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https://www.readbyqxmd.com/read/28918530/exogenous-and-endogenous-increase-in-fungal-ggpp-increased-fungal-taxol-production
#1
Sameh S M Soliman, Kareem A Mosa, Ali A El-Keblawy, Mohamed I Husseiny
Taxol is an anticancer identified in both endophytic fungus and its host plant. Plant Taxol is a diterpenoid with geranylgeranyl diphosphate (GGPP) mediates the biosynthesis of its terpenoid moiety. Previous report has suggested that fungal Taxol may require terpenoid pathway for its biosynthesis. Here in this study, feeding a Taxol-producing endophytic fungus (Paraconiothyrium SSM001) with terpenoid precursors including isopentenyl pyrophosphate (IPP, isoprene) and GGPP enhanced Taxol production threefold and fivefold, respectively, compared to the control...
September 16, 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28916945/simvastatin-enhances-radiation-sensitivity-of-colorectal-cancer-cells
#2
Georgios Karagkounis, Jennifer DeVecchio, Sylvain Ferrandon, Matthew F Kalady
INTRODUCTION: Neoadjuvant chemoradiation (CRT) for rectal cancer induces variable responses, and better response has been associated with improved oncologic outcomes. Our group has previously shown that the administration of HMG-CoA reductase inhibitors, commonly known as statins, is associated with improved response to neoadjuvant CRT in rectal cancer patients. The purpose of this study was to study the effects of simvastatin on colorectal cancer cells and explore its potential as a radiation-sensitizer in vitro...
September 15, 2017: Surgical Endoscopy
https://www.readbyqxmd.com/read/28813599/tetraterpene-synthase-substrate-and-product-specificity-in-the-green-microalga-botryococcus-braunii-race-l
#3
Hem R Thapa, Su Tang, James C Sacchettini, Timothy P Devarenne
Recently, the biosynthetic pathway for lycopadiene, a C40 tetraterpenoid hydrocarbon, was deciphered from the L race of Botryococcus braunii, an alga that produces hydrocarbon oils capable of being converted into combustible fuels. The lycopadiene pathway is initiated by the squalene synthase (SS)-like enzyme lycopaoctaene synthase (LOS), which catalyzes the head-to-head condensation of two C20 geranylgeranyl diphosphate (GGPP) molecules to produce C40 lycopaoctaene. LOS shows unusual substrate promiscuity for SS or SS-like enzymes by utilizing C15 farnesyl diphosphate (FPP) and C20 phytyl diphosphate in addition to GGPP as substrates...
August 25, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28765914/atorvastatin-increases-fads1-fads2-and-elovl5-gene-expression-via-the-geranylgeranyl-pyrophosphate-dependent-rho-kinase-pathway-in-3t3-l1-cells
#4
Noriko Ishihara, Sawako Suzuki, Shou Tanaka, Yasuhiro Watanabe, Daiji Nagayama, Atsuhito Saiki, Tomoaki Tanaka, Ichiro Tatsuno
Numerous clinical studies have reported that statins increase the plasma concentration of arachidonic acid, which is an ω-6 long-chain polyunsaturated fatty acid (LCPUFA), and decrease the concentrations of eicosapentaenoic acid and docosahexaenoic acid, which are ω‑3 LCPUFAs. These findings indicate that statins may affect the endogenous synthesis of LCPUFAs, which is regulated by fatty acid desaturases (FADSs) and elongation of very long‑chain fatty acids proteins (ELOVLs). The present study aimed to investigate the roles of the intrinsic mevalonate cascade and Rho‑dependent pathway in statin‑induced regulation of these desaturases and elongases, as well as cell viability using mouse 3T3‑L1 cells...
