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Metabolic flux

Amit Ghosh, David Ando, Jennifer Gin, Weerawat Runguphan, Charles Denby, George Wang, Edward E K Baidoo, Chris Shymansky, Jay D Keasling, Héctor García Martín
Efficient redirection of microbial metabolism into the abundant production of desired bioproducts remains non-trivial. Here, we used flux-based modeling approaches to improve yields of fatty acids in Saccharomyces cerevisiae. We combined (13)C labeling data with comprehensive genome-scale models to shed light onto microbial metabolism and improve metabolic engineering efforts. We concentrated on studying the balance of acetyl-CoA, a precursor metabolite for the biosynthesis of fatty acids. A genome-wide acetyl-CoA balance study showed ATP citrate lyase from Yarrowia lipolytica as a robust source of cytoplasmic acetyl-CoA and malate synthase as a desirable target for downregulation in terms of acetyl-CoA consumption...
2016: Frontiers in Bioengineering and Biotechnology
Fangzhou Shen, Jian Li, Ying Zhu, Zhuo Wang
Cancer cells have different metabolism in contrast to normal cells. The advancement in omics measurement technology enables the genome-wide characterization of altered cellular processes in cancers, but the metabolic flux landscape of cancer is still far from understood. In this study, we compared the well-reconstructed tissue-specific models of five cancers, including breast, liver, lung, renal, and urothelial cancer, and their corresponding normal cells. There are similar patterns in majority of significantly regulated pathways and enriched pathways in correlated reaction sets...
August 29, 2016: Journal of Bioinformatics and Computational Biology
Delphine Ohayon, Alessia De Chiara, Nicolas Chapuis, Céline Candalh, Julie Mocek, Jean-Antoine Ribeil, Lamya Haddaoui, Norbert Ifrah, Olivier Hermine, Frédéric Bouillaud, Philippe Frachet, Didier Bouscary, Véronique Witko-Sarsat
Cytosolic proliferating cell nuclear antigen (PCNA), a scaffolding protein involved in DNA replication, has been described as a key element in survival of mature neutrophil granulocytes, which are non-proliferating cells. Herein, we demonstrated an active export of PCNA involved in cell survival and chemotherapy resistance. Notably, daunorubicin-resistant HL-60 cells (HL-60R) have a prominent cytosolic PCNA localization due to increased nuclear export compared to daunorubicin-sensitive HL-60 cells (HL-60S)...
October 19, 2016: Scientific Reports
Theerawut Chanmee, Pawared Ontong, Tomomi Izumikawa, Miho Higashide, Nobutoshi Mochizuki, Chatchadawalai Chokchaitaweesuk, Manatsanan Khansai, Kazuki Nakajima, Ikuko Kakizaki, Prachya Kongtawelert, Naoyuki Taniguchi, Naoki Itano
Cancer stem cells (CSCs) represent a small subpopulation of self-renewing oncogenic cells. Like many other stem cells, metabolic reprogramming has been implicated to be a key characteristic of CSCs. However, little is known on how the metabolic features of cancer cells are controlled to orchestrate their CSC-like properties. We recently demonstrated that hyaluronan (HA) overproduction allowed plastic cancer cells to revert to stem-cell states. Here, we adopted stable isotope-assisted tracing and mass spectrometry profiling to elucidate the metabolic features of HA-overproducing breast cancer cells...
October 6, 2016: Journal of Biological Chemistry
Maria Manuela Rigano, Assunta Raiola, Teresa Docimo, Valentino Ruggieri, Roberta Calafiore, Paola Vitaglione, Rosalia Ferracane, Luigi Frusciante, Amalia Barone
Solanum lycopersicum represents an important dietary source of bioactive compounds including the antioxidants flavonoids and phenolic acids. We previously identified two genotypes (IL7-3 and IL12-4) carrying loci from the wild species Solanum pennellii, which increased antioxidants in the fruit. Successively, these lines were crossed and two genotypes carrying both introgressions at the homozygous condition (DHO88 and DHO88-SL) were selected. The amount of total antioxidant compounds was increased in DHOs compared to both ILs and the control genotype M82...
