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ASPP2 Inhibits Tumor Growth by Repressing the Mevalonate Pathway
Liang et al. Cell Death and Disease (2019) 10:830 https://doi.org/10.1038/s41419-019-2054-7 Cell Death & Disease ARTICLE Open Access ASPP2 inhibits tumor growth by repressing the mevalonate pathway in hepatocellular carcinoma Beibei Liang1,RuiChen2, Shaohua Song3,HaoWang4,GuoweiSun5, Hao Yang1,WeiJing6, Xuyu Zhou6,ZhirenFu3, Gang Huang1 and Jian Zhao1 Abstract Cancer is, fundamentally, a disorder of cell growth and proliferation, which requires adequate supplies of energy and nutrients. In this study, we report that the haplo-insufficient tumor suppressor ASPP2, a p53 activator, negatively regulates the mevalonate pathway to mediate its inhibitory effect on tumor growth in hepatocellular carcinoma (HCC). Gene expression profile analysis revealed that the expression of key enzymes in the mevalonate pathway were increased when ASPP2 was downregulated. HCC cells gained higher cholesterol levels and enhanced tumor-initiating capability in response to the depletion of ASPP2. Simvastatin, a mevalonate pathway inhibitor, efficiently abrogated ASPP2 depletion-induced anchorage-independent cell proliferation, resistance to chemotherapy drugs in vitro, and tumor growth in xenografted nude mice. Mechanistically, ASPP2 interacts with SREBP-2 in the nucleus and restricts the transcriptional activity of SREBP-2 on its target genes, which include key enzymes involved in the mevalonate pathway. Moreover, clinical data revealed better prognosis in patients with high levels of ASPP2 and low levels of the mevalonate pathway enzyme HMGCR. Our findings provide functional and mechanistic insights into the critical role of ASPP2 in the regulation of the mevalonate pathway and the importance of this pathway in tumor initiation and tumor growth, which may provide a new therapeutic opportunity for HCC. -
Of Mevalonate Metabolism'
ICANCER RESEARCH57. 3498—3505.AugustIS. 9971 Regulation of Proliferation and Ras Localization in Transformed Cells by Products of Mevalonate Metabolism' Jennifer A. Cuthbert2 and Peter E. Lipsky Department of Internal Medicine. The Unit'ersitv of Texas Southwestern Medical (‘enterat Dallas. Dallas. Texas 75235-9151 ABSTRACT position 186, the removal of the three COOH-terminal amino acids at positions 187—189, and carboxymethylation of the new COOH-termi Lovastatin, an inhibitor of 3-hydroxy.3-methylglutaryl (HMG) CoA nab cysteine. In addition, either palmitybation of other cysteine resi reductase, and 6-fluoromevalonate (Fmev), an inhibitor of diphospho dues in the COOH terminus (H-Ras, N-Ras, and K-RasA) or a mevalonate decarboxylase, blocked the synthesis of downstream meval. onate products, including prenyl-derived lipids, and prevented membrane pobybasic domain (K-RasB) is important in enhancing membrane localization of Ras in the myeloid cell line U.937. In contrast to lovastatin, association (7). These processes occur stepwise, and the first step, that which induced cytosol localization of Ras in U-937 cells, Fmev failed to of farnesybation of the full-length polypeptide, is thereby essential for increase cytosolic Ras and also completely prevented the proliferation of plasma membrane localization (12—14).Thus, compounds and muta U.937 cells. Growth of U-937 cells was restored by the addition of lovas tions that block the process of farnesylation interfere with the trans tatin to Fmev-blocked cells. These results implied that a product of formation and proliferation that are dependent upon mutationally mevalonate metabolism proximal to isopentenyl diphosphate was respon. activated Ras. -
33 34 35 Lipid Synthesis Laptop
BI/CH 422/622 Liver cytosol ANABOLISM OUTLINE: Photosynthesis Carbohydrate Biosynthesis in Animals Biosynthesis of Fatty Acids and Lipids Fatty Acids Triacylglycerides contrasts Membrane lipids location & transport Glycerophospholipids Synthesis Sphingolipids acetyl-CoA carboxylase Isoprene lipids: fatty acid synthase Ketone Bodies ACP priming 4 steps Cholesterol Control of fatty acid metabolism isoprene synth. ACC Joining Reciprocal control of b-ox Cholesterol Synth. Diversification of fatty acids Fates Eicosanoids Cholesterol esters Bile acids Prostaglandins,Thromboxanes, Steroid Hormones and Leukotrienes Metabolism & transport Control ANABOLISM II: Biosynthesis of Fatty Acids & Lipids Lipid Fat Biosynthesis