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https://www.readbyqxmd.com/read/28357594/knockdown-of-ggps1-in-chondrocyte-expedites-fracture-healing-by-accelerating-the-progression-of-endochondral-ossification-in-mice
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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...
March 8, 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
#7
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
https://www.readbyqxmd.com/read/28079933/co-expression-of-peppermint-geranyl-diphosphate-synthase-small-subunit-enhances-monoterpene-production-in-transgenic-tobacco-plants
#8
Jun-Lin Yin, Woon-Seng Wong, In-Cheol Jang, Nam-Hai Chua
Monoterpenes are important for plant survival and useful to humans. In addition to their function in plant defense, monoterpenes are also used as flavors, fragrances and medicines. Several metabolic engineering strategies have been explored to produce monoterpene in tobacco but only trace amounts of monoterpenes have been detected. We investigated the effects of Solanum lycopersicum 1-deoxy-d-xylulose-5-phosphate synthase (SlDXS), Arabidopsis thaliana geranyl diphosphate synthase 1 (AtGPS) and Mentha × piperita geranyl diphosphate synthase small subunit (MpGPS...
February 2017: New Phytologist
https://www.readbyqxmd.com/read/28072828/ggpp-mediated-protein-geranylgeranylation-in-oocyte-is-essential-for-the-establishment-of-oocyte-granulosa-cell-communication-and-primary-secondary-follicle-transition-in-mouse-ovary
#9
Chen Jiang, Fan Diao, Yong-Juan Sang, Na Xu, Rui-Lou Zhu, Xiu-Xing Wang, Zhong Chen, Wei-Wei Tao, Bing Yao, Hai-Xiang Sun, Xing-Xu Huang, Bin Xue, Chao-Jun Li
Folliculogenesis is a progressive and highly regulated process, which is essential to provide ova for later reproductive life, requires the bidirectional communication between the oocyte and granulosa cells. This physical connection-mediated communication conveys not only the signals from the oocyte to granulosa cells that regulate their proliferation but also metabolites from the granulosa cells to the oocyte for biosynthesis. However, the underlying mechanism of establishing this communication is largely unknown...
January 2017: PLoS Genetics
https://www.readbyqxmd.com/read/27933080/identification-of-a-dolabellane-type-diterpene-synthase-and-other-root-expressed-diterpene-synthases-in-arabidopsis
#10
Qiang Wang, Meirong Jia, Jung-Hyun Huh, Andrew Muchlinski, Reuben J Peters, Dorothea Tholl
Arabidopsis thaliana maintains a complex metabolism for the production of secondary or specialized metabolites. Such metabolites include volatile and semivolatile terpenes, which have been associated with direct and indirect defensive activities in flowers and leaves. In comparison, the structural diversity and function of terpenes in Arabidopsis roots has remained largely unexplored despite a substantial number of root-expressed genes in the Arabidopsis terpene synthase (TPS) gene family. We show that five root-expressed TPSs of an expanded subfamily-a type clade in the Arabidopsis TPS family function as class I diterpene synthases that predominantly convert geranylgeranyl diphosphate (GGPP) to different semi-volatile diterpene products, which are in part detectable at low levels in the ecotypes Columbia (Col) and Cape Verde Island (Cvi)...
2016: Frontiers in Plant Science
https://www.readbyqxmd.com/read/27864002/gamma-tocotrienol-reverses-multidrug-resistance-of-breast-cancer-cells-with-a-mechanism-distinct-from-that-of-atorvastatin
#11
Yuedi Ding, Ying Peng, Lili Deng, Jun Fan, Biao Huang
In addition to its antioxidant properties, γ-tocotrienol also has the ability to inhibit HMG-CoA reductase, which is the key enzyme in the mevalonate pathway for cholesterol biosynthesis. Statins, the competitive inhibitors of HMG-CoA reductase, display potent anticancer activity and reversal ability of multidrug resistance in a variety of tumor cells, which is believed to be due to their inhibition of HMG-CoA reductase. Here, we determined the role of the mevalonate pathway in γ-tocotrienol-mediated reversal of multidrug resistance in cancer cells...
