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mevalonate

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https://www.readbyqxmd.com/read/28230855/simvastatin-induced-cell-cycle-arrest-through-inhibition-of-stat3-skp2-axis-and-activation-of-ampk-to-promote-p27-and-p21-accumulation-in-hepatocellular-carcinoma-cells
#1
Sin-Ting Wang, Hsiu J Ho, Jaw-Town Lin, Jeng-Jer Shieh, Chun-Ying Wu
Hepatocellular carcinoma (HCC) is characterized by a poor prognosis and is one of the leading causes of cancer-related death worldwide. Simvastatin, an HMG-CoA reductase inhibitor, which decreases cholesterol synthesis by inhibiting mevalonate pathways and is widely used to treat cardiovascular diseases. Simvastatin exhibits anticancer effects against several malignancies. However, the molecular mechanisms underlying the anticancer effects of simvastatin on HCC are still not well understood. In this study, we demonstrated simvastatin-induced G0/G1 arrest by inducing p21 and p27 accumulation in HepG2 and Hep3B cells...
February 23, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28217906/production-of-taxadiene-by-engineering-of-mevalonate-pathway-in-escherichia-coli-and-endophytic-fungus-alternaria-alternata-tpf6
#2
Guangkai Bian, Yujie Yuan, Hui Tao, Xiaofei Shi, Xiaofang Zhong, Yichao Han, Shuai Fu, Chengxiang Fang, Zixin Deng, Tiangang Liu
Taxol (paclitaxel) is a diterpenoid compound with significant and extensive applications in the treatment of cancer. The production of Taxol and relevant intermediates by engineered microbes is an attractive alternative to the semichemical synthesis of Taxol. In this study, based on a previously developed platform, we first established taxadiene production in mutant E. coli T2 and T4 by engineering of the mevalonate (MVA) pathway. We then developed an Agrobacterium tumefaciens-mediated transformation (ATMT) method and verified the strength of heterologous promoters in Alternaria alternata TPF6...
February 20, 2017: Biotechnology Journal
https://www.readbyqxmd.com/read/28212283/the-effects-of-tocotrienol-and-lovastatin-co-supplementation-on-bone-dynamic-histomorphometry-and-bone-morphogenetic-protein-2-expression-in-rats-with-estrogen-deficiency
#3
Kok-Yong Chin, Saif Abdul-Majeed, Norazlina Mohamed, Soelaiman Ima-Nirwana
Both tocotrienol and statins are suppressors of the mevalonate pathway. Supplementation of tocotrienol among statin users could potentially protect them against osteoporosis. This study aimed to compare the effects of tocotrienol and lovastatin co-supplementation with individual treatments on bone dynamic histomorphometric indices and bone morphogenetic protein-2 (BMP-2) gene expression in ovariectomized rats. Forty-eight female Sprague-Dawley rats were randomized equally into six groups. The baseline was sacrificed upon receipt...
February 15, 2017: Nutrients
https://www.readbyqxmd.com/read/28209347/high-resolution-mass-spectrometry-based-method-applicable-for-a-wide-range-of-3-hydroxy-3-methyl-glutaryl-coenzyme-a-reductase-inhibitors-in-blood-serum-including-intermediates-and-products-of-the-cholesterol-biosynthetic-pathway
#4
Vít Kosek, Milena Stránská, Marie Fenclová, Tomáš Ruml, Libor Vítek, Jana Hajšlová
Statins belong to the major class of hypolipidemic drugs. They act as competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme in the cholesterol biosynthetic pathway. This inhibition not only leads to the depletion of cholesterol and its fatty acid esters, but also to the depletion of the intermediates of this metabolic pathway (mainly pyrophosphates), which can play an important role in tumor proliferation. The aim of the current study was to establish a versatile multi-analyte method capable of quantitative determination of various currently-used statins, together with free cholesterol (FC), cholesterol esters (CEs), and some key intermediates of the mevalonate pathway occurring in human serum...
January 31, 2017: Journal of Chromatography. A
https://www.readbyqxmd.com/read/28208018/pharmacophore-mapping-of-thienopyrimidine-based-monophosphonate-thp-mp-inhibitors-of-the-human-farnesyl-pyrophosphate-synthase
#5
Jaeok Park, Chun Yuen Leung, Alexios N Matralis, Cyrus M Lacbay, Michail Tsakos, Guillermo Fernandez De Troconiz, Albert M Berghuis, Youla S Tsantrizos
The human farnesyl pyrophosphate synthase (hFPPS), a key regulatory enzyme in the mevalonate pathway, catalyzes the biosynthesis of the C-15 isoprenoid farnesyl pyrophosphate (FPP). FPP plays a crucial role in the post-translational prenylation of small GTPases that perform a plethora of cellular functions. Although hFPPS is a well-established therapeutic target for lytic bone diseases, the currently available bisphosphonate drugs exhibit poor cellular uptake and distribution into non-skeletal tissues. Recent drug discovery efforts have focused primarily on allosteric inhibition of hFPPS and the discovery of non-bisphosphonate drugs for potentially treating non-skeletal diseases...