October 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28736281/platycodin-d-suppressed-lps-induced-inflammatory-response-by-activating-lxr%C3%AE-in-lps-stimulated-primary-bovine-mammary-epithelial-cells
#5
Yanan Wang, Xu Zhang, Zhengkai Wei, Jingjing Wang, Yue Zhang, Mingyu Shi, Zhengtao Yang, Yunhe Fu
Platycodin D (PLD), a triterpenoid saponin derived from the root of Platycodon grandiflorum, has been reported to possess anti-inflammatory activity. However, the protective effect of PLD on mastitis has not been reported. In the present study, we aim to investigate the anti-inflammatory feature of PLD on the primary bovine mammary epithelial cells (bMEC) challenged with LPS. The cell viability of bMEC was measured by MTT assay. The quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the gene expression of pro-inflammatory cytokines and western blotting was carried out to measure the expression of LXRα and NF-κB...
July 20, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28694802/the-response-regulator-slr1588-regulates-spsa-but-is-not-crucial-for-salt-acclimation-of-synechocystis-sp-pcc-6803
#6
Kuo Song, Martin Hagemann, Xiaoming Tan, Xuefeng Lu
Cyanobacterial sucrose biosynthesis is stimulated under salt stress, which could be used for biotechnological sugar production. It has been shown that the response regulator Slr1588 negatively regulates the spsA gene encoding sucrose-phosphate synthase and mutation of the slr1588 gene also affected the salt tolerance of Synechocystis (Chen et al., 2014). The latter finding is contrary to earlier observations (Hagemann et al., 1997b). Here, we observed that ectopic expression of slr1588 did not restore the salt tolerance of the slr1588 mutant, making the essential function of this response regulator for salt tolerance questionable...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28666798/insights-into-the-mevalonate-pathway-in-the-anticancer-effect-of-a-platinum-complex-on-human-gastric-cancer-cells
#7
Ling Qiu, Hui Yang, Gaochao Lv, Ke Li, Guiqing Liu, Wei Wang, Shanshan Wang, Xueyu Zhao, Minhao Xie, Jianguo Lin
A platinum(II) complex [Pt(en)]2ZL [en = ethylenediamine; ZL = 1-hydroxy-3(1H-imidazol-1-yl)ethane-1,1-diylbisphosphonic acid, commonly called as zoledronic acid] has been designed and synthesized recently in order to look for new anticancer drugs with high efficacy and low side effects. It exhibited cytotoxic effects on the human cancer cells SGC7901, HepG2, MCF-7, MDA-MB-231, HCT116, and U2OS, and the cytotoxicity against SGC7901 is particularly remarkable. It also showed higher cytotoxicity and better selectivity than the corresponding ligand ZL in inhibiting cancer cells SGC7901 and HepG2 rather than normal cells GES-1 and LO2...
September 5, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28655749/polyprenols-are-synthesized-by-a-plastidial-cis-prenyltransferase-and-influence-photosynthetic-performance
#8
Tariq A Akhtar, Przemysław Surowiecki, Hanna Siekierska, Magdalena Kania, Kristen Van Gelder, Kevin A Rea, Lilia K A Virta, Maritza Vatta, Katarzyna Gawarecka, Jacek Wojcik, Witold Danikiewicz, Daniel Buszewicz, Ewa Swiezewska, Liliana Surmacz
Plants accumulate a family of hydrophobic polymers known as polyprenols, yet how they are synthesized, where they reside in the cell, and what role they serve is largely unknown. Using Arabidopsis thaliana as a model, we present evidence for the involvement of a plastidial cis-prenyltransferase (AtCPT7) in polyprenol synthesis. Gene inactivation and RNAi-mediated knockdown of AtCPT7 eliminated leaf polyprenols, while its overexpression increased their content. Complementation tests in the polyprenol-deficient yeast ∆rer2 mutant and enzyme assays with recombinant AtCPT7 confirmed that the enzyme synthesizes polyprenols of ∼55 carbons in length using geranylgeranyl diphosphate (GGPP) and isopentenyl diphosphate as substrates...
