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Metabolic Engineering

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https://www.readbyqxmd.com/read/28088541/secretory-pathway-optimization-of-cho-producer-cells-by-co-engineering-of-the-mitosrna-1978-target-genes-cers2-and-tbc1d20
#1
Lisa A Pieper, Michaela Strotbek, Till Wenger, Martin Gamer, Monilola A Olayioye, Angelika Hausser
Chinese Hamster Ovary (CHO) cells are the most commonly used host for the production of biopharmaceuticals. Although transcription and translation engineering strategies have been employed to generate high-producer cell clones, the secretory pathway still remains a bottleneck in cellular productivity. In this study we show that ectopic expression of a human mitochondrial genome-encoded small RNA (mitosRNA-1978) in an IgG expressing CHO cell line strongly improved specific productivity by functioning in a microRNA-like fashion...
January 11, 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28088540/multiplexed-site-specific-genome-engineering-for-overproducing-bioactive-secondary-metabolites-in-actinomycetes
#2
Lei Li, Guosong Zheng, Jun Chen, Mei Ge, Weihong Jiang, Yinhua Lu
Actinomycetes produce a large variety of pharmaceutically active compounds, yet production titers often require to be improved for discovery, development and large-scale manufacturing. Here, we describe a new technique, multiplexed site-specific genome engineering (MSGE) via the 'one integrase-multiple attB sites' concept, for the stable integration of secondary metabolite biosynthetic gene clusters (BGCs). Using MSGE, we achieved five-copy chromosomal integration of the pristinamycin II (PII) BGC in Streptomyces pristinaespiralis, resulting in the highest reported PII titers in flask and batch fermentations (2...
January 11, 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28087332/exo-mfa-a-13c-metabolic-flux-analysis-to-dissect-tumor-microenvironment-secreted-exosome-contributions-towards-cancer-cell-metabolism
#3
Abhinav Achreja, Hongyun Zhao, Lifeng Yang, Tae Hyun Yun, Juan Marini, Deepak Nagrath
Dissecting the pleiotropic roles of tumor micro-environment (TME) on cancer progression has been brought to the foreground of research on cancer pathology. Extracellular vesicles such as exosomes, transport proteins, lipids, and nucleic acids, to mediate intercellular communication between TME components and have emerged as candidates for anti-cancer therapy. We previously reported that cancer-associated fibroblast (CAF) derived exosomes (CDEs) contain metabolites in their cargo that are utilized by cancer cells for central carbon metabolism and promote cancer growth...
January 10, 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28089747/metabolic-engineering-of-a-diazotrophic-bacterium-improves-ammonium-release-and-biofertilization-of-plants-and-microalgae
#4
Rafael Ambrosio, Juan Cesar Federico Ortiz-Marquez, Leonardo Curatti
The biological nitrogen fixation carried out by some Bacteria and Archaea is one of the most attractive alternatives to synthetic nitrogen fertilizers. However, with the exception of the symbiotic rhizobia-legumes system, progress towards a more extensive realization of this goal has been slow. In this study we manipulated the endogenous regulation of both nitrogen fixation and assimilation in the aerobic bacterium Azotobacter vinelandii. Substituting an exogenously inducible promoter for the native promoter of glutamine synthetase produced conditional lethal mutant strains unable to grow diazotrophically in the absence of the inducer...
January 9, 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28062280/biotin-independent-strains-of-escherichia-coli-for-enhanced-streptavidin-production
#5
Markus Jeschek, Maximilian O Bahls, Veronika Schneider, Philippe Marlière, Thomas R Ward, Sven Panke
Biotin is an archetypal vitamin used as cofactor for carboxylation reactions found in all forms of life. However, biotin biosynthesis is an elaborate multi-enzymatic process and metabolically costly. Moreover, many industrially relevant organisms are incapable of biotin synthesis resulting in the requirement to supplement defined media. Here we describe the creation of biotin-independent strains of Escherichia coli and Corynebacterium glutamicum through installation of an optimized malonyl-CoA bypass, which re-routes natural fatty acid synthesis, rendering the previously essential vitamin completely obsolete...
