scholarly journals Maize cDNAs Expressed in Endosperm Encode Functional Farnesyl Diphosphate Synthase with Geranylgeranyl Diphosphate Synthase Activity

2006 ◽  
Vol 141 (1) ◽  
pp. 220-231 ◽  
Author(s):  
Miguel Cervantes-Cervantes ◽  
Cynthia E. Gallagher ◽  
Changfu Zhu ◽  
Eleanore T. Wurtzel
Keyword(s):  
Farnesyl Diphosphate ◽  
Farnesyl Diphosphate Synthase ◽  
Geranylgeranyl Diphosphate Synthase ◽  
Geranylgeranyl Diphosphate

scholarly journals Geranylgeranyl Diphosphate Synthase in Fission Yeast Is a Heteromer of Farnesyl Diphosphate Synthase (FPS), Fps1, and an FPS-like Protein, Spo9, Essential for Sporulation

2007 ◽  
Vol 18 (9) ◽  
pp. 3568-3581 ◽  
Author(s):  
Yanfang Ye ◽  
Makoto Fujii ◽  
Aiko Hirata ◽  
Makoto Kawamukai ◽  
Chikashi Shimoda ◽  
...  
Keyword(s):  
Membrane Vesicles ◽  
Farnesyl Diphosphate ◽  
Farnesyl Diphosphate Synthase ◽  
Temperature Sensitive ◽  
Deficient Mutant ◽  
Geranylgeranyl Diphosphate Synthase ◽  
Geranylgeranyl Diphosphate ◽  
Protein Prenylation ◽  
E Coli ◽  
Farnesylated Protein

Both farnesyl diphosphate synthase (FPS) and geranylgeranyl diphosphate synthase (GGPS) are key enzymes in the synthesis of various isoprenoid-containing compounds and proteins. Here, we describe two novel Schizosaccharomyces pombe genes, fps1+and spo9+, whose products are similar to FPS in primary structure, but whose functions differ from one another. Fps1 is essential for vegetative growth, whereas, a spo9 null mutant exhibits temperature-sensitive growth. Expression of fps1+, but not spo9+, suppresses the lethality of a Saccharomyces cerevisiae FPS-deficient mutant and also restores ubiquinone synthesis in an Escherichia coli ispA mutant, which lacks FPS activity, indicating that S. pombe Fps1 in fact functions as an FPS. In contrast to a typical FPS gene, no apparent GGPS homologues have been found in the S. pombe genome. Interestingly, although neither fps1+nor spo9+expression alone in E. coli confers clear GGPS activity, coexpression of both genes induces such activity. Moreover, the GGPS activity is significantly reduced in the spo9 mutant. In addition, the spo9 mutation perturbs the membrane association of a geranylgeranylated protein, but not that of a farnesylated protein. Yeast two-hybrid and coimmunoprecipitation analyses indicate that Fps1 and Spo9 physically interact. Thus, neither Fps1 nor Spo9 alone functions as a GGPS, but the two proteins together form a complex with GGPS activity. Because spo9 was originally identified as a sporulation-deficient mutant, we show here that expansion of the forespore membrane is severely inhibited in spo9Δ cells. Electron microscopy revealed significant accumulation membrane vesicles in spo9Δ cells. We suggest that lack of GGPS activity in a spo9 mutant results in impaired protein prenylation in certain proteins responsible for secretory function, thereby inhibiting forespore membrane formation.

scholarly journals Characterization of Potential Drug Targets Farnesyl Diphosphate Synthase and Geranylgeranyl Diphosphate Synthase in Schistosoma mansoni

2013 ◽  
Vol 57 (12) ◽  
pp. 5969-5976 ◽  
Author(s):  
Peter D. Ziniel ◽  
Janish Desai ◽  
Cynthia L. Cass ◽  
Craig Gatto ◽  
Eric Oldfield ◽  
...  
Keyword(s):  
Schistosoma Mansoni ◽  
Drug Targets ◽  
Protein Characterization ◽  
Farnesyl Diphosphate ◽  
Farnesyl Diphosphate Synthase ◽  
Potential Drug ◽  
Geranylgeranyl Diphosphate Synthase ◽  
Geranylgeranyl Diphosphate ◽  
Potential Drug Targets

