Santos and Lehmann, 2004a, Santos and Lehmann, 2004b; Milchanowski et al., 2004). In addition, FPP is a precursor to other important isoprenoids in Drosophila, including JH III, the corresponding bis-epoxide (JHB3) and the long chain isoprenoid, dolichol, which is necessary for the N-glycosylation of vitellogenin (Martin et al., 1996).