January 3, 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28040464/metabolic-engineering-of-clostridium-tyrobutyricum-for-enhanced-butyric-acid-production-from-glucose-and-xylose
#6
Hongxin Fu, Le Yu, Meng Lin, Jufang Wang, Zhilong Xiu, Shang-Tian Yang
Clostridium tyrobutyricum is a promising microorganism for butyric acid production. However, its ability to utilize xylose, the second most abundant sugar found in lignocellulosic biomass, is severely impaired by glucose-mediated carbon catabolite repression (CCR). In this study, CCR in C. tyrobutyricum was eliminated by overexpressing three heterologous xylose catabolism genes (xylT, xylA and xlyB) cloned from C. acetobutylicum. Compared to the parental strain, the engineered strain Ct-pTBA produced more butyric acid (37...
December 28, 2016: Metabolic Engineering
https://www.readbyqxmd.com/read/28038953/leucine-zipper-mediated-targeting-of-multi-enzyme-cascade-reactions-to-inclusion-bodies-in-escherichia-coli-for-enhanced-production-of-1-butanol
#7
Gui Hwan Han, Wonjae Seong, Yaoyao Fu, Paul K Yoon, Seong Keun Kim, Soo-Jin Yeom, Dae-Hee Lee, Seung-Goo Lee
Metabolons in nature have evolved to facilitate more efficient catalysis of multistep reactions through the co-localization of functionally related enzymes to cellular organelles or membrane structures. To mimic the natural metabolon architecture, we present a novel artificial metabolon that was created by targeting multi-enzyme cascade reactions onto inclusion body (IB) in Escherichia coli. The utility of this system was examined by co-localizing four heterologous enzymes of the 1-butanol pathway onto an IB that was formed in E...
December 27, 2016: Metabolic Engineering
https://www.readbyqxmd.com/read/28038952/metabotypes-of-breast-cancer-cell-lines-revealed-by-non-targeted-metabolomics
#8
Sébastien Dubuis, Franziska Baenke, Nina Scherbichler, Leila T Alexander, Almut Schulze, Nicola Zamboni
We present an analysis of intracellular metabolism by non-targeted, high-throughput metabolomics profiling of 18 breast cell lines. We profiled >900 putatively annotated metabolite ions for >100 samples collected under both normoxic and hypoxic conditions and revealed extensive heterogeneity across all metabolic pathways and cell lines. Cell line-specific metabolome profiles dominated over patterns associated with malignancy or with the clinical nomenclature of breast cancer cells. Such characteristic metabolome profiles were reproducible across different laboratories and experiments and exhibited mild to robust changes with change in experimental conditions...
December 27, 2016: Metabolic Engineering
https://www.readbyqxmd.com/read/28034771/lkb1-promotes-metabolic-flexibility-in-response-to-energy-stress
#9
Seth J Parker, Robert U Svensson, Ajit S Divakaruni, Austin E Lefebvre, Anne N Murphy, Reuben J Shaw, Christian M Metallo
The Liver Kinase B1 (LKB1) tumor suppressor acts as a metabolic energy sensor to regulate AMP-activated protein kinase (AMPK) signaling and is commonly mutated in various cancers, including non-small cell lung cancer (NSCLC). Tumor cells deficient in LKB1 may be uniquely sensitized to metabolic stresses, which may offer a therapeutic window in oncology. To address this question we have explored how functional LKB1 impacts the metabolism of NSCLC cells using (13)C metabolic flux analysis. Isogenic NSCLC cells expressing functional LKB1 exhibited higher flux through oxidative mitochondrial pathways compared to those deficient in LKB1...
