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metabolic flux analysis

Kevin W George, Mitchell Thompson, Joonhoon Kim, Edward E K Baidoo, George Wang, Veronica Teixeira Benites, Christopher J Petzold, Leanne Jade G Chan, Suzan Yilmaz, Petri Turhanen, Paul D Adams, Jay D Keasling, Taek Soon Lee
Isopentenyl pyrophosphate (IPP) toxicity presents a challenge in engineered microbial systems since its formation is unavoidable in terpene biosynthesis. In this work, we develop an experimental platform to study IPP toxicity in isoprenol-producing Escherichia coli. We first characterize the physiological response to IPP accumulation, demonstrating that elevated IPP levels are linked to growth inhibition, reduced cell viability, and plasmid instability. We show that IPP toxicity selects for pathway "breakage", using proteomics to identify a reduction in phosphomevalonate kinase (PMK) as a probable recovery mechanism...
March 9, 2018: Metabolic Engineering
Saratram Gopalakrishnan, Himadri B Pakrasi, Costas D Maranas
Completeness and accuracy of metabolic mapping models impacts the reliability of flux estimation in photoautotrophic systems. In this study, metabolic fluxes under photoautotrophic growth conditions in the widely-used cyanobacterium Synechocystis PCC 6803 are quantified by re-analyzing an existing dataset using genome-scale isotopic instationary13 C-Metabolic Flux Analysis (INST-MFA). The reconstructed carbon mapping model imSyn617 and implemented algorithmic updates afforded an approximately 48% reduction in computation time...
March 8, 2018: Metabolic Engineering
Erzsebet Polyak, Julian Ostrovsky, Min Peng, Stephen D Dingley, Mai Tsukikawa, Young Joon Kwon, Shana E McCormack, Michael Bennett, Rui Xiao, Christoph Seiler, Zhe Zhang, Marni J Falk
Oxidative stress is a known contributing factor in mitochondrial respiratory chain (RC) disease pathogenesis. Yet, no efficient means exists to objectively evaluate the comparative therapeutic efficacy or toxicity of different antioxidant compounds empirically used in human RC disease. We postulated that pre-clinical comparative analysis of diverse antioxidant drugs having suggested utility in primary RC disease using animal and cellular models of RC dysfunction may improve understanding of their integrated effects and physiologic mechanisms, and enable prioritization of lead antioxidant molecules to pursue in human clinical trials...
February 23, 2018: Molecular Genetics and Metabolism
Weilu Lin, Zejian Wang, Mingzhi Huang, Yingping Zhuang, Siliang Zhang
The isotopically non-stationary 13C labelling experiments, as an emerging experimental technique, can estimate the intracellular fluxes of the cell culture under an isotopic transient period. However, to the best of our knowledge, the issue of the structural identifiability analysis of non-stationary isotope experiments is not well addressed in the literature. In this work, the local structural identifiability analysis for non-stationary cumomer balance equations is conducted based on the Taylor series approach...
March 8, 2018: Mathematical Biosciences
Howard Ramirez-Malule, Stefan Junne, Mariano Nicolás Cruz-Bournazou, Peter Neubauer, Rigoberto Ríos-Estepa
Clavulanic acid (CA) is produced by Streptomyces clavuligerus (S. clavuligerus) as a secondary metabolite. Knowledge about the carbon flux distribution along the various routes that supply CA precursors would certainly provide insights about metabolic performance. In order to evaluate metabolic patterns and the possible accumulation of tricarboxylic acid (TCA) cycle intermediates during CA biosynthesis, batch and subsequent continuous cultures with steadily declining feed rates were performed with glycerol as the main substrate...
March 9, 2018: Applied Microbiology and Biotechnology
Yi Ern Cheah, Jamey D Young
Typically,13 C flux analysis relies on assumptions of both metabolic and isotopic steady state. If metabolism is steady but isotope labeling is not allowed to fully equilibrate, isotopically nonstationary metabolic flux analysis (INST-MFA) can be used to estimate fluxes. This requires solution of differential equations that describe the time-dependent labeling of network metabolites, while iteratively adjusting the flux and pool size parameters to match the transient labeling measurements. INST-MFA holds a number of unique advantages over approaches that rely solely upon steady-state isotope enrichments...
March 6, 2018: Current Opinion in Biotechnology
Xiaomei Liu, Qing Zhang, Weixiao Wang, Dongjiao Zuo, Jing Wang, Feng Zhou, Liping Niu, Xiangyang Li, Suping Qin, Yanbo Kou, Fanyun Kong, Wei Pan, Yugang Wang, Dianshuai Gao, Hong Sun, Jessica M Meves, Kuiyang Zheng, Renxian Tang
BACKGROUND/AIMS: Multiple sclerosis (MS) is an autoimmune disease in the central nervous system associated with demyelination and axonal injury. Astrocyte activation is involved in the pathogenesis of MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. This study was designed to find potential lncRNAs in EAE mice and activated astrocytes. METHODS: we performed microarray analysis of lncRNAs from the brain tissues of EAE mice and primary mouse astrocytes treated with IL-9(50 ng/ml)...