Catabolism Fatty Acid Fatty Acid Synthesis Degradation Ketone body Utilization Isoprene Biosynthesis 1 Cholesterol and Steroid Biosynthesis mevalonate kinase Mevalonate to Activated Isoprenes • Two phosphates are transferred stepwise from ATP to mevalonate. • A third phosphate from ATP is added at the hydroxyl, followed by decarboxylation and elimination catalyzed by pyrophospho- mevalonate decarboxylase creates a pyrophosphorylated 5-C product: D3-isopentyl pyrophosphate (IPP) (isoprene). • Isomerization to a second isoprene dimethylallylpyrophosphate (DMAPP) gives two activated isoprene IPP compounds that act as precursors for D3-isopentyl pyrophosphate Isopentyl-D-pyrophosphate all of the other lipids in this class isomerase DMAPP Cholesterol and Steroid Biosynthesis mevalonate kinase Mevalonate to Activated Isoprenes • Two phosphates -
Production of Succinic Acid by E.Coli from Mixtures of Glucose
2005:230 CIV MASTER’S THESIS Production of Succinic Acid by E. coli from Mixtures of Glucose and Fructose ANDREAS LENNARTSSON MASTER OF SCIENCE PROGRAMME Chemical Engineering Luleå University of Technology Department of Chemical Engineering and Geosciences Division of Biochemical and Chemical Engineering 2005:230 CIV • ISSN: 1402 - 1617 • ISRN: LTU - EX - - 05/230 - - SE Abstract Succinic acid, derived from fermentation of renewable feedstocks, has the possibility of replacing petrochemicals as a building block chemical. Another interesting advantage with biobased succinic acid is that the production does not contribute to the accumulation of CO2 to the environment. The produced succinic acid can therefore be considered as a “green” chemical. The bacterium used in this project is a strain of Escherichia coli called AFP184 that has been metabolically engineered to produce succinic acid in large quantities from glucose during anaerobic conditions. The objective with this thesis work was to evaluate whether AFP184 can utilise fructose, both alone and in mixtures with glucose, as a carbon source for the production of succinic acid. Hydrolysis of sucrose yields a mixture of fructose and glucose in equal ratio. Sucrose is a common sugar and the hydrolysate is therefore an interesting feedstock for the production of succinic acid. Fermentations with an initial sugar concentration of 100 g/L were conducted. The sugar ratios used were 100 % fructose, 100 % glucose and a mixture with 50 % fructose and glucose, respectively. The fermentation media used was a lean, low- cost media based on corn steep liquor and a minimal addition of inorganic salts. Fermentations were performed with a 12 L bioreactor and the acid and sugar concentrations were analysed with an HPLC system. -
Construction and Optimization of Mevalonate Pathway for Production Of
Construction and Optimization of Mevalonate Pathway for Production of Isoprenoids in Escherichia coli by Farnaz Nowroozi A dissertation submitted in partial satisfaction of the requirements for the degree of Joint Doctor of Philosophy with University of California, San Francisco in Engineering-Bioengineering in the Graduate Division of the University of California, Berkeley Committee in charge: Professor Jay D. Keasling, Chair Professor Adam P. Arkin Professor Francis C. Szoka Professor Marc K. Hellerstein Fall 2009 1 The dissertation of Farnaz Foroughi-Boroujeni Nowroozi, titled Construction and Optimization of Mevalonate Pathway for production of Isoprenoids in Escherichia coli , is approved: Chair _______________________________ Date ____________________ _______________________________ Date____________________ _______________________________ Date ____________________ _______________________________ Date ____________________ University of California, Berkeley 2 Abstract Construction and Optimization of Mevalonate Pathway for production of Isoprenoids in Escherichia coli by Farnaz Foroughi-Boroujeni Nowroozi Doctor of Philosophy in Bioengineering University of California, Berkeley Professor Jay D. Keasling, Chair The isoprenoid family, containing over 50,000 members, constitutes one of the most structurally diverse groups of natural products. They range from essential and relatively universal primary metabolites, such as sterols, carotenoids, and hormones, to more unique secondary metabolites that serve roles in plant defense and communication and cellular and organismal development. Although these molecules have vast potential in medicine and industry their production is limited by two factors: 1- The yields from harvest and extraction of these compounds from their native sources are low 2- Due to their complex structure, synthetic routes to most isoprenoids are difficult and inefficient Therefore engineering metabolic pathways for production of large quantities of isoprenoids in a microbial host is an attractive approach. -