March 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/27853836/increasing-the-synthesis-of-bioactive-abietane-diterpenes-in-salvia-sclarea-hairy-roots-by-elicited-transcriptional-reprogramming
#12
M C Vaccaro, A Mariaevelina, N Malafronte, N De Tommasi, A Leone
Transcriptional activation of genes belonging to the plastidial MEP-derived isoprenoid pathway by elicitation with methyl jasmonate and coronatine enhanced the content of bioactive abietane diterpenes in Salvia sclarea hairy roots. We have shown that aethiopinone, an abietane diterpene synthesized in Salvia sclarea roots is cytotoxic and induces apoptosis in human melanoma cells. To develop a production platform for this compound and other abietane diterpenes, hairy root technology was combined with the elicitation of methyl jasmonate (MeJA) or the phytotoxin coronatine (Cor)...
February 2017: Plant Cell Reports
https://www.readbyqxmd.com/read/27707890/a-single-gene-encodes-two-differentially-targeted-geranylgeranyl-diphosphate-synthase-isoforms
#13
M Águila Ruiz-Sola, M Victoria Barja, David Manzano, Briardo Llorente, Bert Schipper, Jules Beekwilder, Manuel Rodriguez-Concepcion
A wide diversity of isoprenoids is produced in different plant compartments. Most groups of isoprenoids synthesized in plastids and some produced elsewhere in the plant cell derive from geranylgeranyl diphosphate (GGPP) synthesized by GGPP synthase (GGPPS) enzymes. In Arabidopsis thaliana, 5 genes appear to encode GGPPS isoforms localized in plastids (2), the endoplasmic reticulum (2), and mitochondria (1). However, the loss of function of the plastid-targeted GGPPS11 isoform (referred to as G11) is sufficient to cause lethality...
October 5, 2016: Plant Physiology
https://www.readbyqxmd.com/read/27652005/anti-inflammatory-and-cytoprotective-effects-of-a-squalene-synthase-inhibitor-tak-475-active-metabolite-i-in-immune-cells-simulating-mevalonate-kinase-deficiency-mkd-like-condition
#14
Nobutaka Suzuki, Tatsuo Ito, Hisanori Matsui, Masayuki Takizawa
TAK-475 (lapaquistat acetate) and its active metabolite-I (TAK-475 M-I) inhibit squalene synthase, which catalyzes the conversion of farnesyl diphosphate (FPP) to squalene. FPP is a substrate for synthesis of other mevalonate-derived isoprenoids (MDIs) such as farnesol (FOH), geranlygeranyl diphosphate (GGPP), and geranylgeraniol. In patients with MKD, a rare autosomal recessive disorder, defective activity of mevalonate kinase leads to a shortage of MDIs. MDIs especially GGPP are required for prenylation of proteins, which is a posttranslation modification necessary for proper functioning of proteins like small guanosine triphosphatases...
2016: SpringerPlus
https://www.readbyqxmd.com/read/27620969/pyrazole-based-potent-inhibitors-of-ggt1-synthesis-biological-evaluation-and-molecular-docking-studies
#15
Muhammad Mansha, Udayappan Udhaya Kumari, Zoe Cournia, Nisar Ullah
In this study, a series of pyrazole-based structural analogues of GGTI-DU40 (1) have been synthesized and biologically evaluated for geranylgeranyltransferase 1 (GGT1) and farnesyltransferase (FT) inhibition. The screening results revealed that 2 (IC50 = 2.4 μM) and 5 (IC50 = 3.1 μM) are potent GGT1 inhibitors (GGTIs), possessing higher inhibitory activity compared to the control compound 1 (IC50 = 3.3 μM). The anti-proliferative efficacy of these compounds was further assayed against MDA-MB-231 cells which indicated a significantly higher activity of 2 (IC50 = 7...
November 29, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27569282/geranylgeranyl-pyrophosphate-performs-as-an-endogenous-regulator-of-adipocyte-function-via-suppressing-the-lxr-pathway
#16
Yu-Sheng Yeh, Tsuyoshi Goto, Nobuyuki Takahashi, Kahori Egawa, Haruya Takahashi, Huei-Fen Jheng, Young-Il Kim, Teruo Kawada
Isoprenoids such as geranylgeranyl pyrophosphate (GGPP) influence various biological processes. Here we show that GGPP inhibits adipocyte differentiation via the liver X receptors (LXRs) pathway. Intracellular GGPP levels and GGPP synthase (Ggps) mRNA expression increases during adipocyte differentiation. Ggps expression also increases in white adipose tissue of obese mice. GGPP addition reduces the expression of adipogenic marker genes such as adipocyte fatty acid binding protein, peroxisome proliferator-activated receptor γ, and insulin-stimulated glucose uptake...
