Farnesyl diphosphate synthase (FDPS)

Farnesyl diphosphate synthase (FDPS) is a key enzyme in the mevalonate pathway, responsible for the synthesis of farnesyl diphosphate (FPP) from geranyl diphosphate and isopentenyl diphosphate (UniProt P14324). In the context of bone pharmacology, FDPS is the primary molecular target of nitrogen-containing bisphosphonates (N-BPs). These drugs possess a high affinity for hydroxyapatite, the mineral component of bone, which facilitates their accumulation at sites of high bone turnover (Russell, 2011). Once osteoclasts begin resorbing the bone, the acidic environment releases the bisphosphonates, which are then internalized by the osteoclasts via fluid-phase endocytosis. Inside the cell, N-BPs potently inhibit FDPS, leading to a depletion of isoprenoid pools required for the prenylation of small GTPases like Rho, Rac, and Rab. This loss of prenylation disrupts essential cellular processes, including cytoskeletal organization and vesicular trafficking, ultimately inducing osteoclast apoptosis and reducing bone resorption (StatPearls, 2023).

Other names

Farnesyl pyrophosphate synthaseFPPSGeranyltranstransferaseDimethylallyltranstransferase

Nitrogen-containing bisphosphonates target farnesyl diphosphate synthase (FDPS) through a two-step mechanism: first, they bind to hydroxyapatite in the bone mineral matrix at sites of active remodeling; second, they are internalized by osteoclasts where they competitively inhibit FDPS (Drake et al., 2008). This inhibition prevents the formation of farnesyl diphosphate and geranylgeranyl diphosphate, which are necessary for the post-translational lipid modification (prenylation) of small GTP-binding proteins. The absence of these prenylated proteins leads to the inactivation of osteoclasts and their subsequent programmed cell death, thereby slowing the rate of bone loss in diseases such as osteoporosis and Paget's disease (PubMed: 21660592).