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  • 1
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    Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-11-22
    Description: Acetyl coenzyme A (AcCoA) is the central biosynthetic precursor for fatty-acid synthesis and protein acetylation. In the conventional view of mammalian cell metabolism, AcCoA is primarily generated from glucose-derived pyruvate through the citrate shuttle and ATP citrate lyase in the cytosol. However, proliferating cells that exhibit aerobic glycolysis and those exposed to hypoxia convert glucose to lactate at near-stoichiometric levels, directing glucose carbon away from the tricarboxylic acid cycle and fatty-acid synthesis. Although glutamine is consumed at levels exceeding that required for nitrogen biosynthesis, the regulation and use of glutamine metabolism in hypoxic cells is not well understood. Here we show that human cells use reductive metabolism of alpha-ketoglutarate to synthesize AcCoA for lipid synthesis. This isocitrate dehydrogenase-1 (IDH1)-dependent pathway is active in most cell lines under normal culture conditions, but cells grown under hypoxia rely almost exclusively on the reductive carboxylation of glutamine-derived alpha-ketoglutarate for de novo lipogenesis. Furthermore, renal cell lines deficient in the von Hippel-Lindau tumour suppressor protein preferentially use reductive glutamine metabolism for lipid biosynthesis even at normal oxygen levels. These results identify a critical role for oxygen in regulating carbon use to produce AcCoA and support lipid synthesis in mammalian cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710581/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710581/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Metallo, Christian M -- Gameiro, Paulo A -- Bell, Eric L -- Mattaini, Katherine R -- Yang, Juanjuan -- Hiller, Karsten -- Jewell, Christopher M -- Johnson, Zachary R -- Irvine, Darrell J -- Guarente, Leonard -- Kelleher, Joanne K -- Vander Heiden, Matthew G -- Iliopoulos, Othon -- Stephanopoulos, Gregory -- P30 CA014051/CA/NCI NIH HHS/ -- R01 CA122591/CA/NCI NIH HHS/ -- R01 DK075850-01/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Nov 20;481(7381):380-4. doi: 10.1038/nature10602.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22101433" target="_blank"〉PubMed〈/a〉
    Keywords: Acetyl Coenzyme A/biosynthesis/metabolism ; Aryl Hydrocarbon Receptor Nuclear Translocator/metabolism ; Basic Helix-Loop-Helix Transcription Factors/genetics/metabolism ; CD8-Positive T-Lymphocytes/cytology ; Carbon/metabolism ; Carcinoma, Renal Cell/metabolism/pathology ; *Cell Hypoxia ; Cell Line, Tumor ; Cells, Cultured ; Citric Acid Cycle ; Glutamine/*metabolism ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Isocitrate Dehydrogenase/deficiency/genetics/*metabolism ; Ketoglutaric Acids/metabolism ; Kidney Neoplasms/metabolism/pathology ; *Lipogenesis ; Oxidation-Reduction ; Oxygen/metabolism ; Palmitic Acid/metabolism ; Von Hippel-Lindau Tumor Suppressor Protein/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Isoprenoid pathway optimization for Taxol precursor overproduction in Escherichia coli (2010)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2010-10-12
    Description: Taxol (paclitaxel) is a potent anticancer drug first isolated from the Taxus brevifolia Pacific yew tree. Currently, cost-efficient production of Taxol and its analogs remains limited. Here, we report a multivariate-modular approach to metabolic-pathway engineering that succeeded in increasing titers of taxadiene--the first committed Taxol intermediate--approximately 1 gram per liter (~15,000-fold) in an engineered Escherichia coli strain. Our approach partitioned the taxadiene metabolic pathway into two modules: a native upstream methylerythritol-phosphate (MEP) pathway forming isopentenyl pyrophosphate and a heterologous downstream terpenoid-forming pathway. Systematic multivariate search identified conditions that optimally balance the two pathway modules so as to maximize the taxadiene production with minimal accumulation of indole, which is an inhibitory compound found here. We also engineered the next step in Taxol biosynthesis, a P450-mediated 5alpha-oxidation of taxadiene to taxadien-5alpha-ol. More broadly, the modular pathway engineering approach helped to unlock the potential of the MEP pathway for the engineered production of terpenoid natural products.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3034138/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3034138/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ajikumar, Parayil Kumaran -- Xiao, Wen-Hai -- Tyo, Keith E J -- Wang, Yong -- Simeon, Fritz -- Leonard, Effendi -- Mucha, Oliver -- Phon, Too Heng -- Pfeifer, Blaine -- Stephanopoulos, Gregory -- 1-R01-GM085323-01A1/GM/NIGMS NIH HHS/ -- R01 GM085323/GM/NIGMS NIH HHS/ -- R01 GM085323-02/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2010 Oct 1;330(6000):70-4. doi: 10.1126/science.1191652.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20929806" target="_blank"〉PubMed〈/a〉
