Genomes and Genes
Summary: An enzyme involved in the MEVALONATE pathway, it catalyses the synthesis of farnesyl diphosphate from isopentenyl diphosphate and dimethylallyl diphosphate.
- Hosfield D, Zhang Y, Dougan D, Broun A, Tari L, Swanson R, et al. Structural basis for bisphosphonate-mediated inhibition of isoprenoid biosynthesis. J Biol Chem. 2004;279:8526-9 pubmed..Together, these FPPS complexes provide a structural template for the design of novel inhibitors that may prove useful for the treatment of osteoporosis and other clinical indications including cancer. ..
- Thompson K, Rojas Navea J, Rogers M. Alkylamines cause Vgamma9Vdelta2 T-cell activation and proliferation by inhibiting the mevalonate pathway. Blood. 2006;107:651-4 pubmed
- Koyama T, Gotoh Y, Nishino T. Intersubunit location of the active site of farnesyl diphosphate synthase: reconstruction of active enzymes by hybrid-type heteromeric dimers of site-directed mutants. Biochemistry. 2000;39:463-9 pubmed..Commun. 212, 681-686], respectively. These results suggest that the subunits of the FPP synthase interact with each other to form a shared active site in the homodimer structure rather than an independent active site in each subunit. ..
- Grove J, Brown R, Watts D. The intracellular target for the antiresorptive aminobisphosphonate drugs in Dictyostelium discoideum is the enzyme farnesyl diphosphate synthase. J Bone Miner Res. 2000;15:971-81 pubmed..However, both mutant strains overproduce FDP synthase. It is concluded that FDP synthase is the intracellular target for the aBP drugs. ..
- Lee P, Mijts B, Schmidt Dannert C. Investigation of factors influencing production of the monocyclic carotenoid torulene in metabolically engineered Escherichia coli. Appl Microbiol Biotechnol. 2004;65:538-46 pubmed..Lycopene was efficiently converted into torulene during aerobic cultures, indicating that the engineered torulene synthesis pathway is well coordinated, and maintains the functionality and integrity of the carotenogenic enzyme complex. ..
- Thabet I, Guirimand G, Courdavault V, Papon N, Godet S, Dutilleul C, et al. The subcellular localization of periwinkle farnesyl diphosphate synthase provides insight into the role of peroxisome in isoprenoid biosynthesis. J Plant Physiol. 2011;168:2110-6 pubmed publisher..This finding is discussed in relation to the subcellular distribution of FPS isoforms in plants and animals and opens new perspectives towards the understanding of isoprenoid biosynthesis. ..
- Montalvetti A, Fernandez A, Sanders J, Ghosh S, Van Brussel E, Oldfield E, et al. Farnesyl pyrophosphate synthase is an essential enzyme in Trypanosoma brucei. In vitro RNA interference and in vivo inhibition studies. J Biol Chem. 2003;278:17075-83 pubmed..These results establish that FPPS is essential for parasite viability and validate this enzyme as a target for drug development. ..
- Sugden C, Roper J, Williams J. Engineered gene over-expression as a method of drug target identification. Biochem Biophys Res Commun. 2005;334:555-60 pubmed..This confirms FDP synthase as the primary target of aBPs and suggests a general method of drug target identification based upon engineered gene over-expression. ..
- Bergstrom J, Bostedor R, Masarachia P, Reszka A, Rodan G. Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase. Arch Biochem Biophys. 2000;373:231-41 pubmed
- Jahnke W, Rondeau J, Cotesta S, Marzinzik A, Pelle X, Geiser M, et al. Allosteric non-bisphosphonate FPPS inhibitors identified by fragment-based discovery. Nat Chem Biol. 2010;6:660-6 pubmed publisher..This allosteric and druggable pocket allows the development of a new generation of FPPS inhibitors that are optimized for direct antitumor effects in soft tissue. ..
- Krisans S, Ericsson J, Edwards P, Keller G. Farnesyl-diphosphate synthase is localized in peroxisomes. J Biol Chem. 1994;269:14165-9 pubmed
- Huang C, Gabelli S, Oldfield E, Amzel L. Binding of nitrogen-containing bisphosphonates (N-BPs) to the Trypanosoma cruzi farnesyl diphosphate synthase homodimer. Proteins. 2010;78:888-99 pubmed publisher..This mechanism of binding of N-BPs to TcFPPS is different to that reported for the binding of the same compounds to human FPPS. Proteins 2010. (c) 2009 Wiley-Liss, Inc. ..
