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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
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
Megan Brafford May, Ashley Glode
Statin use leads to a reduction in the downstream products of the mevalonate pathway. Knowledge of this pathway has led scientists to investigate the role of statins in cancer prevention and treatment. Statins appear to possess a variety of pleiotropic effects, including inhibition of cell proliferation; enhanced apoptosis; and modulation of inflammation, endothelial function, and angiogenesis. In cancer specifically, experimental studies have found that statins may induce cancer cell apoptosis and inhibit tumor growth, angiogenesis, and metastasis...
March 2016: Journal of the Advanced Practitioner in Oncology
Lívia Queiroz de Sousa, Kátia da Conceição Machado, Samara Ferreira de Carvalho Oliveira, Lidiane da Silva Araújo, Evaldo Dos Santos Monção-Filho, Ana Amélia de Carvalho Melo-Cavalcante, Gerardo Magela Vieira-Júnior, Paulo Michel Pinheiro Ferreira
Amphibians present pharmacologically active aliphatic, aromatic and heterocyclic molecules in their skin as defense against microorganisms, predators and infections, such as steroids, alkaloids, biogenic amines, guanidine derivatives, proteins and peptides. Based on the discovered bioactive potential of bufadienolides, this work reviewed the contribution of amphibians, especially from members of Bufonidae family, as source of new cytotoxic and antitumor molecules, highlighting the mechanisms responsible for such amazing biological potentialities...
January 7, 2017: Toxicon: Official Journal of the International Society on Toxinology
Tao Cheng, Hui Liu, Huibin Zou, Ningning Chen, Mengxun Shi, Congxia Xie, Guang Zhao, Mo Xian
BACKGROUND: As an important bulk chemical for synthetic rubber, isoprene can be biosynthesized by robust microbes. But rational engineering and optimization are often demanded to make the in vivo process feasible due to the complexities of cellular metabolism. Alternative synthetic biochemistry strategies are in fast development to produce isoprene or isoprenoids in vitro. RESULTS: This study set up an in vitro enzyme synthetic chemistry process using 5 enzymes in the lower mevalonate pathway to produce isoprene from mevalonate...
January 9, 2017: Microbial Cell Factories
Qiangwen Chen, Jiaping Yan, Xiangxiang Meng, Feng Xu, Weiwei Zhang, Yongling Liao, Jinwang Qu
Ginkgolides and bilobalide, collectively termed terpene trilactones (TTLs), are terpenoids that form the main active substance of Ginkgo biloba. Terpenoids in the mevalonate (MVA) biosynthetic pathway include acetyl-CoA C-acetyltransferase (AACT) and mevalonate kinase (MVK) as core enzymes. In this study, two full-length (cDNAs) encoding AACT (GbAACT, GenBank Accession No. KX904942) and MVK (GbMVK, GenBank Accession No. KX904944) were cloned from G. biloba. The deduced GbAACT and GbMVK proteins contain 404 and 396 amino acids with the corresponding open-reading frame (ORF) sizes of 1215 bp and 1194 bp, respectively...
January 2, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Fan Wang, Xiaomei Lv, Wenping Xie, Pingping Zhou, Yongqiang Zhu, Zhen Yao, Chengcheng Yang, Xiaohong Yang, Lidan Ye, Hongwei Yu
Current studies on microbial isoprene biosynthesis have mostly focused on regulation of the upstream mevalonic acid (MVA) or methyl-erythritol-4-phosphate (MEP) pathway. However, the downstream bottleneck restricting isoprene biosynthesis capacity caused by the weak expression and low activity of plant isoprene synthase (ISPS) under microbial fermentation conditions remains to be alleviated. Here, based on a previously constructed Saccharomyces cerevisiae strain with enhanced precursor supply, we strengthened the downstream pathway through increasing both the expression and activity of ISPS to further improve isoprene production...
January 2017: Metabolic Engineering
Huan Qiu, Hwan Su Yoon, Debashish Bhattacharya
Red algae comprise an anciently diverged, species-rich phylum with morphologies that span unicells to large seaweeds. Here, leveraging a rich red algal genome and transcriptome dataset, we used 298 single-copy orthologous nuclear genes from 15 red algal species to erect a robust multi-gene phylogeny of Rhodophyta. This tree places red seaweeds (Bangiophyceae and Florideophyceae) at the base of the mesophilic red algae with the remaining non-seaweed mesophilic lineages forming a well-supported sister group. The early divergence of seaweeds contrasts with the evolution of multicellular land plants and brown algae that are nested among multiple, unicellular or filamentous sister lineages...