Engineering a Mevalonate Pathway in Escherichia Coli for Production of Terpenoids
ARTICLES Engineering a mevalonate pathway in Escherichia coli for production of terpenoids Vincent JJ Martin1,2,3, Douglas J Pitera1,3,Sydnor T Withers1,Jack D Newman1 & Jay D Keasling1 Isoprenoids are the most numerous and structurally diverse family of natural products. Terpenoids, a class of isoprenoids often isolated from plants, are used as commercial flavor and fragrance compounds and antimalarial or anticancer drugs. Because plant tissue extractions typically yield low terpenoid concentrations, we sought an alternative method to produce high-value terpenoid compounds, such as the antimalarial drug artemisinin, in a microbial host. We engineered the expression of a synthetic amorpha-4,11-diene synthase gene and the mevalonate isoprenoid pathway from Saccharomyces cerevisiae in Escherichia coli. Concentrations of amorphadiene, the sesquiterpene olefin precursor to artemisinin, reached 24 µg caryophyllene equivalent/ml. Because isopentenyl and dimethylallyl pyrophosphates are the universal precursors to all isoprenoids, the strains developed in this study can serve as platform hosts for the production of any terpenoid compound for which a terpene synthase gene is available. http://www.nature.com/naturebiotechnology Terpenoids comprise a highly diverse class of natural products from certain cancers10,11, and irufloven, a third-generation semisynthetic which numerous commercial flavors, fragrances and medicines are analog of the sesquiterpene illudin S that are in late-stage clinical derived. These valuable compounds are commonly isolated from trials for the treatment of various refractory and relapsed can- plants, microbes and marine organisms. For example, terpenoids cers12,13.In general, these drugs are extracted from the host plant, in extracted from plants are used as anticancer and antimalarial which they accumulate in very small amounts, before further drugs1,2.Because these compounds are naturally produced in small derivatization or use. -
The Formate Channel Foca Exports the Products of Mixed-Acid Fermentation
The formate channel FocA exports the products of mixed-acid fermentation Wei Lü, Juan Du, Nikola J. Schwarzer, Elke Gerbig-Smentek, Oliver Einsle, and Susana L. A. Andrade1 Institute of Organic Chemistry and Biochemistry and BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-Universität Freiburg, 79104 Freiburg, Germany Edited by Christopher Miller, Howard Hughes Medical Institute, Brandeis University, Waltham, MA, and approved July 10, 2012 (received for review March 11, 2012) Formate is a major metabolite in the anaerobic fermentation of and is then oxidized to CO2 by a periplasmic formate de- glucose by many enterobacteria. It is translocated across cellular hydrogenase, FDH-N or FDH-O, resulting in the generation of membranes by the pentameric ion channel/transporter FocA that, proton motive force (11–13). In addition, the complex pathway together with the nitrite channel NirC, forms the formate/nitrite of mixed-acid fermentation produces acetate, ethanol, lactate, transporter (FNT) family of membrane transport proteins. Here we and succinate as further end products (Fig. 1A). FocA acts as have carried out an electrophysiological analysis of FocA from Sal- a passive exporter for formate anions generated in the cyto- monella typhimurium to characterize the channel properties and plasm, but a remarkable functional switch of transport mode was assess its specificity toward formate and other possible permeat- found for this protein when the pH of the growth medium ing ions. Single-channel currents for formate, hypophosphite and dropped below 6.8 (14). With ample protons available in the nitrite revealed two mechanistically distinct modes of gating that periplasm, the cell switches to active import of formate and reflect different types of structural rearrangements in the trans- again uses FocA for the task. -