- Sanders J, Song Y, Chan J, Zhang Y, Jennings S, Kosztowski T, et al. Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption. J Med Chem. 2005;48:2957-63 pubmed..As such, they represent useful new leads for the discovery of new bone resorption, antiinfective and anticancer drugs. ..
- Tarshis L, Proteau P, Kellogg B, Sacchettini J, Poulter C. Regulation of product chain length by isoprenyl diphosphate synthases. Proc Natl Acad Sci U S A. 1996;93:15018-23 pubmed..A model was constructed to show how the growth of a long chain prenyl product may proceed by creation of a hydrophobic passageway from the FPS active site to the outside surface of the enzyme. ..
- Yin F, Cao R, Goddard A, Zhang Y, Oldfield E. Enthalpy versus entropy-driven binding of bisphosphonates to farnesyl diphosphate synthase. J Am Chem Soc. 2006;128:3524-5 pubmed
- Li C, Larkins B. Identification of a maize endosperm-specific cDNA encoding farnesyl pyrophosphate synthetase. Gene. 1996;171:193-6 pubmed..Southern blot analysis indicated that there are at least two FPS gene copies in the maize genome. The cloned FPS is expressed preferentially in maize endosperm and is up-regulated in the endosperm mutants, o2 and fl2. ..
- Hemmerlin A, Rivera S, Erickson H, Poulter C. Enzymes encoded by the farnesyl diphosphate synthase gene family in the Big Sagebrush Artemisia tridentata ssp. spiciformis. J Biol Chem. 2003;278:32132-40 pubmed..Specific cellular functions are proposed for each of the three enzymes, and a scenario for evolution of isoprenyl synthases in plants is presented. ..
- Sen S, Trobaugh C, Béliveau C, Richard T, Cusson M. Cloning, expression and characterization of a dipteran farnesyl diphosphate synthase. Insect Biochem Mol Biol. 2007;37:1198-206 pubmed..Although DmFPPS-1b does not efficiently couple homologous GPP compounds, homodimethylallyl diphosphate (HDMAPP), which is precursor to all homologous JH structures, was a reactive substrate. ..
- Manzano D, Fernàndez Busquets X, Schaller H, Gonzalez V, Boronat A, Arró M, et al. The metabolic imbalance underlying lesion formation in Arabidopsis thaliana overexpressing farnesyl diphosphate synthase (isoform 1S) leads to oxidative stress and is triggered by the developmental decline of endogenous HMGR activity. Planta. 2004;219:982-92 pubmed
- Coxon F, Thompson K, Rogers M. Recent advances in understanding the mechanism of action of bisphosphonates. Curr Opin Pharmacol. 2006;6:307-12 pubmed..In addition, the identification of BP analogues that inhibit different enzymes in the mevalonate pathway could lead to the development of novel inhibitors of bone resorption with potential applications in the treatment of bone disease. ..
- Durrant J, Cao R, Gorfe A, Zhu W, Li J, Sankovsky A, et al. Non-bisphosphonate inhibitors of isoprenoid biosynthesis identified via computer-aided drug design. Chem Biol Drug Des. 2011;78:323-32 pubmed publisher..These results are of interest because farnesyl diphosphate synthase inhibitors are being pursued as both anti-infective and anticancer agents, and undecaprenyl diphosphate synthase inhibitors are antibacterial drug leads. ..
- Mao J, Mukherjee S, Zhang Y, Cao R, Sanders J, Song Y, et al. Solid-state NMR, crystallographic, and computational investigation of bisphosphonates and farnesyl diphosphate synthase-bisphosphonate complexes. J Am Chem Soc. 2006;128:14485-97 pubmed
- Tarshis L, Yan M, Poulter C, Sacchettini J. Crystal structure of recombinant farnesyl diphosphate synthase at 2.6-A resolution. Biochemistry. 1994;33:10871-7 pubmed..The location and metal ion binding properties of these sequences suggest that the conserved aspartate residues participate in substrate binding of catalysis. ..