February 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28196976/biosynthetic-studies-on-terpenoids-produced-by-streptomyces
#6
REVIEW
Tomohisa Kuzuyama
Terpenoids are a large and highly diverse group of natural products. All terpenoids are biosynthesized from isoprenyl diphosphate formed by the consecutive condensation of the five-carbon monomer isopentenyl diphosphate (IPP) to its isomer dimethylallyl diphosphate (DMAPP). Two distinct biosynthetic pathways produce the essential primary metabolites IPP and DMAPP: the 2-C-methylerythritol 4-phosphate pathway and the mevalonate pathway. The isoprenyl substrates can be cyclized by terpene cyclase into single-ring or multi-ring products, which can be further diversified by subsequent modification reactions, such as hydroxylation and glycosylation...
February 15, 2017: Journal of Antibiotics
https://www.readbyqxmd.com/read/28188954/comparative-glandular-trichome-transcriptome-based-gene-characterization-reveals-reasons-for-differential-menthol-biosynthesis-in-mentha-species
#7
Md Qussen Akhtar, Nida Qamar, Pallavi Yadav, Pallavi Kulkarni, Ajay Kumar, Ajit Kumar Shasany
The genes involved in menthol biosynthesis are reported earlier in Mentha × piperita. But the information on these genes is not available in Mentha arvensis. To bridge the gap in knowledge on differential biosynthesis of monoterpenes leading to compositional variation in the essential oil of these species, a comparative transcriptome analysis of the glandular trichome was carried out. In addition to the MVA and MEP pathway genes, about 210 and 196 different terpene synthases (TPS) transcripts were identified from annotation in M...
February 11, 2017: Physiologia Plantarum
https://www.readbyqxmd.com/read/28188410/simvastatin-inhibits-il-1%C3%AE-induced-apoptosis-and-extracellular-matrix-degradation-by-suppressing-the-nf-kb-and-mapk-pathways-in-nucleus-pulposus-cells
#8
Tu Ji, Li Wentian, Zhang Yukun, Wu Xinghuo, Song Yu, Kang Liang, Liu Wei, Wang Kun, Li Shuai, Hua Wenbin, Yang Cao
Statins are widely used hypocholesterolemic drugs that block the mevalonate pathway. Some studies have shown that statins may have the potential to inhibit intervertebral disk (IVD) degeneration (IDD). Interleukin (IL)-1β, a catabolic cytokine, is a key regulator of IDD. This study aimed to investigate the mechanism underlying the effect of simvastatin on IDD. The viability of nucleus pulposus (NP) cells was determined by the methyl-thiazolyl-tetrazolium (MTT) assay. The apoptosis of NP cells was measured by flow cytometric analysis, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and western blotting of relevant apoptotic proteins...
February 10, 2017: Inflammation
https://www.readbyqxmd.com/read/28185100/effects-of-acetoacetyl-coa-synthase-expression-on-production-of-farnesene-in-saccharomyces-cerevisiae
#9
Stefan Tippmann, Raphael Ferreira, Verena Siewers, Jens Nielsen, Yun Chen
Efficient production of sesquiterpenes in Saccharomyces cerevisiae requires a high flux through the mevalonate pathway. To achieve this, the supply of acetyl-CoA plays a crucial role, partially because nine moles of acetyl-CoA are necessary to produce one mole of farnesyl diphosphate, but also to overcome the thermodynamic constraint imposed on the first reaction, in which acetoacetyl-CoA is produced from two moles of acetyl-CoA by acetoacetyl-CoA thiolase. Recently, a novel acetoacetyl-CoA synthase (nphT7) has been identified from Streptomyces sp...
February 9, 2017: Journal of Industrial Microbiology & Biotechnology
https://www.readbyqxmd.com/read/28181143/the-complex-interplay-among-hepatocytes-and-immune-cells-at-the-crossroad-between-inflammation-and-cholesterol-metabolism-in-hyperglycemia
#10
Maurizio Bifulco, Simona Pisanti, Elena Ciaglia
An intriguing piece of evidence for the inflammatory story of type 2 diabetes has come to the light. A recent study by Okin and colleagues adds new clues to the interplay between cholesterol metabolism and immunity and how it impacts glucose homeostasis in inflammatory conditions. But some questions are a still unsolved conundrum. Here we suggest to better dissect the regulatory mechanism of Mevalonate pathway and to underpin a new causative link between immunometabolic dysregulation and diabetes.