Accelerated Electro-Fermentation of Acetoin in Escherichia Coli by Identifying Physiological Limitations of the Electron Transfer Kinetics and the Central Metabolism
microorganisms Article Accelerated Electro-Fermentation of Acetoin in Escherichia coli by Identifying Physiological Limitations of the Electron Transfer Kinetics and the Central Metabolism 1, 1 1,2, Sebastian Beblawy y, Laura-Alina Philipp and Johannes Gescher * 1 Department of Applied Biology, Institute for Applied Biosciences, Karlsruhe Institute of Technology, Fritz-Haber-Weg 2, 76131 Karlsruhe, Germany; [email protected] (S.B.); [email protected] (L.-A.P.) 2 Institute for Biological Interfaces, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany * Correspondence: [email protected] Current affiliation: Environmental Biotechnology, Centre for Applied Geosciences, University of Tübingen, y Schnarrenbergstr. 94-96, 72074 Tübingen, Germany. Received: 25 September 2020; Accepted: 21 November 2020; Published: 23 November 2020 Abstract: Anode-assisted fermentations offer the benefit of an anoxic fermentation routine that can be applied to produce end-products with an oxidation state independent from the substrate. The whole cell biocatalyst transfers the surplus of electrons to an electrode that can be used as a non-depletable electron acceptor. So far, anode-assisted fermentations were shown to provide high carbon efficiencies but low space-time yields. This study aimed at increasing space-time yields of an Escherichia coli-based anode-assisted fermentation of glucose to acetoin. The experiments build on an obligate respiratory strain, that was advanced using selective adaptation and targeted strain development. Several transfers under respiratory conditions led to point mutations in the pfl, aceF and rpoC gene. These mutations increased anoxic growth by three-fold. Furthermore, overexpression of genes encoding a synthetic electron transport chain to methylene blue increased the electron transfer rate by 2.45-fold. -
Evolution of Carotenoid and Isoprenoid Biosynthesis in Photosynthetic and Non-Photosynthetic Organisms
EVOLUTION OF CAROTENOID AND ISOPRENOID BIOSYNTHESIS IN PHOTOSYNTHETIC AND NON-PHOTOSYNTHETIC ORGANISMS HARTMUT K. LICHTENTHALER Botanisches Institut II, University of Karlsruhe, Kaiserstr. 12, D-76128 Karlsruhe, Germany Email: [email protected] Abstract Sterols and carotenoids are typical representatives of the group of isoprenoid lipids in plants. All isoprenoids are synthesized by condensation of the two active C5-units: dimethylallyl diphosphate, DMAPP, and isopentenyl diphosphate, IPP. Like animals, higher plants form their sterols via the classical cytosolic acetate/mevalonate (MVA) pathway of IPP biosynthesis. Plants as photosynthetic organisms, however possess a second, non- mevalonate pathway for IPP biosynthesis, the DOXP/MEP pathway. The latter operates in the chloroplasts and is responsible for the formation of carotenoids and all other plastidic isoprenoid lipids (phytol, prenylquinones). Although there exists some cooperation between both IPP producing pathways, one can never fully compensate for the other. Thus, in higher plants sterols are primarily made via the MVA pathway and carotenoids via the DOXP pathway. This also applies to several algae groups, such as red algae and Heterokontophyta. In the large and diverging group of 'Green Algae' the situation is more complex. The more advanced evolutionary groups (Charales, Zygnematales) possess, like higher plants, both IPP forming pathways and represent an evolutionary link to these. In contrast, the proper Chlorophyta, often single cell organisms (Chlorella, Scenedesmus, Trebouxia), represent a separate phylum and synthesize sterols and carotenoids via the DOXP pathway whereas the MVA pathway is lost. The common ancestor of both groups, Mesostigma viride, again exhibits both IPP pathways. In the photosynthetic Euglenophyta the situation is inverse, both the sterols and the carotenoids are formed exclusively via the MVA pathway, the DOXP pathway is lost during the secondary endosymbiosis. -
Controlled Sumoylation of the Mevalonate Pathway Enzyme HMGS-1 Regulates Metabolism During Aging