March 2, 2018: Cellular Physiology and Biochemistry
Lucía Trilla-Fuertes, Angelo Gámez-Pozo, Jorge M Arevalillo, Mariana Díaz-Almirón, Guillermo Prado-Vázquez, Andrea Zapater-Moros, Hilario Navarro, Rosa Aras-López, Irene Dapía, Rocío López-Vacas, Paolo Nanni, Sara Llorente-Armijo, Pedro Arias, Alberto M Borobia, Paloma Maín, Jaime Feliú, Enrique Espinosa, Juan Ángel Fresno Vara
Metabolic reprogramming is a hallmark of cancer. It has been described that breast cancer subtypes present metabolism differences and this fact enables the possibility of using metabolic inhibitors as targeted drugs in specific scenarios. In this study, breast cancer cell lines were treated with metformin and rapamycin, showing a heterogeneous response to treatment and leading to cell cycle disruption. The genetic causes and molecular effects of this differential response were characterized by means of SNP genotyping and mass spectrometry-based proteomics...
February 9, 2018: Oncotarget
Achim Dickmanns, Christopher P Zschiedrich, Johannes Arens, Iwan Parfentev, Jan Gundlach, Romina Hofele, Piotr Neumann, Henning Urlaub, Boris Görke, Ralf Ficner, Jorg Stulke
Utilization of energy-rich carbon sources such as glucose is fundamental to the evolutionary success of bacteria. Glucose can be catabolized via glycolysis for feeding the intermediary metabolism. The methylglyoxal synthase MgsA produces methylglyoxal from the glycolytic intermediate dihydroxyacetone phosphate. Methylglyoxal is toxic, requiring stringent regulation of MgsA activity. In the Gram-positive bacterium Bacillus subtilis , an interaction with the phosphoprotein Crh controls MgsA activity. In the absence of preferred carbon sources, Crh is present in the nonphosphorylated state and binds to and thereby inhibits MgsA...
March 7, 2018: Journal of Biological Chemistry
Sarah J Mitchell, Michel Bernier, Miguel A Aon, Sonia Cortassa, Eun Young Kim, Evandro F Fang, Hector H Palacios, Ahmed Ali, Ignacio Navas-Enamorado, Andrea Di Francesco, Tamzin A Kaiser, Tyler B Waltz, Ning Zhang, James L Ellis, Peter J Elliott, David W Frederick, Vilhelm A Bohr, Mark S Schmidt, Charles Brenner, David A Sinclair, Anthony A Sauve, Joseph A Baur, Rafael de Cabo
The role in longevity and healthspan of nicotinamide (NAM), the physiological precursor of NAD+ , is elusive. Here, we report that chronic NAM supplementation improves healthspan measures in mice without extending lifespan. Untargeted metabolite profiling of the liver and metabolic flux analysis of liver-derived cells revealed NAM-mediated improvement in glucose homeostasis in mice on a high-fat diet (HFD) that was associated with reduced hepatic steatosis and inflammation concomitant with increased glycogen deposition and flux through the pentose phosphate and glycolytic pathways...
March 6, 2018: Cell Metabolism
Chunyan Jiao, Cheng Song, Siyan Zheng, Yingpeng Zhu, Qing Jin, Yongping Cai, Yi Lin
Alkaloids are the main active ingredients in the medicinal plant Dendrobium officinale . Based on the published genomic and transcriptomic data, a proposed terpenoid indole alkaloid (TIA) biosynthesis pathway may be present in D. officinale . In this study, protocorm-like bodies (PLBs) with a high-yielding production of alkaloids were obtained by the optimization of tryptophan, secologanin and methyl jasmonate (MeJA) treatment. The results showed that the total alkaloid content was 2.05 times greater than that of the control group when the PLBs were fed with 9 µM tryptophan, 6 µM secologanin and 100 µM MeJA after 36 days...
March 3, 2018: International Journal of Molecular Sciences
Punith Naik, Jack P Wang, Ronald Sederoff, Vincent Chiang, Cranos Williams, Joel J Ducoste
Lignin is a polymer present in the secondary cell walls of all vascular plants. It is a known barrier to pulping and the extraction of high-energy sugars from cellulosic biomass. The challenge faced with predicting outcomes of transgenic plants with reduced lignin is due in part to the presence of unique protein-protein interactions that influence the regulation and metabolic flux in the pathway. Yet, it is unclear why certain plants have evolved to create these protein complexes. In this study, we use mathematical models to investigate the role that the protein complex, formed specifically between Ptr4CL3 and Ptr4CL5 enzymes, have on the monolignol biosynthesis pathway...
2018: PloS One
Kaspar Valgepea, Renato de Souza Pinto Lemgruber, Tanus Abdalla, Steve Binos, Nobuaki Takemori, Ayako Takemori, Yuki Tanaka, Ryan Tappel, Michael Köpke, Séan Dennis Simpson, Lars Keld Nielsen, Esteban Marcellin
Background: The global demand for affordable carbon has never been stronger, and there is an imperative in many industrial processes to use waste streams to make products. Gas-fermenting acetogens offer a potential solution and several commercial gas fermentation plants are currently under construction. As energy limits acetogen metabolism, supply of H2 should diminish substrate loss to CO2 and facilitate production of reduced and energy-intensive products. However, the effects of H2 supply on CO-grown acetogens have yet to be experimentally quantified under controlled growth conditions...