February 8, 2017: Endocrine
https://www.readbyqxmd.com/read/28178435/an-up-to-date-approach-to-a-patient-with-a-suspected-autoinflammatory-disease
#11
REVIEW
Merav Lidar, Eitan Giat
Autoinflammatory diseases (AID) are characterized by seemingly unprovoked self-limited attacks of fever and systemic inflammation potentially leading to amyloidosis. Familial Mediterranean fever (FMF) is the most common AID and therefore the most studied. Besides FMF, the other main hereditary AID are tumor necrosis factor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD), and cryopyrin-associated periodic fever syndrome (CAPS). These hereditary diseases result from a mutant gene that is involved in the regulation of inflammation, resulting in a characteristic clinical phenotype...
January 30, 2017: Rambam Maimonides Medical Journal
https://www.readbyqxmd.com/read/28157221/microbial-modulation-of-bacoside-a-biosynthetic-pathway-and-systemic-defense-mechanism-in-bacopa-monnieri-under-meloidogyne-incognita-stress
#12
Rupali Gupta, Akanksha Singh, Madhumita Srivastava, Vivek Singh, M M Gupta, Rakesh Pandey
Plant-associated beneficial microbes have been explored to fulfill the imperative function for plant health. However, their impact on the host secondary metabolite production and nematode disease management remains elusive. Our present work has shown that chitinolytic microbes viz., Chitiniphilus sp. MTN22 and Streptomyces sp. MTN14 singly as well as in combination modulated the biosynthetic pathway of bacoside A and systemic defense mechanism against Meloidogyne incognita in Bacopa monnieri. Interestingly, expression of bacoside biosynthetic pathway genes (3-Hydroxy-3-methylglutaryl coenzyme A reductase, mevalonate diphosphate decarboxylase, and squalene synthase) were upregulated in plants treated with the microbial combination in the presence as well as in absence of M...
February 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28138930/recombinant-3-hydroxy-3-methyl-glutaryl-coa-reductase-from-candida-glabrata-rec-cghmgr-obtained-by-heterologous-expression-as-a-novel-therapeutic-target-model-for-testing-synthetic-drugs
#13
Dulce Andrade-Pavón, Roberto I Cuevas-Hernández, José G Trujillo-Ferrara, César Hernández-Rodríguez, J Antonio Ibarra, Lourdes Villa-Tanaca
The enzyme 3-hydroxy-3-methyl-glutaryl CoA reductase (HMGR) is a glycoprotein of the endoplasmic reticulum that participates in the mevalonate pathway, the precursor of cholesterol in human and ergosterol in fungi. This enzyme has three domains: transmembrane, binding, and soluble. In this study, we expressed and purified the soluble fraction of the HMGR enzyme from Candida glabrata (CgHMGR) in an Escherichia coli heterologous system and used it as a model for studying its inhibitory activity. The soluble fraction of CgHMGR was fused to the maltose binding protein (MBP), purified, and characterized...
January 30, 2017: Applied Biochemistry and Biotechnology
https://www.readbyqxmd.com/read/28137282/dynamic-control-of-erg20-expression-combined-with-minimized-endogenous-downstream-metabolism-contributes-to-the-improvement-of-geraniol-production-in-saccharomyces-cerevisiae
#14
Jianzhi Zhao, Chen Li, Yan Zhang, Yu Shen, Jin Hou, Xiaoming Bao
BACKGROUND: Microbial production of monoterpenes provides a promising substitute for traditional chemical-based methods, but their production is lagging compared with sesquiterpenes. Geraniol, a valuable monoterpene alcohol, is widely used in cosmetic, perfume, pharmaceutical and it is also a potential gasoline alternative. Previously, we constructed a geraniol production strain by engineering the mevalonate pathway together with the expression of a high-activity geraniol synthase. RESULTS: In this study, we further improved the geraniol production through reducing the endogenous metabolism of geraniol and controlling the precursor geranyl diphosphate flux distribution...
January 31, 2017: Microbial Cell Factories
https://www.readbyqxmd.com/read/28130383/large-scale-collection-of-full-length-cdna-and-transcriptome-analysis-in-hevea-brasiliensis
#15
Yuko Makita, Kiaw Kiaw Ng, G Veera Singham, Mika Kawashima, Hideki Hirakawa, Shusei Sato, Ahmad Sofiman Othman, Minami Matsui
Natural rubber has unique physical properties that cannot be replaced by products from other latex-producing plants or petrochemically produced synthetic rubbers. Rubber from Hevea brasiliensis is the main commercial source for this natural rubber that has a cis-polyisoprene configuration. For sustainable production of enough rubber to meet demand elucidation of the molecular mechanisms involved in the production of latex is vital. To this end, we firstly constructed rubber full-length cDNA libraries of RRIM 600 cultivar and sequenced around 20,000 clones by the Sanger method and over 15,000 contigs by Illumina sequencer...
