Reactome | holo-FDPS dimer binds NBPs

holo-FDPS dimer binds NBPs

Stable Identifier

R-HSA-9717841

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol

Synonyms

holo-FDPS dimer binds FDPS inhibitors

ReviewStatus

5/5

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The mevalonate pathway is responsible for the biosynthesis of all isoprenoids, metabolites that are vital for normal cellular functions. Two key isoprenoids, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are responsible for the post-translational prenylation of small GTP-binding proteins, and serve as the biosynthetic precursors to numerous other biomolecules. The downstream metabolite of FPP and GGPP is squalene, the precursor to steroids, bile acids, lipoproteins, and vitamin D.

Nitrogen-containing bisphosphonates (NBPs) are drugs used to treat diseases characterized by excessive bone resorption such as Paget's disease of bone, bone metastases, multiple myeloma (Simoni et al. 2008), and osteoporosis. NBPs act by inhibiting farnesyl pyrophosphate synthase (FDPS) involved in the mevalonate pathway (Bergstrom et al. 2000, Dunford et al. 2001, Dunford et al. 2008, Räikkönen et al. 2011). Inhibition of FDPS in osteoclasts prevents the biosynthesis of the isoprenoid lipids FPP and GGPP, which are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. Loss of bone-resorptive activity and osteoclast apoptosis is primarily due to the loss of geranylgeranylated small GTPases (Review - Cremers et al. 2019). Approved NBPs include the second generation NBPs pamidronic acid and alendronic acid and the third generation NBPs ibandronic acid, zoledronic acid, minodronic acid and risedronate.

Literature References

PubMed ID	Title	Journal	Year
11160603	Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates Luckman, SP, Dunford, JE, Ebetino, FH, Thompson, K, Poulter, CD, Rogers, MJ, Hahn, FM, Coxon, FP	J. Pharmacol. Exp. Ther.	2001
18327899	Structure-activity relationships among the nitrogen containing bisphosphonates in clinical use and other analogues: time-dependent inhibition of human farnesyl pyrophosphate synthase Russell, RG, Kwaasi, AA, Barnett, BL, Dunford, JE, Oppermann, U, Rogers, MJ, Kavanagh, KL, Ebetino, FH	J. Med. Chem.	2008
18937434	Design, synthesis, and biological evaluation of novel aminobisphosphonates possessing an in vivo antitumor activity through a gammadelta-T lymphocytes-mediated activation mechanism Provera, S, Limongelli, V, Dieli, F, Kwaasi, A, Invidiata, FP, Marchioro, C, Baruchello, R, Gebbia, N, Caccamo, N, Novellino, E, Buccheri, S, Marinelli, L, Dunford, J, Simoni, D, Eleopra, M, Tolomeo, M, Marchetti, P, Rondanin, R	J. Med. Chem.	2008
20394422	Synthesis, chiral high performance liquid chromatographic resolution and enantiospecific activity of a potent new geranylgeranyl transferase inhibitor, 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid Kirsten, ML, Dunford, JE, Baron, RA, McKenna, CE, Ebetino, FH, Stewart, CA, Marma, MS, Seabra, MC, Bala, JL, Lundy, MW, Kashemirov, BA, Rogers, MJ, Mallard-Favier, I, Coxon, FP, Rojas, J, Błazewska, KM	J Med Chem	2010
21420384	Correlation between time-dependent inhibition of human farnesyl pyrophosphate synthase and blockade of mevalonate pathway by nitrogen-containing bisphosphonates in cultured cells Räikkönen, J, Mönkkönen, H, Dunford, JE, Mönkkönen, J, Taskinen, M, Auriola, S	Biochem Biophys Res Commun	2011
10620343	Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase Reszka, AA, Rodan, G, Bostedor, RG, Masarachia, PJ, Bergstrom, JD	Arch. Biochem. Biophys.	2000