Controlled sumoylation of the mevalonate pathway enzyme HMGS-1 regulates metabolism during aging Amir Sapira,b, Assaf Tsurc, Thijs Koormand, Kaitlin Chinga,b, Prashant Mishraa, Annabelle Bardenheiera,b, Lisa Podolskyc, Ulrike Bening-Abu-Shachc, Mike Boxemd, Tsui-Fen Choue, Limor Brodayc,1, and Paul W. Sternberga,b,1 aDivision of Biology and Biological Engineering and bHoward Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125; cDepartment of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; dDevelopmental Biology, Utrecht University, 3584 CH, Utrecht, The Netherlands; and eDivision of Medical Genetics, Department of Pediatrics, and Los Angeles Biomedical Research Institute, Harbor–UCLA Medical Center, Torrance, CA 90502 Contributed by Paul W. Sternberg, August 6, 2014 (sent for review July 3, 2014) Many metabolic pathways are critically regulated during develop- Many cellular processes and physiological states rely on vari- ment and aging but little is known about the molecular mecha- able levels of mevalonate pathway metabolites, suggesting that nisms underlying this regulation. One key metabolic cascade in the pathway activity is highly regulated during the organism’s life eukaryotes is the mevalonate pathway. It catalyzes the synthesis of cycle. Elucidating the molecular details of this regulation is the sterol and nonsterol isoprenoids, such as cholesterol and ubiqui- first step in understanding how pathway dysregulation leads to none, as well as other metabolites. In humans, an age-dependent diseases. For example, as part of the tumorigenic process of decrease in ubiquinone levels and changes in cholesterol homeo- breast cancer cells, the expression of many mevalonate pathway stasis suggest that mevalonate pathway activity changes with age. -
Elucidating Flux Regulation of the Fermentation Modes of Lactococcus Lactis a Mutlilevel Study
Downloaded from orbit.dtu.dk on: Oct 10, 2021 Elucidating Flux Regulation of the Fermentation Modes of Lactococcus lactis A Mutlilevel Study Chan, Siu Hung Joshua Link to article, DOI: 10.11581/DTU:00000016 Publication date: 2014 Document Version Publisher's PDF, also known as Version of record Link back to DTU Orbit Citation (APA): Chan, S. H. J. (2014). Elucidating Flux Regulation of the Fermentation Modes of Lactococcus lactis: A Mutlilevel Study. Technical University of Denmark. https://doi.org/10.11581/DTU:00000016 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Elucidating Flux Regulation of the Fermentation Modes of Lactococcus lactis: A Mutlilevel Study PhD Thesis Siu Hung Joshua Chan November, 2014 Supervisors: Associate Professor Christian Solem Professor Peter Ruhdal Jensen Systems Biotechnology and Biorefining National Food Institute Technical University of Denmark Summary The long history of application to the dairy industry has established Lactococcus lactis (L. -
On-Line Analysis and in Situ Ph Monitoring of Mixed Acid Fermentation by Escherichia Coli Using Combined FTIR and Raman Techniques
This is a repository copy of On-line analysis and in situ pH monitoring of mixed acid fermentation by Escherichia coli using combined FTIR and Raman techniques. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/164855/ Version: Published Version Article: Metcalfe, G.D., Smith, T.W. and Hippler, M. orcid.org/0000-0002-3956-3922 (2020) On-line analysis and in situ pH monitoring of mixed acid fermentation by Escherichia coli using combined FTIR and Raman techniques. Analytical and Bioanalytical Chemistry. ISSN 1618-2642 https://doi.org/10.1007/s00216-020-02865-5 Reuse This article is distributed under the terms of the Creative Commons Attribution (CC BY) licence. This licence allows you to distribute, remix, tweak, and build upon the work, even commercially, as long as you credit the authors for the original work. More information and the full terms of the licence here: https://creativecommons.org/licenses/ Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Analytical and Bioanalytical Chemistry https://doi.org/10.1007/s00216-020-02865-5 RESEARCH PAPER On-line analysis and in situ pH monitoring of mixed acid fermentation by Escherichia coli using combined FTIR and Raman techniques George D. Metcalfe1 & Thomas W. Smith1,2 & Michael Hippler1 Received: 27 May 2020 /Revised: 23 July 2020 /Accepted: 5 August 2020 # The Author(s) 2020 Abstract We introduce an experimental setup allowing continuous monitoring of bacterial fermentation processes by simultaneous optical density (OD) measurements, long-path FTIR headspace monitoring of CO2, acetaldehyde and ethanol, and liquid Raman spectroscopy of acetate, formate, and phosphate anions, without sampling.