December 26, 2016: Metabolic Engineering
https://www.readbyqxmd.com/read/27988388/analysis-of-mitochondrial-metabolism-in-situ-combining-stable-isotope-labeling-with-selective-permeabilization
#10
Yannic Nonnenmacher, Roberta Palorini, Aymeric Fouquier d'Herouël, Lisa Krämer, Meina Neumann-Schaal, Ferdinando Chiaradonna, Alexander Skupin, Andre Wegner, Karsten Hiller
To date, it is well-established that mitochondrial dysfunction does not only play a vital role in cancer but also in other pathological conditions such as neurodegenerative diseases and inflammation. An important tool for the analysis of cellular metabolism is the application of stable isotope labeled substrates, which allow for the tracing of atoms throughout metabolic networks. While such analyses yield very detailed information about intracellular fluxes, the determination of compartment specific fluxes is far more challenging...
December 15, 2016: Metabolic Engineering
https://www.readbyqxmd.com/read/27856334/quantitative-metabolic-flux-analysis-reveals-an-unconventional-pathway-of-fatty-acid-synthesis-in-cancer-cells-deficient-for-the-mitochondrial-citrate-transport-protein
#11
Lei Jiang, Adam Boufersaoui, Chendong Yang, Bookyung Ko, Dinesh Rakheja, Gerardo Guevara, Zeping Hu, Ralph J DeBerardinis
The mitochondrial citrate transport protein (CTP), encoded by SLC25A1, accommodates bidirectional trafficking of citrate between the mitochondria and cytosol, supporting lipid biosynthesis and redox homeostasis. Genetic CTP deficiency causes a fatal neurodevelopmental syndrome associated with the accumulation of L- and D-2-hydroxyglutaric acid, and elevated CTP expression is associated with poor prognosis in several types of cancer, emphasizing the importance of this transporter in multiple human pathologies...
November 14, 2016: Metabolic Engineering
https://www.readbyqxmd.com/read/27847310/dual-loss-of-succinate-dehydrogenase-sdh-and-complex-i-activity-is-necessary-to-recapitulate-the-metabolic-phenotype-of-sdh-mutant-tumors
#12
Doriane Lorendeau, Gianmarco Rinaldi, Ruben Boon, Pieter Spincemaille, Kristine Metzger, Christian Jäger, Stefan Christen, Xiangyi Dong, Sabine Kuenen, Karin Voordeckers, Patrik Verstreken, David Cassiman, Pieter Vermeersch, Catherine Verfaillie, Karsten Hiller, Sarah-Maria Fendt
Mutations in succinate dehydrogenase (SDH) are associated with tumor development and neurodegenerative diseases. Only in tumors, loss of SDH activity is accompanied with the loss of complex I activity. Yet, it remains unknown whether the metabolic phenotype of SDH mutant tumors is driven by loss of complex I function, and whether this contributes to the peculiarity of tumor development versus neurodegeneration. We addressed this question by decoupling loss of SDH and complex I activity in cancer cells and neurons...
November 12, 2016: Metabolic Engineering
https://www.readbyqxmd.com/read/27825806/genome-scale-metabolic-modeling-of-cancer
#13
Avlant Nilsson, Jens Nielsen
Cancer cells reprogram metabolism to support rapid proliferation and survival. Energy metabolism is particularly important for growth and genes encoding enzymes involved in energy metabolism are frequently altered in cancer cells. A genome scale metabolic model (GEM) is a mathematical formalization of metabolism which allows simulation and hypotheses testing of metabolic strategies. It has successfully been applied to many microorganisms and is now used to study cancer metabolism. Generic models of human metabolism have been reconstructed based on the existence of metabolic genes in the human genome...
November 4, 2016: Metabolic Engineering
https://www.readbyqxmd.com/read/27989803/folic-acid-production-by-engineered-ashbya-gossypii
#14
Cristina Serrano-Amatriain, Rodrigo Ledesma-Amaro, Rubén López-Nicolás, Gaspar Ros, Alberto Jiménez, José Luis Revuelta
Folic acid (vitamin B9) is the common name of a number of chemically related compounds (folates), which play a central role as cofactors in one-carbon transfer reactions. Folates are involved in the biosynthesis and metabolism of nucleotides and amino acids, as well as supplying methyl groups to a broad range of substrates, such as hormones, DNA, proteins, and lipids, as part of the methyl cycle. Humans and animals cannot synthesize folic acid and, therefore, need them in the diet. Folic acid deficiency is an important and underestimated problem of micronutrient malnutrition affecting billions of people worldwide...
