No. 22 (1.Feb.2005)
FDPS - Human farnesyl diphosphate synthase in complex with risedronate
PDB Code: 1YQ7, 1YV5 (15.feb.2005)
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Description
A key branch point enzyme of the mevalonate pathway is farnesyl diphosphate synthase (FDPS, FPPS, EC 2.5.1.10 ), a Mg 2+ -dependent homodimeric enzyme, localized in peroxisomes. FDPS catalyzes the formation of both geranyl and farnesylpyrophosphate from isopentenylpyrophosphate and dimethylallyl pyrophosphate. Post-translational modification of C-terminal C AAX sequences by covalent attachment of these isoprenyl chains is crucial for intracellular localization and proper function of small GTPases such as Ras, Rac, Rho , and CDC42.
Interest in understanding FDPS activity stems from the recent discovery that FDPS is the molecular target of nitrogen-containing bisphosphonates. These compounds disrupt cell growth through FDPS inhibition in parasitic organisms in vitro. In humans, bisphosphonates are targeted to bone tissue where FDPS inhibition in bone-resorbing osteoclasts is a current therapeutic approach for treating post-menopausal osteoporosis. Because of their bone-targeting properties, bisphosphonates have also found use as agents to treat tumor-induced hypercalcemia, Paget's disease, and osteolytic metastases.