December 2, 2016: PLoS Currents
Miaomiao Liu, Shanfa Lu
Plastoquinone (PQ) and ubiquinone (UQ) are two important prenylquinones, functioning as electron transporters in the electron transport chain of oxygenic photosynthesis and the aerobic respiratory chain, respectively, and play indispensable roles in plant growth and development through participating in the biosynthesis and metabolism of important chemical compounds, acting as antioxidants, being involved in plant response to stress, and regulating gene expression and cell signal transduction. UQ, particularly UQ10, has also been widely used in people's life...
2016: Frontiers in Plant Science
Jung-Hun Kim, Chonglong Wang, Hui-Jung Jang, Myeong-Seok Cha, Ju-Eon Park, Seon-Yeong Jo, Eui-Sung Choi, Seon-Won Kim
BACKGROUND: Isoprene, a volatile C5 hydrocarbon, is an important platform chemical used in the manufacturing of synthetic rubber for tires and various other applications, such as elastomers and adhesives. RESULTS: In this study, Escherichia coli MG1655 harboring Populus trichocarpa isoprene synthase (PtispS) and the exogenous mevalonate (MVA) pathway produced 80 mg/L isoprene. Codon optimization and optimal expression of the ispS gene via adjustment of the RBS strength and inducer concentration increased isoprene production to 199 and 337 mg/L, respectively...
December 23, 2016: Microbial Cell Factories
Chen-Ze Zhao, Xu-Ming Zhao, Jian Yang, Yun Mou, Bin Chen, Huan-Dong Wu, Dong-Pu Dai, Jie Ding, Shen-Jiang Hu
Farnesyl pyrophosphate synthase (FPPS) is a key enzyme in the mevalonate pathway. In our previous studies, we find that inhibition of FPPS attenuates angiotensin II-induced cardiac hypertrophy and fibrosis by suppressing RhoA while FPPS and Ras are up-regulated in pressure overload rats. In this study, we evaluate the effects and mechanisms of FPPS inhibition in pressure overload mice. Male FPPS-small interfering RNA (SiRNA) transgenic (Tg) mice and non-transgenic littermate control (NLC) were randomly divided into suprarenal abdominal aortic constriction (AAC) group and sham operation group...
December 23, 2016: Scientific Reports
Jeffrey M Vinokur, Matthew C Cummins, Tyler P Korman, James U Bowie
Extreme acidophiles are capable of growth at pH values near zero. Sustaining life in acidic environments requires extensive adaptations of membranes, proton pumps, and DNA repair mechanisms. Here we describe an adaptation of a core biochemical pathway, the mevalonate pathway, in extreme acidophiles. Two previously known mevalonate pathways involve ATP dependent decarboxylation of either mevalonate 5-phosphate or mevalonate 5-pyrophosphate, in which a single enzyme carries out two essential steps: (1) phosphorylation of the mevalonate moiety at the 3-OH position and (2) subsequent decarboxylation...
December 22, 2016: Scientific Reports
Kento Motoyama, Hideaki Unno, Ai Hattori, Tomohiro Takaoka, Hiroshi Ishikita, Hiroshi Kawaide, Tohru Yoshimura, Hisashi Hemmi
The biosynthesis of isopentenyl diphosphate--a fundamental precursor for isoprenoids--via the mevalonate pathway is completed by diphosphomevalonate decarboxylase. This enzyme catalyzes the formation of isopentenyl diphosphate through the ATP-dependent phosphorylation of the 3-hydroxyl group of (R)-5-diphosphomevalonate followed by decarboxylation coupled with the elimination of the 3-phosphate group. In this reaction, a conserved aspartate residue has been proposed to be involved in the phosphorylation step as the general base catalyst that abstracts a proton from the 3-hydroxyl group...
December 21, 2016: Journal of Biological Chemistry
Annika Frank, Michael Groll
Isoprenoids constitute one of the most diverse classes of natural products. As a compound class, they are essential to basic metabolic processes including cell-wall biosynthesis, post-translational protein modifications, and signaling. In addition, isoprenoid secondary metabolites are highly valuable natural products with a wide range of biotechnological applications. The biosynthesis of their two universal building blocks, isopentenyl diphosphate and dimethylallyl diphosphate, was thought to proceed exclusively by way of mevalonate as a key intermediate until a novel pathway involving methylerithritol phosphate (MEP) was discovered in the early 1990s...