October 28, 2016: Metabolic Engineering
https://www.readbyqxmd.com/read/27989805/engineering-a-functional-1-deoxy-d-xylulose-5-phosphate-dxp-pathway-in-saccharomyces-cerevisiae
#15
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
https://www.readbyqxmd.com/read/27989804/metabolic-engineering-of-cyanobacteria-for-the-photosynthetic-production-of-succinate
#16
Ethan I Lan, Crystal T Wei
Succinate is an important commodity chemical currently used in the food, pharmaceutical, and polymer industries. It can also be chemically converted into other major industrial chemicals such as 1,4-butanediol, butadiene, and tetrahydrofuran. Here we metabolically engineered a model cyanobacterium Synechococcus elongatus PCC 7942 to photosynthetically produce succinate. We expressed the genes encoding for α-ketoglutarate decarboxylase and succinate semialdehyde dehydrogenase in S. elongatus PCC 7942, resulting in a strain capable of producing 120mg/L of succinate...
October 27, 2016: Metabolic Engineering
https://www.readbyqxmd.com/read/28034770/combining-gal4p-mediated-expression-enhancement-and-directed-evolution-of-isoprene-synthase-to-improve-isoprene-production-in-saccharomyces-cerevisiae
#17
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
https://www.readbyqxmd.com/read/28017690/deciphering-flux-adjustments-of-engineered-e-coli-cells-during-fermentation-with-changing-growth-conditions
#18
Lian He, Yu Xiu, J Andrew Jones, Edward E K Baidoo, Jay D Keasling, Yinjie J Tang, Mattheos A G Koffas
Microbial fermentation conditions are dynamic, due to transcriptional induction, nutrient consumption, or changes to incubation conditions. In this study, (13)C-metabolic flux analysis was used to characterize two violacein-producing E. coli strains with vastly different productivities, and to profile their metabolic adjustments resulting from external perturbations during fermentation. The two strains were first grown at 37°C in stage 1, and then the temperature was transitioned to 20°C in stage 2 for the optimal expression of the violacein synthesis pathway...
January 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28013086/rational-synthetic-pathway-refactoring-of-natural-products-biosynthesis-in-actinobacteria
#19
REVIEW
Gao-Yi Tan, Tiangang Liu
Natural products (NPs) and their derivatives are widely used as frontline treatments for many diseases. Actinobacteria spp. are used to produce most of NP antibiotics and have also been intensively investigated for NP production, derivatization, and discovery. However, due to the complicated transcriptional and metabolic regulation of NP biosynthesis in Actinobacteria, especially in the cases of genome mining and heterologous expression, it is often difficult to rationally and systematically engineer synthetic pathways to maximize biosynthetic efficiency...
January 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/27998670/improvement-of-1-3-propanediol-production-using-an-engineered-cyanobacterium-synechococcus-elongatus-by-optimization-of-the-gene-expression-level-of-a-synthetic-metabolic-pathway-and-production-conditions
#20
Yasutaka Hirokawa, Yuki Maki, Taizo Hanai
The introduction of a synthetic metabolic pathway consisting of multiple genes derived from various organisms enables cyanobacteria to directly produce valuable chemicals from carbon dioxide. We previously constructed a synthetic metabolic pathway composed of genes from Escherichia coli, Saccharomyces cerevisiae, and Klebsiella pneumoniae. This pathway enabled 1,3-propanediol (1,3-PDO) production from cellular DHAP via glycerol in the cyanobacterium, Synechococcus elongatus PCC 7942. The production of 1,3-PDO (3...
January 2017: Metabolic Engineering
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