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https://www.readbyqxmd.com/read/27864002/gamma-tocotrienol-reverses-multidrug-resistance-of-breast-cancer-cells-with-a-mechanism-distinct-from-that-of-atorvastatin
#1
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...
November 15, 2016: 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
#2
M C Vaccaro, M E Alfieri, 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)...
November 16, 2016: Plant Cell Reports
https://www.readbyqxmd.com/read/27707890/a-single-gene-encodes-two-differentially-targeted-geranylgeranyl-diphosphate-synthase-isoforms
#3
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
#4
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
#5
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...
September 3, 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
#6
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
#7
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
#8
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
#9
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...
July 22, 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
#10
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
https://www.readbyqxmd.com/read/27342751/exploration-of-ggtase-i-substrate-requirements-part-2-synthesis-and-biochemical-analysis-of-novel-saturated-geranylgeranyl-diphosphate-analogs
#11
Kayla J Temple, Elia N Wright, Carol A Fierke, Richard A Gibbs
Protein prenylation is a type of post-translational modification that aids certain proteins in localizing to the plasma member where they activate cell signaling. To better understand the isoprenoid requirements and differences of FTase and GGTase-I, a series of saturated geranylgeranyl diphosphate analogs were synthesized and screened against both mammalian FTase and GGTase-I. Of our library of compounds, several analogs proved to be substrates of GGTase-I, with 11d having a krel=0.95 when compared to GGPP (krel=1...
August 1, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27342750/exploration-of-ggtase-i-substrate-requirements-part-1-synthesis-and-biochemical-evaluation-of-novel-aryl-modified-geranylgeranyl-diphosphate-analogs
#12
Kayla J Temple, Elia N Wright, Carol A Fierke, Richard A Gibbs
Protein geranylgeranylation is a type of post-translational modification that aids in the localization of proteins to the plasma member where they elicit cellular signals. To better understand the isoprenoid requirements of GGTase-I, a series of aryl-modified geranylgeranyl diphosphate analogs were synthesized and screened against mammalian GGTase-I. Of our seven-member library of compounds, six analogs proved to be substrates of GGTase-I, with 6d having a krel=1.93 when compared to GGPP (krel=1.0).
August 1, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27336844/alteration-of-rhoa-prenylation-ameliorates-cardiac-and-vascular-remodeling-in-spontaneously-hypertensive-rats
#13
Jian Yang, Yu-Ning Chen, Zao-Xian Xu, Yun Mou, Liang-Rong Zheng
BACKGROUND: In our previous study, farnesyl pyrophosphate synthase (FPPS) was shown to be increased in spontaneously hypertensive rats (SHR) and in mice with angiotensin-II induced cardiac hypertrophy. Overexpression of FPPS induced cardiac hypertrophy and fibrosis in mice, accompanied by an increase in the synthesis of farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). In the present study, we investigated the mechanisms of reversing cardiovascular remodeling in SHR by inhibiting FPPS...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27280996/purification-and-characterization-of-geranylgeranyl-diphosphate-synthase-from-methanobacterium-thermoformicicum-sf-4
#14
A Tachibana, T Tanaka, M Taniguchi, O Susumu
Geranylgeranyl diphosphate (GGPP) synthase [EC 2.5.1.29] was purified to homogeneity from Methanobacterium thermoformicicum SF-4. The enzyme was a dimeric protein consisting of two identical subunits (Mr = 39,000) and catalyzed prenyl transfer reactions using isopentenyl diphosphate (Km = 30.8 μM) and either dimethylallyl diphosphate (Km=16.8 μM), geranyl diphosphate (Km=12.6 μM), or farnesyl diphosphate (Km=14.7 μM) as allylic partners. During a sequential elongation, C5→C10→C15→C20' intermediates were accumulated with various ratios to the final product GGPP...
January 1993: Bioscience, Biotechnology, and Biochemistry
https://www.readbyqxmd.com/read/27181081/synergistic-antiproliferative-effects-of-zoledronic-acid-and-fluvastatin-on-human-pancreatic-cancer-cell-lines-an-in-vitro-study
#15
Mahitab Elsayed, Daisuke Kobayashi, Toshio Kubota, Naoya Matsunaga, Ryusei Murata, Yuko Yoshizawa, Natsuki Watanabe, Tohru Matsuura, Yuya Tsurudome, Takashi Ogino, Shigehiro Ohdo, Takao Shimazoe
Bisphosphonates and statins are known to have antitumor activities against different types of cancer cell lines. In the present study, we investigated the antiproliferative effects of the combination of zoledronic acid (ZOL), a bisphophosphonate, and fluvastatin (FLU), a statin, in vitro on two types of human pancreatic cancer cell lines, Mia PaCa-2 and Suit-2. The pancreatic cancer cell lines were treated with ZOL and FLU both individually and in combination to evaluate their antiproliferative effects using WST-8 cell proliferation assay...