ABSTRACTSchistosomiasis affects over 200 million people worldwide, with over 200,000 deaths annually. Currently, praziquantel is the only drug available against schistosomiasis. We report here thatSchistosoma mansonifarnesyl diphosphate synthase (SmFPPS) and geranylgeranyl diphosphate synthase (SmGGPPS) are potential drug targets for the treatment of schistosomiasis. We expressed active, recombinantSmFPPS andSmGGPPS for subsequent kinetic characterization and testing against a variety of bisphosphonate inhibitors. RecombinantSmFPPS was found to be a soluble 44.2-kDa protein, whileSmGGPPS was a soluble 38.3-kDa protein. Characterization of the substrate utilization of the two enzymes indicates that they have overlapping substrate specificities. AgainstSmFPPS, several bisphosphonates had 50% inhibitory concentrations (IC50s) in the low micromolar to nanomolar range; these inhibitors had significantly less activity againstSmGGPPS. Several lipophilic bisphosphonates were active againstex vivoadult worms, with worm death occurring over 4 to 6 days. These results indicate that FPPS and GGPPS could be of interest in the context of the emerging resistance to praziquantel in schistosomiasis therapy.

scholarly journals Conversion from Farnesyl Diphosphate Synthase to Geranylgeranyl Diphosphate Synthase by Random Chemical Mutagenesis

1996 ◽  
Vol 271 (17) ◽  
pp. 10087-10095 ◽  
Author(s):  
Shin-ichi Ohnuma ◽  
Takeshi Nakazawa ◽  
Hisashi Hemmi ◽  
Anna-Maria Hallberg ◽  
Tanetoshi Koyama ◽  
...  
Keyword(s):  
Farnesyl Diphosphate ◽  
Farnesyl Diphosphate Synthase ◽  
Chemical Mutagenesis ◽  
Geranylgeranyl Diphosphate Synthase ◽  
Geranylgeranyl Diphosphate

scholarly journals Synthesis of isoprenoid bisphosphonate ethers through C–P bond formations: Potential inhibitors of geranylgeranyl diphosphate synthase

2014 ◽  
Vol 10 ◽  
pp. 1645-1650 ◽  
Author(s):  
Xiang Zhou ◽  
Jacqueline E Reilly ◽  
Kathleen A Loerch ◽  
Raymond J Hohl ◽  
David F Wiemer
Keyword(s):  
Phosphonic Acid ◽  
Active Compound ◽  
Farnesyl Diphosphate ◽  
Farnesyl Diphosphate Synthase ◽  
Geranylgeranyl Diphosphate Synthase ◽  
Geranylgeranyl Diphosphate ◽  
Related Enzyme ◽  
Potential Inhibitors ◽  
New Compounds ◽  
Acid Salts

A set of bisphosphonate ethers has been prepared through sequential phosphonylation and alkylation of monophosphonate ethers. After formation of the corresponding phosphonic acid salts, these compounds were tested for their ability to inhibit the enzyme geranylgeranyl diphosphate synthase (GGDPS). Five of the new compounds show IC50 values of less than 1 μM against GGDPS with little to no activity against the related enzyme farnesyl diphosphate synthase (FDPS). The most active compound displayed an IC50 value of 82 nM when assayed with GGDPS, and no activity against FDPS even at a 10 μM concentration.

scholarly journals The balance of protein farnesylation and geranylgeranylation during the progression of nonalcoholic fatty liver disease

2020 ◽  
Vol 295 (15) ◽  
pp. 5152-5162
Author(s):  
Yue Zhao ◽  
Tian-Yu Wu ◽  
Meng-Fei Zhao ◽  
Chao-Jun Li
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Mevalonate Pathway ◽  
Farnesyl Diphosphate ◽  
Geranylgeranyl Diphosphate Synthase ◽  
Geranylgeranyl Diphosphate ◽  
Protein Prenylation ◽  
Nonalcoholic Fatty Liver

Protein prenylation is an essential posttranslational modification and includes protein farnesylation and geranylgeranylation using farnesyl diphosphate or geranylgeranyl diphosphate as substrates, respectively. Geranylgeranyl diphosphate synthase is a branch point enzyme in the mevalonate pathway that affects the ratio of farnesyl diphosphate to geranylgeranyl diphosphate. Abnormal geranylgeranyl diphosphate synthase expression and activity can therefore disrupt the balance of farnesylation and geranylgeranylation and alter the ratio between farnesylated and geranylgeranylated proteins. This change is associated with the progression of nonalcoholic fatty liver disease (NAFLD), a condition characterized by hepatic fat overload. Of note, differential accumulation of farnesylated and geranylgeranylated proteins has been associated with differential stages of NAFLD and NAFLD-associated liver fibrosis. In this review, we summarize key aspects of protein prenylation as well as advances that have uncovered the regulation of associated metabolic patterns and signaling pathways, such as Ras GTPase signaling, involved in NAFLD progression. Additionally, we discuss unique opportunities for targeting prenylation in NAFLD/hepatocellular carcinoma with agents such as statins and bisphosphonates to improve clinical outcomes.

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