July 2017: Plant Cell
https://www.readbyqxmd.com/read/28652177/inhibition-of-il-6-and-il-8-production-in-lps-stimulated-human-gingival-fibroblasts-by-glycyrrhizin-via-activating-lxr%C3%AE
#9
Na Zhang, Hui Lv, Bo-Hong Shi, Xin Hou, Xin Xu
The aim of this study was to clarify the anti-inflammatory effects and its molecular mechanism of glycyrrhizin on LPS-stimulated human gingival fibroblasts (HGFs), which will be of benefit for periodontitis treatment. An MTT assay was performed to assess the effects of glycyrrhizin on cellular viability. The levels of IL-6 and IL-8 were measured by ELISA. The expression of iNOS, COX-2, NF-κB, and LXRα were detected by western blot analysis. The results showed that glycyrrhizin significantly inhibited LPS-induced IL-6 and IL-8 production, as well as COX-2 and iNOS expression...
June 23, 2017: Microbial Pathogenesis
https://www.readbyqxmd.com/read/28607067/a-recruiting-protein-of-geranylgeranyl-diphosphate-synthase-controls-metabolic-flux-toward-chlorophyll-biosynthesis-in-rice
#10
Fei Zhou, Cheng-Yuan Wang, Michael Gutensohn, Ling Jiang, Peng Zhang, Dabing Zhang, Natalia Dudareva, Shan Lu
In plants, geranylgeranyl diphosphate (GGPP) is produced by plastidic GGPP synthase (GGPPS) and serves as a precursor for vital metabolic branches, including chlorophyll, carotenoid, and gibberellin biosynthesis. However, molecular mechanisms regulating GGPP allocation among these biosynthetic pathways localized in the same subcellular compartment are largely unknown. We found that rice contains only one functionally active GGPPS, OsGGPPS1, in chloroplasts. A functionally active homodimeric enzyme composed of two OsGGPPS1 subunits is located in the stroma...
June 27, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28559264/synergistic-activity-between-statins-and-bisphosphonates-against-acute-experimental-toxoplasmosis
#11
Zhu-Hong Li, Catherine Li, Sergio H Szajnman, Juan B Rodriguez, Silvia N J Moreno
Bisphosphonates are widely used for the treatment of bone disorders. These drugs also inhibit the growth of a variety of protozoan parasites, such as Toxoplasma gondii, the etiologic agent of toxoplasmosis. The target of the most potent bisphosphonates is the isoprenoid biosynthesis pathway enzyme farnesyl diphosphate synthase (FPPS). Based on our previous work on the inhibitory effect of sulfur-containing linear bisphosphonates against T. gondii, we investigated the potential synergistic interaction between one of these derivatives, 1-[(n-heptylthio)ethyl]-1,1-bisphosphonate (C7S), and statins, which are potent inhibitors of the host 3-hydroxy-3-methyl glutaryl-coenzyme A reductase (3-HMG-CoA reductase)...
August 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28555000/recent-advances-in-the-development-of-mammalian-geranylgeranyl-diphosphate-synthase-inhibitors
#12
REVIEW
Staci L Haney, Veronica S Wills, David F Wiemer, Sarah A Holstein
The enzyme geranylgeranyl diphosphate synthase (GGDPS) catalyzes the synthesis of the 20-carbon isoprenoid geranylgeranyl diphosphate (GGPP). GGPP is the isoprenoid donor for protein geranylgeranylation reactions catalyzed by the enzymes geranylgeranyl transferase (GGTase) I and II. Inhibitors of GGDPS result in diminution of protein geranylgeranylation through depletion of cellular GGPP levels, and there has been interest in GGDPS inhibitors as potential anti-cancer agents. Here we discuss recent advances in the development of GGDPS inhibitors, including insights gained by structure-function relationships, and review the preclinical data that support the continued development of this novel class of drugs...