2016: Frontiers in Plant Science
Mohammad Massumi, Farzaneh Pourasgari, Amarnadh Nalla, Battsetseg Batchuluun, Kristina Nagy, Eric Neely, Rida Gull, Andras Nagy, Michael B Wheeler
The ability to yield glucose-responsive pancreatic beta-cells from human pluripotent stem cells in vitro will facilitate the development of the cell replacement therapies for the treatment of Type 1 Diabetes. Here, through the sequential in vitro targeting of selected signaling pathways, we have developed an abbreviated five-stage protocol (25-30 days) to generate human Embryonic Stem Cell-Derived Beta-like Cells (ES-DBCs). We showed that Geltrex, as an extracellular matrix, could support the generation of ES-DBCs more efficiently than that of the previously described culture systems...
2016: PloS One
Lien M Dos Santos, Tatiane M da Silva, Juliana H Azambuja, Priscila T Ramos, Pathise S Oliveira, Elita F da Silveira, Nathalia S Pedra, Kennia Galdino, Carlus A T do Couto, Mayara S P Soares, Rejane G Tavares, Roselia M Spanevello, Francieli M Stefanello, Elizandra Braganhol
Methionine is an essential amino acid involved in critical metabolic process, and regulation of methionine flux through metabolism is important to supply this amino acid for cell needs. Elevation in plasma methionine commonly occurs due to mutations in methionine-metabolizing enzymes, such as methionine adenosyltransferase. Hypermethioninemic patients exhibit clinical manifestations, including neuronal and liver disorders involving inflammation and tissue injury, which pathophysiology is not completely established...
October 17, 2016: Molecular and Cellular Biochemistry
Chloé Najac, Sabrina M Ronen
Metabolic reprogramming is an important hallmark of cancer. Alterations in many metabolic pathways support the requirement for cellular building blocks that are essential for cancer cell proliferation. This metabolic reprogramming can be imaged using magnetic resonance spectroscopy (MRS). H MRS can inform on alterations in the steady-state levels of cellular metabolites, but the emergence of hyperpolarized C MRS has now also enabled imaging of metabolic fluxes in real-time, providing a new method for tumor detection and monitoring of therapeutic response...
October 2016: Topics in Magnetic Resonance Imaging: TMRI
Peng Zou, Longhua Liu, Louise D Zheng, Kyle K Payne, Masoud H Manjili, Michael O Idowu, Jinfeng Zhang, Eva M Schmelz, Zhiyong Cheng
Overactive mitochondrial fission was shown to promote cell transformation and tumor growth. It remains elusive how mitochondrial quality is regulated in such conditions. Here, we show that upregulation of mitochondrial fission protein, dynamin related protein-1 (Drp1), was accompanied with increased mitochondrial biogenesis markers (PGC1α, NRF1, and Tfam) in breast cancer cells. However, mitochondrial number was reduced, which was associated with lower mitochondrial oxidative capacity in breast cancer cells...
2016: Oxidative Medicine and Cellular Longevity
Jeong Wook Lee, Jongho Yi, Tae Yong Kim, Sol Choi, Jung Ho Ahn, Hyohak Song, Moon-Hee Lee, Sang Yup Lee
Succinic acid (SA) is a four carbon dicarboxylic acid of great industrial interest that can be produced by microbial fermentation. Here we report development of a high-yield homo-SA producing Mannheimia succiniciproducens strain by metabolic engineering. The PALFK strain (ldhA(-), pta(-), ackA(-), fruA(-)) was developed based on optimization of carbon flux towards SA production while minimizing byproducts formation through the integrated application of in silico genome-scale metabolic flux analysis, omics analyses, and reconstruction of central carbon metabolism...