September 23, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27564465/dynamic-structure-and-inhibition-of-a-malaria-drug-target-geranylgeranyl-diphosphate-synthase
#17
Clarisse G Ricci, Yi-Liang Liu, Yonghui Zhang, Yang Wang, Wei Zhu, Eric Oldfield, J Andrew McCammon
We report a molecular dynamics investigation of the structure, function, and inhibition of geranylgeranyl diphosphate synthase (GGPPS), a potential drug target, from the malaria parasite Plasmodium vivax. We discovered several GGPPS inhibitors, benzoic acids, and determined their structures crystallographically. We then used molecular dynamics simulations to investigate the dynamics of three such inhibitors and two bisphosphonate inhibitors, zoledronate and a lipophilic analogue of zoledronate, as well as the enzyme's product, GGPP...
September 13, 2016: Biochemistry
https://www.readbyqxmd.com/read/27490479/structure-of-the-ent-copalyl-diphosphate-synthase-ptmt2-from-streptomyces-platensis-cb00739-a-bacterial-type-ii-diterpene-synthase
#18
Jeffrey D Rudolf, Liao-Bin Dong, Hongnan Cao, Catherine Hatzos-Skintges, Jerzy Osipiuk, Michael Endres, Chin-Yuan Chang, Ming Ma, Gyorgy Babnigg, Andrzej Joachimiak, George N Phillips, Ben Shen
Terpenoids are the largest and most structurally diverse family of natural products found in nature, yet their presence in bacteria is underappreciated. The carbon skeletons of terpenoids are generated through carbocation-dependent cyclization cascades catalyzed by terpene synthases (TSs). Type I and type II TSs initiate cyclization via diphosphate ionization and protonation, respectively, and protein structures of both types are known. Most plant diterpene synthases (DTSs) possess three α-helical domains (αβγ), which are thought to have arisen from the fusion of discrete, ancestral bacterial type I TSs (α) and type II TSs (βγ)...
August 31, 2016: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/27462771/anti-cancer-effects-of-nitrogen-containing-bisphosphonates-on-human-cancer-cells
#19
Pengfei Jiang, Peiying Zhang, Rajesh Mukthavaram, Natsuko Nomura, Sandeep C Pingle, Dayu Teng, Shu Chien, Fang Guo, Santosh Kesari
Zoledronic acid, a potent nitrogen-containing bisphosphonate (NBP), has been extensively used to limit bone turnover in a various diseases including tumors. Recent clinical studies have demonstrated direct anti-cancer effects of zoledronic acid, in addition to its clinical benefits for skeletal-related events. Here we investigated the effects of 4 clinically available NBPs on human tumor cell proliferation. Our data demonstrate a potent anti-proliferative effect of zoledronic acid against glioblastoma (GBM) cell lines, breast cancer cells and GBM patient-derived lines...
September 6, 2016: Oncotarget
https://www.readbyqxmd.com/read/27346340/ecto-atpase-cd39-inactivates-isoprenoid-derived-v%C3%AE-9v%C3%AE-2%C3%A2-t-cell-phosphoantigens
#20
Georg Gruenbacher, Hubert Gander, Andrea Rahm, Marco Idzko, Oliver Nussbaumer, Martin Thurnher
In humans, Vγ9Vδ2 T cells respond to self and pathogen-associated, diphosphate-containing isoprenoids, also known as phosphoantigens (pAgs). However, activation and homeostasis of Vγ9Vδ2 T cells remain incompletely understood. Here, we show that pAgs induced expression of the ecto-ATPase CD39, which, however, not only hydrolyzed ATP but also abrogated the γδ T cell receptor (TCR) agonistic activity of self and microbial pAgs (C5 to C15). Only mevalonate-derived geranylgeranyl diphosphate (GGPP, C20) resisted CD39-mediated hydrolysis and acted as a regulator of CD39 expression and activity...
July 12, 2016: Cell Reports
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