- Mekkriengkrai D, Sando T, Hirooka K, Sakdapipanich J, Tanaka Y, Fukusaki E, et al. Cloning and characterization of farnesyl diphosphate synthase from the rubber-producing mushroom Lactarius chrysorrheus. Biosci Biotechnol Biochem. 2004;68:2360-8 pubmed..The purified obtained protein showed FPS activity in which geranyl diphosphate (GPP) served as primary substrate, with a 2.4-fold higher k(cat)/K(m) value for GPP than for dimethylallyl diphosphate (DMAPP). ..
- Gupta S, Mehan R, Tansey T, Chen H, Goping G, Goldberg I, et al. Differential binding of proteins to peroxisomes in rat hepatoma cells: unique association of enzymes involved in isoprenoid metabolism. J Lipid Res. 1999;40:1572-84 pubmed..Based on these observations, the significance and a possible regulatory model in the formation of isoprenoid end-products are discussed. ..
- Lin Y, Park J, De Schutter J, Huang X, Berghuis A, Sebag M, et al. Design and synthesis of active site inhibitors of the human farnesyl pyrophosphate synthase: apoptosis and inhibition of ERK phosphorylation in multiple myeloma cells. J Med Chem. 2012;55:3201-15 pubmed publisher..An analogue of this series was used to demonstrate inhibition of the intended biological target, resulting in apoptosis and down-regulation of ERK phosphorylation in human MM cell lines. ..
- Szkopinska A, Płochocka D. Farnesyl diphosphate synthase; regulation of product specificity. Acta Biochim Pol. 2005;52:45-55 pubmed..FPPS belongs to enzymes encoded by gene families. In plants this offers the possibility of differential regulation in response to environmental changes or to herbivore or pathogen attack. ..
- Martin D, Piulachs M, Cunillera N, Ferrer A, Belles X. Mitochondrial targeting of farnesyl diphosphate synthase is a widespread phenomenon in eukaryotes. Biochim Biophys Acta. 2007;1773:419-26 pubmed..Taken together, these data suggest that mitochondrial targeting of FPS may be widespread among eukaryotes. ..
- Kovacs W, Tape K, Shackelford J, Duan X, Kasumov T, Kelleher J, et al. Localization of the pre-squalene segment of the isoprenoid biosynthetic pathway in mammalian peroxisomes. Histochem Cell Biol. 2007;127:273-90 pubmed
- Leon A, Liu L, Yang Y, Hudock M, Hall P, Yin F, et al. Isoprenoid biosynthesis as a drug target: bisphosphonate inhibition of Escherichia coli K12 growth and synergistic effects of fosmidomycin. J Med Chem. 2006;49:7331-41 pubmed
- Sanchez V, Crespo A, Gutkind J, Turjanski A. Investigation of the catalytic mechanism of farnesyl pyrophosphate synthase by computer simulation. J Phys Chem B. 2006;110:18052-7 pubmed
- De Schutter J, Shaw J, Lin Y, Tsantrizos Y. Design of potent bisphosphonate inhibitors of the human farnesyl pyrophosphate synthase via targeted interactions with the active site 'capping' phenyls. Bioorg Med Chem. 2012;20:5583-91 pubmed publisher..These novel analogs were designed to bind deeper into the GPP sub-pocket by displacing the side chains of the 'capping' residue Phe 113 and engaging in favorable ?-interactions with the side chain of Phe112. ..
- Kavanagh K, Guo K, Dunford J, Wu X, Knapp S, Ebetino F, et al. The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Proc Natl Acad Sci U S A. 2006;103:7829-34 pubmed..These experiments reveal the molecular binding characteristics of an important pharmacological target and provide a route for further optimization of these important drugs. ..
- Manzano D, Busquets A, Closa M, Hoyerova K, Schaller H, Kaminek M, et al. Overexpression of farnesyl diphosphate synthase in Arabidopsis mitochondria triggers light-dependent lesion formation and alters cytokinin homeostasis. Plant Mol Biol. 2006;61:195-213 pubmed
- Masferrer A, Arró M, Manzano D, Schaller H, Fernàndez Busquets X, Moncaleán P, et al. Overexpression of Arabidopsis thaliana farnesyl diphosphate synthase (FPS1S) in transgenic Arabidopsis induces a cell death/senescence-like response and reduced cytokinin levels. Plant J. 2002;30:123-32 pubmed..The finding that wild-type and transgenic plants accumulated similar increased amounts of sterols when grown in the presence of exogenous MVA suggests that FPS1S is not limiting for sterol biosynthesis. ..
- Dunford J, Thompson K, Coxon F, Luckman S, Hahn F, Poulter C, et al. 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. 2001;296:235-42 pubmed
- Thulasiram H, Erickson H, Poulter C. Chimeras of two isoprenoid synthases catalyze all four coupling reactions in isoprenoid biosynthesis. Science. 2007;316:73-6 pubmed..Stereochemical and mechanistic considerations suggest that the four coupling enzymes could have evolved from a common ancestor through relatively small changes in the catalytic site. ..
- Cunillera N, Arró M, Delourme D, Karst F, Boronat A, Ferrer A. Arabidopsis thaliana contains two differentially expressed farnesyl-diphosphate synthase genes. J Biol Chem. 1996;271:7774-80 pubmed..The significance of the occurrence of different FPS isoforms in plants is discussed in the context of the complex organization of the plant isoprenoid pathway. ..
- Kimmel D. Mechanism of action, pharmacokinetic and pharmacodynamic profile, and clinical applications of nitrogen-containing bisphosphonates. J Dent Res. 2007;86:1022-33 pubmed
- Albertsen L, Chen Y, Bach L, Rattleff S, Maury J, Brix S, et al. Diversion of flux toward sesquiterpene production in Saccharomyces cerevisiae by fusion of host and heterologous enzymes. Appl Environ Microbiol. 2011;77:1033-40 pubmed publisher..This simple test case of synthetic biology demonstrates that engineering the spatial organization of metabolic enzymes around a branch point has great potential for diverting flux toward a desired product. ..
- Ogawa T, Yoshimura T, Hemmi H. Connected cavity structure enables prenyl elongation across the dimer interface in mutated geranylfarnesyl diphosphate synthase from Methanosarcina mazei. Biochem Biophys Res Commun. 2011;409:333-7 pubmed publisher..In particular, replacement of isoleucine 112 on the ?-helix greatly elongated the product chain-length, probably by connecting the reaction cavities of two subunits across the dimer interface. ..
- Beattie J, Nicol F, Gordon M, Reid M, Cantlay L, Horgan G, et al. Ginger phytochemicals mitigate the obesogenic effects of a high-fat diet in mice: a proteomic and biomarker network analysis. Mol Nutr Food Res. 2011;55 Suppl 2:S203-13 pubmed publisher..05) increased by consumption of phytochemical-supplemented diets. Dietary ginger phytochemicals target cholesterol metabolism and fatty acid oxidation in mice, with anti-obesogenic but also hypercholesterolemic consequences. ..
- Gu W, Wu Q, Chao J, Xi B, Li L, Shen X. [Molecular cloning of farnesyl pyrophosphate synthase from Alisma orientale (Sam.) Juzep. and its distribution pattern and bioinformatics analysis]. Yao Xue Xue Bao. 2011;46:605-12 pubmed..It can be primarily deduced that FPPS gene should be an important control point in the synthetic pathway of Alisma terpenes. This study may facilitate the quality of medicinal plants through gene engineering in the future. ..
- Fujisaki S, Hara H, Nishimura Y, Horiuchi K, Nishino T. Cloning and nucleotide sequence of the ispA gene responsible for farnesyl diphosphate synthase activity in Escherichia coli. J Biochem. 1990;108:995-1000 pubmed..The maxicell analysis indicated that a protein of molecular weight 36,000, approximately consistent with the molecular weight of the deduced ORF-2-encoded protein, is the gene product. ..
- Yang J, Zhu H, Chen G, Ye Y, Zhao C, Mou Y, et al. Inhibition of farnesyl pyrophosphate synthase attenuates angiotensin II-induced cardiac hypertrophy and fibrosis in vivo. Int J Biochem Cell Biol. 2013;45:657-66 pubmed publisher..In conclusion, FPPS might play an important role in Ang II-induced cardiac hypertrophy and fibrosis in vivo, at least in part through RhoA, p-38 MAPK and TGF-?1. ..