October 13, 2016: Metabolic Engineering
Zhenle Yang, Hongying Ji, Dantong Liu
Cyperus esculentus is unique in that it can accumulate rich oil in tuber. However, the underlying mechanism of tuber oil biosynthesis is still unclear. Our transcriptional analyses of the pathways from pyruvate production up to triacylglycerol (TAG) accumulation in tuber revealed many distinct species-specific lipid expression patterns from oil seeds and fruits, indicating that in C. esculentus tuber, (1) carbon flux from sucrose toward plastid pyruvate could be produced mostly through cytosolic glycolytic pathway, (2) acetyl-CoA synthetase might be an important contributor to acetyl-CoA formation for plastid fatty acid biosynthesis, (3) expression pattern for stearoyl-ACP desaturase was associated with high oleic acid composition, (4) it was most likely that endoplasmic reticulum-associated acyl-CoA synthetase played a significant role in the export of fatty acids between the plastid and ER, (5) lipid phosphate phosphatase (LPP)-δ was most probably related to the formation of DAG pool in Kennedy pathway, (6) diacylglyceroltransacylase 2 (DGAT2) and phospholipid:diacylglycerolacyltransferase 1 (PDAT1) might play crucial roles in tuber oil biosynthesis...
October 13, 2016: Plant & Cell Physiology
Hyo Min Park, Kim A Russo, Grigory Karateev, Michael Park, Elena Dubikovskaya, Lance J Kriegsfeld, Andreas Stahl
Alterations in hepatic free fatty acid (FFA) uptake and metabolism contribute to development of prevalent liver disorders such as hepatosteatosis. However, detecting dynamic changes in FFA uptake by the liver in live model organisms has proven difficult. To enable non-invasive real-time imaging of FFA flux in the liver, we generated transgenic mice with liver-specific expression of luciferase and performed bioluminescence imaging with an FFA probe. Our approach enabled us to observe the changes in FFA hepatic uptake under different physiological conditions in live animals...
October 11, 2016: Gastroenterology
Lykke Sylow, Maximilian Kleinert, Erik A Richter, Thomas E Jensen
Skeletal muscle extracts glucose from the blood to maintain demand for carbohydrates as an energy source during exercise. Such uptake involves complex molecular signalling processes that are distinct from those activated by insulin. Exercise-stimulated glucose uptake is preserved in insulin-resistant muscle, emphasizing exercise as a therapeutic cornerstone among patients with metabolic diseases such as diabetes mellitus. Exercise increases uptake of glucose by up to 50-fold through the simultaneous stimulation of three key steps: delivery, transport across the muscle membrane and intracellular flux through metabolic processes (glycolysis and glucose oxidation)...
October 14, 2016: Nature Reviews. Endocrinology
Jilong Wang, Suthamat Niyompanich, Yi-Shu Tai, Jingyu Wang, Wenqin Bai, Prithviraj Mahida, Tuo Gao, Kechun Zhang
: Chromosomal integration of heterologous metabolic pathways is optimal for industrially relevant fermentation, as plasmid-based fermentation causes extra metabolic burden and genetic instabilities. In this work, chromosomal integration was adapted for the production of mevalonate which can be readily converted into β-methyl-δ-valerolactone, a monomer for the production of mechanically tunable polyesters. The mevalonate pathway driven by a constitutive promoter was integrated into the chromosome of Escherichia coli to replace the native fermentation gene adhE or ldhA The engineered strains (CMEV-1 and CMEV-2) did not require inducer or antibiotic, and showed slightly higher maximal productivities (0...
October 7, 2016: Applied and Environmental Microbiology
Perrin H Beatty, Matthias S Klein, Jeffrey J Fischer, Ian A Lewis, Douglas G Muench, Allen G Good
A comprehensive understanding of plant metabolism could provide a direct mechanism for improving nitrogen use efficiency (NUE) in crops. One of the major barriers to achieving this outcome is our poor understanding of the complex metabolic networks, physiological factors, and signaling mechanisms that affect NUE in agricultural settings. However, an exciting collection of computational and experimental approaches has begun to elucidate whole-plant nitrogen usage and provides an avenue for connecting nitrogen-related phenotypes to genes...