    Keywords: Alkenes/*metabolism ; Bioreactors ; Cytochrome P-450 Enzyme System/genetics/metabolism ; Diterpenes/*metabolism ; Erythritol/analogs & derivatives/metabolism ; Escherichia coli K12/enzymology/genetics/*metabolism ; Farnesyltranstransferase/genetics/metabolism ; Fermentation ; *Genetic Engineering ; Hemiterpenes/metabolism ; Indoles/metabolism ; Isomerases/genetics/metabolism ; Metabolic Networks and Pathways/genetics ; Metabolomics ; NADPH-Ferrihemoprotein Reductase/genetics/metabolism ; Organophosphorus Compounds/metabolism ; Oxidation-Reduction ; Paclitaxel/*biosynthesis ; Recombinant Fusion Proteins/metabolism ; Sugar Phosphates/metabolism ; Taxoids/metabolism ; Taxus/enzymology ; Terpenes/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 3
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    Biofuels. Engineering alcohol tolerance in yeast (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-10-04
    Description: Ethanol toxicity in the yeast Saccharomyces cerevisiae limits titer and productivity in the industrial production of transportation bioethanol. We show that strengthening the opposing potassium and proton electrochemical membrane gradients is a mechanism that enhances general resistance to multiple alcohols. The elevation of extracellular potassium and pH physically bolsters these gradients, increasing tolerance to higher alcohols and ethanol fermentation in commercial and laboratory strains (including a xylose-fermenting strain) under industrial-like conditions. Production per cell remains largely unchanged, with improvements deriving from heightened population viability. Likewise, up-regulation of the potassium and proton pumps in the laboratory strain enhances performance to levels exceeding those of industrial strains. Although genetically complex, alcohol tolerance can thus be dominated by a single cellular process, one controlled by a major physicochemical component but amenable to biological augmentation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401034/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401034/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lam, Felix H -- Ghaderi, Adel -- Fink, Gerald R -- Stephanopoulos, Gregory -- R01 GM035010/GM/NIGMS NIH HHS/ -- R01-GM035010/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Oct 3;346(6205):71-5. doi: 10.1126/science.1257859. Epub 2014 Oct 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. Whitehead Institute for Biomedical Research, Cambridge, MA, USA. ; Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. ; Whitehead Institute for Biomedical Research, Cambridge, MA, USA. gfink@wi.mit.edu gregstep@mit.edu. ; Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. gfink@wi.mit.edu gregstep@mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25278607" target="_blank"〉PubMed〈/a〉
    Keywords: *Biofuels ; Cation Transport Proteins/genetics ; Cell Culture Techniques ; Cell Membrane/metabolism ; Chemical Engineering ; *Drug Resistance, Fungal/genetics ; Ethanol/*metabolism/pharmacology ; Fermentation ; Genetic Engineering ; Glucose/metabolism ; Hydrogen-Ion Concentration ; Phosphates/*metabolism ; Potassium Compounds/*metabolism ; Proton Pumps/genetics ; Proton-Translocating ATPases/genetics ; Saccharomyces cerevisiae/drug effects/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Up-Regulation ; Xylose/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
    Electronic Resource
    Electronic Resource
    The modular multivariable controller: I: Steady-state properties (1992)
    Hoboken, NJ : Wiley-Blackwell
    AIChE Journal 38 (1992), S. 1254-1278 
    Details
    ISSN: 0001-1541
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: The modular multivariable controller (MMC) represents a multivariable controller design methodology which is based on the solution of multiobjective optimization problems using the strategy of lexicographic goal programming; priority-driven, sequential satisfaction of objectives. This article formally introduces the concept of the MMC, analyzes its static characterstics, and proposes a specific methodology for the design of steady-state MMCs. It is shown that the framework of MMC can explicitly handle all types of control objectives (for example, equality or inequality specifications on controlled outputs), and constraints on manipulations. Its priority-driven, sequential satisfaction of control objectives leads to a modular, hierarchical structure of controllers with specific objectives. The modular character of MMC allows the explicit maintenance, tuning, and reconfiguration of multivariable control systems, while its hierarchical structure explicitly expresses engineering decisions and trade-offs. Its static design incorporates uncertainty in process gains and automatic reconfiguration to account for failure in sensors and/or actuators. The design of an MMC for a heavy oil fractionator is presented to illustrate the controller's character and the proposed methodology for the design of static MMCs.
    Additional Material: 7 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/aic.690380812
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