December 20, 2016: Chemical Reviews
James Kirby, Kevin L Dietzel, Gale Wichmann, Rossana Chan, Eugene Antipov, Nathan Moss, Edward E K Baidoo, Peter Jackson, Sara P Gaucher, Shayin Gottlieb, Jeremy LaBarge, Tina Mahatdejkul, Kristy M Hawkins, Sheela Muley, Jack D Newman, Pinghua Liu, Jay D Keasling, Lishan Zhao
Isoprenoids are used in many commercial applications and much work has gone into engineering microbial hosts for their production. Isoprenoids are produced either from acetyl-CoA via the mevalonate pathway or from pyruvate and glyceraldehyde 3-phosphate via the 1-deoxy-D-xylulose 5-phosphate (DXP) pathway. Saccharomyces cerevisiae exclusively utilizes the mevalonate pathway to synthesize native isoprenoids and in fact the alternative DXP pathway has never been found or successfully reconstructed in the eukaryotic cytosol...
October 27, 2016: Metabolic Engineering
Wojciech Senkowski, Malin Jarvius, Jenny Rubin, Johan Lengqvist, Mats G Gustafsson, Peter Nygren, Kim Kultima, Rolf Larsson, Mårten Fryknäs
Cancer cell lines grown as two-dimensional (2D) cultures have been an essential model for studying cancer biology and anticancer drug discovery. However, 2D cancer cell cultures have major limitations, as they do not closely mimic the heterogeneity and tissue context of in vivo tumors. Developing three-dimensional (3D) cell cultures, such as multicellular tumor spheroids, has the potential to address some of these limitations. Here, we combined a high-throughput gene expression profiling method with a tumor spheroid-based drug-screening assay to identify context-dependent treatment responses...
November 17, 2016: Cell Chemical Biology
Bingyin Peng, Manuel R Plan, Panagiotis Chrysanthopoulos, Mark P Hodson, Lars K Nielsen, Claudia E Vickers
Sesquiterpenes are C15 isoprenoids with utility as fragrances, flavours, pharmaceuticals, and potential biofuels. Microbial fermentation is being examined as a competitive approach for bulk production of these compounds. Competition for carbon allocation between synthesis of endogenous sterols and production of the introduced sesquiterpene limits yields. Achieving balance between endogenous sterols and heterologous sesquiterpenes is therefore required to achieve economical yields. In the current study, the yeast Saccharomyces cerevisiae was used to produce the acyclic sesquiterpene alcohol, trans-nerolidol...
January 2017: Metabolic Engineering
Yasar Sertbas, Meltem Sertbas, Ugur Ersoy, Bulent Bilir, Seracettin Gunaydin, Ali Ozdemir
OBJECTIVE: To investigate the effect of ezetimibe on platelet functions as a drug which increases mevalonate levels. METHODS: This retrospective study was conducted in Istanbul, Turkey, and comprised record of normolipidaemic and hyperlipidaemic patients taken from the outpatient clinic from October 2004 to February 2015,. The results were taken from the baseline and third-month data of ezetimibe treatment. SPSS 22 was used for statistical analysis. RESULTS: Of the total, there were 50(53%) normolipidaemic patients and 45(47%) hyperlipidaemic ones...
December 2016: JPMA. the Journal of the Pakistan Medical Association
Wei-Fan Liang, Lan-Yu Cui, Jin-Yu Cui, Kai-Wen Yu, Song Yang, Tian-Min Wang, Chang-Ge Guan, Chong Zhang, Xin-Hui Xing
Acetyl-CoA is not only an important intermediate metabolite for cells but also a significant precursor for production of industrially interesting metabolites. Methylobacterium extorquens AM1, a model strain of methylotrophic cell factories using methanol as carbon source, is of interest because it produces abundant coenzyme A compounds capable of directing to synthesis of different useful compounds from methanol. However, acetyl-CoA is not always efficiently accumulated in M. extorquens AM1, as it is located in the center of three cyclic central metabolic pathways...
January 2017: Metabolic Engineering
Lijun Ye, Chunzhi Zhang, Changhao Bi, Qingyan Li, Xueli Zhang
BACKGROUND: Plasmid expression is a popular method in studies of MVA pathway for isoprenoid production in Escherichia coli. However, heterologous gene expression with plasmid is often not stable and might burden growth of host cells, decreases cell mass and product yield. In this study, MVA pathway was divided into three modules, and two heterologous modules were integrated into the E. coli chromosome. These modules were individually modulated with regulatory parts to optimize efficiency of the pathway in terms of downstream isoprenoid production...
December 1, 2016: Microbial Cell Factories
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