January 27, 2017: DNA Research: An International Journal for Rapid Publication of Reports on Genes and Genomes
https://www.readbyqxmd.com/read/28129677/monogenic-auto-in%C3%AF-ammatory-syndromes-a-review-of-the-literature
#16
Gholamreza Azizi, Shahin Khadem Azarian, Sepideh Nazeri, Ali Mosayebian, Saleh Ghiasy, Ghazal Sadri, Ali Mohebi, Nikoo Hossein Khan Nazer, Sanaz Afraei, Abbas Mirshafiey
Auto-inflammatory syndromes are a new group of distinct hereditable disorders characterized by episodes of seemingly unprovoked inflammation (most commonly in skin, joints, gut, and eye), the absence of a high titer of auto-antibodies or auto-reactive T cells, and an inborn error of innate immunity. A narrative literature review was carried out of studies related to auto-inflammatory syndromes to discuss the pathogenesis and clinical manifestation of these syndromes. This review showed that the main monogenic auto-inflammatory syndromes are familial Mediterranean fever (FMF), mevalonate kinase deficiency (MKD), Blau syndrome, TNF receptor-associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndrome (CAPS), and pyogenic arthritis with pyoderma gangrenosum and acne (PAPA)...
December 2016: Iranian Journal of Allergy, Asthma, and Immunology
https://www.readbyqxmd.com/read/28123123/-acute-phase-reaction-following-bisphosphonates
#17
Hiroshi Tsurukami
Bisphosphonates are effective in decreasing bone resorption, the incidence of fragility fracure, and pain from bone metastases. Although relatively well tolerated, the initial dose(s)of intravenous or oral monthly aminobisphosphonates can be associated with an acute phase response, a nonspecific physiologic reaction associated with increased levels of inflammatory cytokines, fever, and flu like symptoms including fatigue, nausea, and myalgia within 3 days of dosing and lasting 7 days or less. Nitrogen-BPs(N-BPs)inhibit osteoclast function by acting as potent inhibitors of the enzyme farnesyl diphosphate(FPP)synthase in the mevalonate biosynthetic pathway...
2017: Clinical Calcium
https://www.readbyqxmd.com/read/28118603/disabled-cell-density-sensing-leads-to-dysregulated-cholesterol-synthesis-in-glioblastoma
#18
Diane M Kambach, Alan S Halim, A Gesine Cauer, Qian Sun, Carlos A Tristan, Orieta Celiku, Aparna H Kesarwala, Uma Shankavaram, Eric Batchelor, Jayne M Stommel
A hallmark of cellular transformation is the evasion of contact-dependent inhibition of growth. To find new therapeutic targets for glioblastoma, we looked for pathways that are inhibited by high cell density in astrocytes but not in glioma cells. Here we report that glioma cells have disabled the normal controls on cholesterol synthesis. At high cell density, astrocytes turn off cholesterol synthesis genes and have low cholesterol levels, but glioma cells keep this pathway on and maintain high cholesterol...
January 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28098152/human-farnesyl-pyrophosphate-synthase-is-allosterically-inhibited-by-its-own-product
#19
Jaeok Park, Michal Zielinski, Alexandr Magder, Youla S Tsantrizos, Albert M Berghuis
Farnesyl pyrophosphate synthase (FPPS) is an enzyme of the mevalonate pathway and a well-established therapeutic target. Recent research has focused around a newly identified druggable pocket near the enzyme's active site. Pharmacological exploitation of this pocket is deemed promising; however, its natural biological function, if any, is yet unknown. Here we report that the product of FPPS, farnesyl pyrophosphate (FPP), can bind to this pocket and lock the enzyme in an inactive state. The Kd for this binding is 5-6 μM, within a catalytically relevant range...
January 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28095071/mevalonate-kinase-deficiency-associated-with-ataxia-and-retinitis-pigmentosa-in-two-brothers-with-mvk-gene-mutations
#20
Ulrich Kellner, Heidi Stöhr, Silke Weinitz, Ghazaleh Farmand, Bernhard H F Weber
PURPOSE: To report the clinical and molecular genetic findings in two brothers with retinitis pigmentosa (RP) and mevalonate kinase deficiency (MKD). METHODS: The brothers were examined clinically and with fundus autofluorescence, near-infrared autofluorescence, and spectral domain optical coherence tomography. Targeted resequencing was done with a custom designed gene panel containing 78 genes associated with RP. Mutations were confirmed by direct Sanger sequencing...
January 17, 2017: Ophthalmic Genetics
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