Farnesyl pyrophosphate synthase (FPPS)

Farnesyl pyrophosphate synthase (FPPS), also known as FDPS in humans, is a key homodimeric enzyme in the mevalonate pathway and isoprenoid biosynthesis. It catalyzes the sequential condensation of dimethylallyl pyrophosphate with two units of isopentenyl pyrophosphate to form farnesyl diphosphate (FPP). FPP is a crucial precursor for a wide variety of essential metabolites and lipids, including sterols, dolichols, carotenoids, ubiquinones (CoQ), sesquiterpenes, and serves as a substrate for protein prenylation (farnesylation and geranylgeranylation). FPPS activity is regulated, including by a negative feedback mechanism where FPP itself binds to an allosteric pocket. It is a well-established therapeutic target, particularly inhibited by nitrogen-containing bisphosphonates (N-BPs) used to treat conditions like Paget's disease and multiple myeloma characterized by excessive bone resorption. Inhibition of FPPS disrupts GTPase prenylation, affecting osteoclast function. Due to delivery challenges with N-BPs, non-bisphosphonate inhibitors are being explored, including for potential cancer therapy.

Other names

FDPS

Inhibition of FPPS reduces levels of farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), impairing the prenylation and intracellular localization of GTPase signaling proteins (such as Ras, Rho, Rac). This disrupts essential cellular processes, particularly in osteoclasts, affecting bone resorption, cell movement, cytoskeletal rearrangement, and apoptosis.