Farnesyl pyrophosphate synthase (FPPS) (FPPS)

Farnesyl pyrophosphate synthase (FPPS) is a key enzyme in the mevalonate pathway, responsible for the synthesis of farnesyl pyrophosphate, a precursor for cholesterol and essential isoprenoids (UniProt: P14324). In the skeletal system, FPPS is the primary molecular target for nitrogen-containing bisphosphonates, which are drugs characterized by a high affinity for bone hydroxyapatite (PubMed: 11460480). This mineral affinity allows the drugs to be deposited in the bone matrix and subsequently released and internalized by osteoclasts during bone resorption. Once inside the osteoclast, bisphosphonates potently inhibit FPPS, which prevents the post-translational prenylation of small GTP-binding proteins such as Rho, Rac, and Rab (StatPearls: Bisphosphonates). These proteins are crucial for maintaining the osteoclast's cytoskeleton, ruffled border, and overall survival. The resulting loss of function leads to osteoclast apoptosis and a significant reduction in bone turnover, making this target vital for treating osteoporosis, Paget's disease, and bone-related complications of cancer.

Other names

Farnesyl diphosphate synthaseFDPSGeranyltranstransferaseDimethylallyltranstransferaseBone hydroxyapatite-binding FPPS

Inhibition of farnesyl pyrophosphate synthase (FPPS) in osteoclasts following release from bone hydroxyapatite, which prevents the prenylation of small GTPases and leads to osteoclast apoptosis.