SREBP1A/1C/2 (SREBF1A/1C/2), together with NF-Y, bind and transactivate the promoter of the FDPS gene (Ericsson et al. 1996, Pai et al. 1998, Amemiya-Kudo et al. 2002, Reed et al. 2008, Rome et al. 2008, Ishimoto et al. 2010). The binding of NF-Y synergistically enhances the binding of SREBP1 (Ericsson et al. 1996). SREBP1A activates FDPS more strongly than does SREBP2 or SREBP1C (Amemiya-Kudo et al. 2002).
Further condensation of an isopentenyl pyrophosphate (IPPP) with geranyl pyrophosphate (GPP) to form farnesyl pyrophosphate (FAPP) is catalyzed by the prenyltransferases FPP synthase and GGPP synthase (Kavanagh et al, 2006).
The family of enzymes called prenyltransferases is involved in the biosynthesis of isoprenoids. Two members of this family are known to catalyse the sequential condensation of isopentenyl pyrophosphate (IPPP) to DMAPP: farnesyl pyrophosphate synthase dimer (FPPS dimer) and geranylgeranyl pyrophosphate synthetase hexamer (GGPPS hexamer) (Kavanaugh et al, 2006). Both enzymes utlise Mg2+ as cofactor (Chang et al. 2021).
The FDPS gene is transcribed to yield mRNA and the mRNA is translated to yield protein. SREBF1A/1C/2 (SREBP1A/1C/2) and NF-Y bind the promoter of the Farnesyl Diphosphate Synthase (FDPS) gene and activate transcription (Ericsson et al. 1996, Jackson et al. 1996, Horton et al. 1998, Pai et al. 1998, Sakakura 2001, Amemiya-Kudo et al. 2002, Reed et al. 2008, Ishimoto et al. 2010, reviewed in Horton et al. 2002).
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.