2018: Biotechnology for Biofuels
Jason Solocinski, Quinn A Osgood, Eric Rosiek, Lukas Underwood, Oleg Zikanov, Nilay Chakraborty
Dry state preservation at ambient temperatures (lyopreservation) is a biomimetic alternative to low temperature stabilization (cryopreservation) of biological materials. Lyopreservation is hypothesized to rely upon the creation of a glassy environment, which is commonly observed in desiccation-tolerant organisms. Non-uniformities in dried samples have been indicated as one of the reasons for instability in storage outcome. The current study presents a simple, fast, and uniform surface tension based technique that can be implemented for lyopreservation of mammalian cells...
2018: PloS One
Kentaro Ueda, Tsubasa Nakajima, Katsunori Yoshikawa, Yoshihiro Toya, Fumio Matsuda, Hiroshi Shimizu
The role of the oxidative pentose phosphate pathway (oxPPP) in Synechocystis sp. PCC 6803 under mixotrophic conditions was investigated by13 C metabolic flux analysis. Cells were cultured under low (10 μmol m-2  s-1 ) and high light intensities (100 μmol m-2  s-1 ) in the presence of glucose. The flux of CO2 fixation by ribulose bisphosphate carboxylase/oxygenase under the high light condition was approximately 3-fold higher than that under the low light condition. Although no flux of the oxPPP was observed under the high light condition, flux of 0...
February 27, 2018: Journal of Bioscience and Bioengineering
Silvia Escudero, Elma Zaganjor, Susan Lee, Christopher P Mill, Ann M Morgan, Emily B Crawford, Jiahao Chen, Thomas E Wales, Rida Mourtada, James Luccarelli, Gregory H Bird, Ulrich Steidl, John R Engen, Marcia C Haigis, Joseph T Opferman, Loren D Walensky
MCL-1 is a BCL-2 family protein implicated in the development and chemoresistance of human cancer. Unlike its anti-apoptotic homologs, Mcl-1 deletion has profound physiologic consequences, indicative of a broader role in homeostasis. We report that the BCL-2 homology 3 (BH3) α helix of MCL-1 can directly engage very long-chain acyl-CoA dehydrogenase (VLCAD), a key enzyme of the mitochondrial fatty acid β-oxidation (FAO) pathway. Proteomic analysis confirmed that the mitochondrial matrix isoform of MCL-1 (MCL-1Matrix ) interacts with VLCAD...
March 1, 2018: Molecular Cell
Laura Berliocchi, Carlotta Chiappini, Annagrazia Adornetto, Debora Gentile, Silvia Cerri, Rossella Russo, Giacinto Bagetta, Maria Tiziana Corasaniti
BACKGROUND: d-Limonene is a natural monoterpene abundant in Citrus essential oils. It is endowed with several biological activities, including inhibition of carcinogenesis and promotion of tumour regression. Recently, d-limonene has been shown to modulate autophagic markers in vitro at concentrations found in vivo, in clinical pharmacokinetic studies. Autophagy is an intracellular catabolic process serving as both an adaptive metabolic response and a quality control mechanism. Because autophagy defects have been linked to a wide range of human pathologies, including neurodegeneration and cancer, there is a need for new pharmacological tools to control deregulated autophagy...
February 1, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Mohammad Tajparast, Dominic Frigon
Feast-famine cycles in biological wastewater resource recovery systems select for bacterial species that accumulate intracellular storage compounds such as poly-β-hydroxybutyrate (PHB), glycogen, and triacylglycerols (TAG). These species survive better the famine phase and resume rapid substrate uptake at the beginning of the feast phase faster than microorganisms unable to accumulate storage. However, ecophysiological conditions favouring the accumulation of either storage compounds remain to be clarified, and predictive capabilities need to be developed to eventually rationally design reactors producing these compounds...
2018: PloS One
Paul Günther Baptist Heymann, Katharina Sabine Elisabeth Henkenius, Thomas Ziebart, Andreas Braun, Klara Hirthammer, Frank Halling, Andreas Neff, Robert Mandic
BACKGROUND/AIM: Laser photochemotherapy is a new approach in cancer treatment using low-level laser therapy (LLLT) to enhance the effect of chemotherapy. MATERIALS AND METHODS: In order to evaluate the effect of LLLT on tumor cells, HeLa cells were treated with cisplatin or zoledronic acid (ZA) followed by LLLT. Cell viability was evaluated with 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide assay. Oxidative phosphorylation and glycolysis were measured using extracellular flux analysis...
March 2018: Anticancer Research
Surya N Mulukutla, Jean W Hsu, Ruchi Gaba, Kurt M Bohren, Anu Guthikonda, Dinakar Iyer, Nadim J Ajami, