Farnesyl diphosphate synthase

Mevalonate kinase deficiency. Mevalonate kinase and farnesyl-diphosphate synthase are localized in the peroxisome and are involved in the synthesis of isoprenoids. Mevalonate kinase deficiency causes severe developmental delay, dysmorphic features and early death. Mevalonate deficiency has also been observed in the hyperimmuno-globulinemia-and periodic fever syndrome. 

Prenylation, the key step in terpene biosynthesis, is catalyzed by prenyltransferases. These enzymes are responsible for the condensation of isopentenyl pyrophosphate (IPP) with an allyl pyrophosphate, thus yielding isoprenoids. Numerous studies have been performed with fluorinated substrates in order to determine the mechanism of the reactions that involve these enzymes prenyltransferases, farnesyl diphosphate synthase (FDPSase), famesyltransferase (PFTase), and IPP isomerase. These studies are based on the potential ability of fluorine atoms to destabilize cationic intermediates, and then slow down S l type processes in these reactions. 

Fnjisaki, S., Hara, H., Nishimura, Y., Horiuchi, K., and Nishino, T. (1990). Cloning and nncleotide seqnence of the ispA gene responsible for farnesyl diphosphate synthase activity in Escherichia coli. J Biochem 108 995-1000. 

Bergstrom, J.D., Bostedor, R.G., Masarachia, P.J., Reszka, A.A., and Rodan, G. (2000). Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase. Arch Biochem Biophys 373 231-241. 

Dunford, J.E., Thompson, K., Coxon, F.P., Luckman, S.P., Hahn, F.M., Poulter, C.D., Ebetino, F.H., and Rogers, M.J. (2001). Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther 296 235-242. 

Levy, M.E., Parker, R.A., Ferrell, R.E., Zmuda, J.M., and Greenspan, S.L. (2007). Farnesyl diphosphate synthase a novel genoty pe association with bone mmeral density in elderly women. Maturitas 57 247-252. 

Huang, C.H., Gabelli, S.B., Oldfield, E., and Amzel, L.M. (2010). Binding of nitrogen-containing bisphosphonates (N-BPs) to the Trypanosoma cruzi farnesyl diphosphate synthase homodimer. Proteins 78 888-899. 

Delourme, D., Lacroute, F. and Karst, F. (1994) Cloning oi an Arabidopsis thaliana cDNA coding for farnesyl diphosphate synthase by functional complementation in yeast. Plant Mol. Biol, 26,1867-73. 

Joly, A. and Edwards, P.A. (1993) Effect of site-directed mutagenesis of conserved aspartate and arginine residues upon farnesyl diphosphate synthase activity. /. Biol. Chem., 268, 26983-9. 

Matsushita, Y., Kang, W. and Charlwood, B.V. (1996) Cloning and analysis of a cDNA encoding farnesyl diphosphate synthase from Artemisia annua. Gene, 172,207-9. 

To date over 30 plant terpenoid synthases have been cloned as cDNAs, and many of these were found to encode enzymes of secondary metabolism (43). Isolation and analysis of six genomic clones encoding monoterpene ((—)-pinene and (—)-limonene), sesquiterpene ((E)-a-bisabolene and S-selinene) and diterpene (abietadiene) synthases from Abies grandis, and a diterpene (taxadiene) synthase from Taxus brevifolia have been reported (44). Overexpression of a cotton farnesyl diphosphate synthase (EPPS) in transgenic Artemesia annua has resulted in 3- to 4-fold increase in the yield of the sesquiterpenoid anti-malarial drug, artemisinin, in hairy roots (45). 

Olmos JM, Zarrabeitia MT, Hernandez JL et al (2012) Common allelic variants of the farnesyl diphosphate synthase gene influence the response of osteoporotic women to bisphosphonates. Pharmacogenomics J 12 227-232... 

Shibuya et al. (1990) and Gebler and Poulter (1992) provided experimental support that DMAT synthase catalyzes an electrophilic aromatic substitution (Fig. 4) similar to that of other prenyl transferases such as farnesyl diphosphate synthase. A positively charged alkyl intermediate—an allyl carbocation—is... 

Another study with glandular trichomes from Ocimun basilicum, revealed that relative levels of GPPS and FPPS (farnesyl diphosphate synthase) activities did not correlate with the total amount of terpenes produced nonetheless, it showed some correlation with the ratio monoterpene/sequiterpene [324]. 

The same research group have reported a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS) by lipophilic bisphosphonates (538-539, 541, 547-549, 550-554). Nuclear magnetic... 

Thulasiram HV, Dale Poulter C. Farnesyl diphosphate synthase the art of compromise between substrate selectivity and stereoselectivity. J Am Chem Soc 2006 128 15819-23. 

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