August 1, 2016: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/27133418/potential-of-tocotrienols-in-the-prevention-and-therapy-of-alzheimer-s-disease
#16
REVIEW
Weiming Xia, Huanbiao Mo
Currently there is no cure for Alzheimer's disease (AD); clinical trials are underway to reduce amyloid generation and deposition, a neuropathological hallmark in brains of AD patients. While genetic factors and neuroinflammation contribute significantly to AD pathogenesis, whether increased cholesterol level is a causative factor or a result of AD is equivocal. Prenylation of proteins regulating neuronal functions requires mevalonate-derived farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP)...
May 2016: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/27121042/geranylgeranyl-regulated-transport-of-the-prenyltransferase-ubiad1-between-membranes-of-the-er-and-golgi
#17
Marc M Schumacher, Dong-Jae Jun, Youngah Jo, Joachim Seemann, Russell A DeBose-Boyd
UbiA prenyltransferase domain-containing protein-1 (UBIAD1) utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K2 subtype menaquinone-4. Previously, we found that sterols trigger binding of UBIAD1 to endoplasmic reticulum (ER)-localized HMG-CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids, including GGpp. This binding inhibits sterol-accelerated degradation of reductase, which contributes to feedback regulation of the enzyme. The addition to cells of geranylgeraniol (GGOH), which can become converted to GGpp, triggers release of UBIAD1 from reductase, allowing for its maximal degradation and permitting ER-to-Golgi transport of UBIAD1...
July 2016: Journal of Lipid Research
https://www.readbyqxmd.com/read/27050299/a-squalene-synthase-like-enzyme-initiates-production-of-tetraterpenoid-hydrocarbons-in-botryococcus-braunii-race-l
#18
Hem R Thapa, Mandar T Naik, Shigeru Okada, Kentaro Takada, István Molnár, Yuquan Xu, Timothy P Devarenne
The green microalga Botryococcus braunii is considered a promising biofuel feedstock producer due to its prodigious accumulation of hydrocarbon oils that can be converted into fuels. B. braunii Race L produces the C40 tetraterpenoid hydrocarbon lycopadiene via an uncharacterized biosynthetic pathway. Structural similarities suggest this pathway follows a biosynthetic mechanism analogous to that of C30 squalene. Confirming this hypothesis, the current study identifies C20 geranylgeranyl diphosphate (GGPP) as a precursor for lycopaoctaene biosynthesis, the first committed intermediate in the production of lycopadiene...
2016: Nature Communications
https://www.readbyqxmd.com/read/27042994/simvastatin-reduces-cancerogenic-potential-of-renal-cancer-cells-via-geranylgeranyl-pyrophosphate-and-mevalonate-pathway
#19
Mathias Woschek, Niels Kneip, Katrin Jurida, Ingo Marzi, Borna Relja
Simvastatin is a cholesterol-lowering drug, inhibiting 3-hydroxy-3-methylglutaryl-coenzyme CoA (HMG-CoA) reductase. Previous studies have indicated the anticancerous effects of simvastatin. Here, we evaluated the anticancerous potential of simvastatin in renal cell carcinoma (RCC) cell lines. RCC occurs with an incidence of 2-3% of all cancer entities with high chemoresistance rate. Therefore, the understanding of underlying mechanisms for RCC activity and the development of alternative therapies are essential...
2016: Nutrition and Cancer
https://www.readbyqxmd.com/read/27016018/simvastatin-enhances-nmda-receptor-glun2b-expression-and-phosphorylation-of-glun2b-and-glun2a-through-increased-histone-acetylation-and-src-signaling-in-hippocampal-ca1-neurons
#20
Tingting Chen, Baofeng Zhang, Guoxi Li, Lei Chen, Ling Chen
Simvastatin (SV) can improve cognitive deficits in Alzheimer's disease patients and mice. Herein, we report that the administration of SV (20 mg/kg) for 5 days in mice (SV-mice) or the treatment of slices with SV (10 μM) for 4 h (SV-slices) could increase the density of NMDA-evoked inward currents (INMDA) in hippocampal CA1 pyramidal cells, which were blocked by farnesol (FOH) that converts farnesyl pyrophosphate (FPP), but not geranylgeraniol (GGOH) that increases geranylgeranylpyrophosphate (GGPP). Sensitivity of INMDA to ifenprodil in SV-mice or SV-slices was significantly increased...
August 2016: Neuropharmacology
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