May 27, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28463490/structural-insights-into-the-cotb2-catalyzed-cyclization-of-geranylgeranyl-diphosphate-to-the-diterpene-cyclooctat-9-en-7-ol
#13
Takeo Tomita, Seung-Young Kim, Kazuya Teramoto, Ayuko Meguro, Taro Ozaki, Ayako Yoshida, Yudai Motoyoshi, Naoki Mori, Ken Ishigami, Hidenori Watanabe, Makoto Nishiyama, Tomohisa Kuzuyama
The diterpene cyclase CotB2 catalyzes the cyclization of geranylgeranyl diphosphate (GGPP) to the tricyclic cyclooctat-9-en-7-ol, which is characterized by a 5-8-5-fused ring skeleton. We have previously proposed a cyclization cascade involving a unique carbon-carbon bond rearrangement combined with multiple hydride shifts, all occurring at a single active site. Here, we report the first high-resolution X-ray crystal structure of CotB2 with bound substrate analog geranylgeranyl thiodiphosphate (GGSPP). In the GGSPP-bound form, GGSPP folds into a unique S-shaped conformation that probably reflects the substrate-bound state prior to ionization of the substrate GGPP...
June 16, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28357594/knockdown-of-ggps1-in-chondrocyte-expedites-fracture-healing-by-accelerating-the-progression-of-endochondral-ossification-in-mice
#14
Bingyang Dai, Qiangqiang Li, Xiaoxiao Song, Yuxiang Ge, Jing Wu, Kaijia Zhang, Chao Wang, Yifeng Zhang, Huajian Teng, Chaojun Li, Qing Jiang
Bone fracture healing is achieved through the proliferation and differentiation of stem cells, while bone marrow stem cells (BMSCs) contribute to endochondral ossification. During fracture healing, mesenchymal progenitor cells first form a cartilaginous blastema that becomes vascularized to recruit precursor cells of osteoblasts through the bone morphogenetic protein 2 (Bmp2)/Smad-dependent Runx2 pathway. Statins deplete geranylgeranyl diphosphate (GGPP), which participates in the regulation of BMSCs differentiation, through the inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, leading to impaired protein geranylgeranylation, which strongly impacts the bone synthesis induced by Bmp2...
March 29, 2017: Journal of Bone and Mineral Metabolism
https://www.readbyqxmd.com/read/28344327/mevalonate-cascade-inhibition-by-simvastatin-induces-the-intrinsic-apoptosis-pathway-via-depletion-of-isoprenoids-in-tumor-cells
#15
Javad Alizadeh, Amir A Zeki, Nima Mirzaei, Sandipan Tewary, Adel Rezaei Moghadam, Aleksandra Glogowska, Pandian Nagakannan, Eftekhar Eftekharpour, Emilia Wiechec, Joseph W Gordon, Fred Y Xu, Jared T Field, Ken Y Yoneda, Nicholas J Kenyon, Mohammad Hashemi, Grant M Hatch, Sabine Hombach-Klonisch, Thomas Klonisch, Saeid Ghavami
The mevalonate (MEV) cascade is responsible for cholesterol biosynthesis and the formation of the intermediate metabolites geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate (FPP) used in the prenylation of proteins. Here we show that the MEV cascade inhibitor simvastatin induced significant cell death in a wide range of human tumor cell lines, including glioblastoma, astrocytoma, neuroblastoma, lung adenocarcinoma, and breast cancer. Simvastatin induced apoptotic cell death via the intrinsic apoptotic pathway...
March 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28343347/bioanalysis-of-farnesyl-pyrophosphate-in-human-plasma-by-high-performance-liquid-chromatography-coupled-to-triple-quadrupole-tandem-mass-spectrometry-and-hybrid-quadrupole-orbitrap-high-resolution-mass-spectrometry
#16
Hiroshi Sugimoto, Mie Iguchi, Fumihiro Jinno
The isoprenoids farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are pivotal intermediates for cholesterol homeostasis and cell signaling in the mevalonate pathway. We developed a sensitive and selective high-performance liquid chromatography tandem triple quadrupole mass spectrometry (LC-QQQ-MS) method for FPP in human plasma without the need for a derivatization process. We optimized the sample preparation procedure to extract FPP and (13)C5-FPP (as internal standard) from sample fluids using methanol...