- Mörck C, Olsen L, Kurth C, Persson A, Storm N, Svensson E, et al. Statins inhibit protein lipidation and induce the unfolded protein response in the non-sterol producing nematode Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2009;106:18285-90 pubmed publisher..2 substrates, resulting in developmental arrest in C. elegans. These results provide a mechanism for the pleiotropic effects of statins and suggest that statins could be used clinically where UPR activation may be of therapeutic benefit. ..
- Kinjoh T, Kaneko Y, Itoyama K, Mita K, Hiruma K, Shinoda T. Control of juvenile hormone biosynthesis in Bombyx mori: cloning of the enzymes in the mevalonate pathway and assessment of their developmental expression in the corpora allata. Insect Biochem Mol Biol. 2007;37:808-18 pubmed..Altogether, our results point to a relationship between JH biosynthesis and expression of most JH biosynthetic enzymes in the CA. ..
- Scholte A, Vederas J. Incorporation of deuterium-labelled analogs of isopentenyl diphosphate for the elucidation of the stereochemistry of rubber biosynthesis. Org Biomol Chem. 2006;4:730-42 pubmed..Results indicate that rubber chain elongation occurs with loss of the pro-S hydrogen of IPP, addition of the allylic diphosphate to the si face of IPP and inversion of stereochemistry at the carbon bearing the diphosphate. ..
- Tomoo T, Suzuki M. [Preclinical and clinical profile of zoledronic acid (Zometa) for hypercalcemia of malignancy]. Nihon Yakurigaku Zasshi. 2005;126:353-7 pubmed
- Szkopinska A, Swiezewska E, Skoneczny M. A novel family of longer chain length dolichols present in oleate-induced yeast Saccharomyces cerevisiae. Biochimie. 2001;83:427-32 pubmed
- Spear D, Kutsunai S, Correll C, Edwards P. Molecular cloning and promoter analysis of the rat liver farnesyl diphosphate synthase gene. J Biol Chem. 1992;267:14462-9 pubmed..These results suggest that the FPP synthase gene may be regulated at the transcriptional level by a different mechanism than other sterol regulated genes. ..
- Notarnicola M, Messa C, Cavallini A, Bifulco M, Tecce M, Eletto D, et al. Higher farnesyl diphosphate synthase activity in human colorectal cancer inhibition of cellular apoptosis. Oncology. 2004;67:351-8 pubmed..This study provides the first evidence of the presence of FPPs activity in human CRC. Moreover, FPPs enzyme was found to play a significant role in colon cancer proliferation. ..
- Mao J, Gao Y, Odeh S, Robinson H, Montalvetti A, Docampo R, et al. Crystallization and preliminary X-ray diffraction study of the farnesyl diphosphate synthase from Trypanosoma brucei. Acta Crystallogr D Biol Crystallogr. 2004;60:1863-6 pubmed..3 A resolution. It shows mostly helical structure and resembles the structure of avian farnesyl diphosphate synthase, but with the addition of two loop regions. ..
- Szajnman S, Montalvetti A, Wang Y, Docampo R, Rodriguez J. Bisphosphonates derived from fatty acids are potent inhibitors of Trypanosoma cruzi farnesyl pyrophosphate synthase. Bioorg Med Chem Lett. 2003;13:3231-5 pubmed..As bisphosphonates are FDA clinically approved for treatment of bone resorption disorders, their potential innocuousness makes them good candidates to control tropical diseases. ..
- Heemers H, Vanderhoydonc F, Roskams T, Shechter I, Heyns W, Verhoeven G, et al. Androgens stimulate coordinated lipogenic gene expression in normal target tissues in vivo. Mol Cell Endocrinol. 2003;205:21-31 pubmed..Taken together, these findings provide evidence for a coordinate regulation of lipogenic gene expression not only in prostate cancer cell lines in culture but also in non-cancerous androgen-responsive tissues in vivo. ..
- Zhu J, Khalil S, Mitchell R, Bissinger B, Egekwu N, Sonenshine D, et al. Mevalonate-Farnesal Biosynthesis in Ticks: Comparative Synganglion Transcriptomics and a New Perspective. PLoS ONE. 2016;11:e0141084 pubmed publisher..scapularis genome, the only tick genome available. These data suggest that ticks do not synthesize JH III but have the mevalonate pathway and may produce a JH III precursor. ..