Farnesyl diphosphate synthase (FDPS) (FDPS)

Farnesyl diphosphate synthase (FDPS) is a central enzyme in the mevalonate pathway, catalyzing the production of farnesyl pyrophosphate (FPP), a 15-carbon isoprenoid [1, 4]. FPP serves as a critical intermediate for the production of cholesterol, steroid hormones, and ubiquinone, and is a substrate for protein farnesylation [1, 7]. Related prenyltransferases, such as geranylgeranyl diphosphate synthase (GGPS1) and protein prenyltransferases (FTase and GGTases), further extend these isoprenoid chains to support protein geranylgeranylation [6, 10]. FDPS is the primary molecular target of nitrogen-containing bisphosphonates, which are widely used to treat bone-resorption disorders like osteoporosis and Paget's disease [3, 8, 9]. By inhibiting FDPS, these drugs prevent the prenylation of small GTPases in osteoclasts, leading to their apoptosis and a subsequent decrease in bone loss [11, 13]. Beyond bone health, FDPS is increasingly recognized for its role in cancer progression and as a potential target for anti-tumor and anti-parasitic therapies [3, 4, 7].

Other names

Farnesyl pyrophosphate synthaseFPPSFPSFPP synthaseFPP synthetaseFarnesyl pyrophosphate synthetaseDimethylallyltranstransferaseGeranyltranstransferase

Nitrogen-containing bisphosphonates (NBPs) act as potent inhibitors of farnesyl diphosphate synthase (FDPS). By binding to the enzyme's active site, they prevent the condensation of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) into farnesyl pyrophosphate (FPP). This inhibition leads to a deficiency of FPP and its downstream product, geranylgeranyl pyrophosphate (GGPP), which are essential for the post-translational prenylation of small GTPases like Ras, Rho, and Rab. In osteoclasts, the lack of prenylated proteins disrupts essential signaling pathways and the cytoskeleton, ultimately triggering apoptosis and inhibiting bone resorption [1, 8, 11, 13].