October 10, 2016: Plants (Basel, Switzerland)
Gabriel A Knudsen, Michael F Hughes, J Michael Sanders, Samantha M Hall, Linda S Birnbaum
: 2-Ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB) and bis(2-ethylhexyl)tetrabromophthalate (BEH-TEBP) are novel brominated flame retardants used in consumer products. A parallelogram approach was used to predict human dermal absorption and flux for EH-TBB and BEH-TEBP. [(14)C]-EH-TBB or [(14)C]-BEH-TEBP was applied to human or rat skin at 100nmol/cm(2) using a flow-through system. Intact rats received analogous dermal doses. Treated skin was washed and tape-stripped to remove "unabsorbed" [(14)C]-radioactivity after continuous exposure (24h)...
October 9, 2016: Toxicology and Applied Pharmacology
Rémi Peyraud, Ludovic Cottret, Lucas Marmiesse, Jérôme Gouzy, Stéphane Genin
Bacterial pathogenicity relies on a proficient metabolism and there is increasing evidence that metabolic adaptation to exploit host resources is a key property of infectious organisms. In many cases, colonization by the pathogen also implies an intensive multiplication and the necessity to produce a large array of virulence factors, which may represent a significant cost for the pathogen. We describe here the existence of a resource allocation trade-off mechanism in the plant pathogen R. solanacearum. We generated a genome-scale reconstruction of the metabolic network of R...
October 2016: PLoS Pathogens
Jie Zhang, Alan R Light, Charles L Hoppel, Caitlin Campbell, Carol J Chandler, Dustin J Burnett, Elaine C Souza, Gretchen A Casazza, Ronald W Hughen, Nancy L Keim, John W Newman, Gary R Hunter, Jose R Fernandez, W Timothy Garvey, Mary-Ellen Harper, Oliver Fiehn, Sean H Adams
With insulin-resistance or type 2 diabetes mellitus, mismatches between mitochondrial fatty acid fuel delivery and oxidative phosphorylation/tricarboxylic acid cycle activity may contribute to inordinate accumulation of short- or medium-chain acylcarnitine fatty acid derivatives (markers of incomplete long-chain fatty acid oxidation [FAO]). We reasoned that incomplete FAO in muscle would be ameliorated concurrent with improved insulin sensitivity and fitness following a ∼14 wk training and weight loss intervention in obese, sedentary, insulin-resistant women...
October 12, 2016: Experimental Physiology
Aline G Cozer, Márcia Trapp, Claudia Vieira Marques, Tiago L Martins, Jorge Felipe A Model, Vanessa Schein, Luiz Carlos Kucharski, Roselis S M Da Silva
The present work assesses in vitro the role of human Stanniocalcin 1 (hSTC-1) in glucose metabolism in white retroperitoneal adipose tissue (WRAT) from fed rat. In the fed state, hSTC1 increases the incorporation of (14)C from glucose into lipids in the rat WRAT. The increase in lipogenesis capacity supports the hypothesis that the activity of the glycerol-3-phosphate-generating pathway (glycolysis) from glucose is regulated by hSTC-1. The effect of hSTC-1 on de novo fatty acid synthesis and on glucose oxidation in WRAT is supported by an 85 % increase in (14)CO2 production from (14)C-glucose...
October 11, 2016: Lipids
Yijun Liu, Nathalie Muñoz, Ang-Chen Tsai, Timothy M Logan, Teng Ma
Spontaneous aggregation and the associated enhancement of stemness have been observed in many anchorage dependent cells. Recently, aggregation of human mesenchymal stem cells (hMSCs) in non-adherent culture has been shown to reverse expansion-induced heterogeneity and loss of stemness and reprogram the hMSC to reacquire their primitive phenotype, a phenomenon that can significantly enhance therapeutic applications of hMSC. The objective of this study was to investigate the mechanistic basis underlying the connection between multi-cellular aggregation and stemness enhancement in hMSC by testing the hypothesis that cellular events induced during 3D aggregation on non-adherent substratum induces changes in mitochondrial metabolism that promote the expression of stem cell genes Oct4, Sox2, and Nanog...
October 11, 2016: Stem Cells
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