March 25, 2017: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/28300835/geranylgeranyl-diphosphate-synthase-inhibition-induces-apoptosis-that-is-dependent-upon-ggpp-depletion-erk-phosphorylation-and-caspase-activation
#17
Sherry S Agabiti, Jin Li, Andrew J Wiemer
Bisphosphonates are diphosphate analogs that inhibit the intermediate enzymes of the mevalonate pathway. Here, we compared the effects of a farnesyl diphosphate synthase inhibitor, zoledronate, and a geranylgeranyl diphosphate synthase (GGDPS) inhibitor, digeranyl bisphosphonate (DGBP), on lymphocytic leukemia cell proliferation and apoptosis. Both zoledronate and DGBP inhibited proliferation with DGBP doing so more potently. DGBP was markedly less toxic than zoledronate toward the viability of healthy human peripheral blood mononuclear cells...
March 16, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28284309/alleviation-of-metabolic-bottleneck-by-combinatorial-engineering-enhanced-astaxanthin-synthesis-in-saccharomyces-cerevisiae
#18
Pingping Zhou, Wenping Xie, Aipeng Li, Fan Wang, Zhen Yao, Qi Bian, Yongqiang Zhu, Hongwei Yu, Lidan Ye
Highly efficient biosynthesis of the commercially valuable carotenoid astaxanthin by microbial cells is an attractive alternative to chemical synthesis and microalgae extraction. With the goal of enhancing heterologous astaxanthin production in Saccharomyces cerevisiae, metabolic engineering and protein engineering were integrated to improve both the expression and activity of rate-limiting enzymes. Firstly, to increase the supply of β-carotene as a key precursor for astaxanthin, a positive mutant of GGPP synthase (CrtE03M) was overexpressed together with three other rate-limiting enzymes tHMG1, CrtI and CrtYB...
May 2017: Enzyme and Microbial Technology
https://www.readbyqxmd.com/read/28270685/cyclization-mechanism-of-phomopsene-synthase-mass-spectrometry-based-analysis-of-various-site-specifically-labeled-terpenes
#19
Sandip S Shinde, Atsushi Minami, Zhi Chen, Tetsuo Tokiwano, Tomonobu Toyomasu, Nobuo Kato, Takeshi Sassa, Hideaki Oikawa
Elucidation of the cyclization mechanism catalyzed by terpene synthases is important for the rational engineering of terpene cyclases. We developed a chemoenzymatic method for the synthesis of systematically deuterium-labeled geranylgeranyl diphosphate (GGPP), starting from site-specifically deuterium-labeled isopentenyl diphosphates (IPPs) using IPP isomerase and three prenyltransferases. We examined the cyclization mechanism of tetracyclic diterpene phomopsene with phomopsene synthase. A detailed EI-MS analysis of phomopsene labeled at various positions allowed us to propose the structures corresponding to the most intense peaks, and thus elucidate a cyclization mechanism involving double 1,2-alkyl shifts and a 1,2-hydride shift via a dolabelladien-15-yl cation...
May 2017: Journal of Antibiotics
https://www.readbyqxmd.com/read/28128232/functional-characterization-of-nes-and-ges-responsible-for-the-biosynthesis-of-e-nerolidol-and-e-e-geranyllinalool-in-tripterygium-wilfordii
#20
Ping Su, Tianyuan Hu, Yujia Liu, Yuru Tong, Hongyu Guan, Yifeng Zhang, Jiawei Zhou, Luqi Huang, Wei Gao
Triptolide and celastrol, two principal bioactive compounds in Tripterygium wilfordii, are produced from geranylgeranyl diphosphate (GGPP) and farnesyl diphosphate ((E,E)-FPP) through terpenoid biosynthesis pathway. However, little is known about T. wilfordii terpene synthases which could competitively utilize GGPP and (E,E)-FPP as substrates, producing C15 and C20 tertiary alcohols. Here we firstly cloned the genes encoding nerolidol synthase (NES) and geranyllinalool synthases (GES1, GES2), which are responsible for the biosynthesis of (E)-nerolidol and (E,E)-geranyllinalool...
January 27, 2017: Scientific Reports
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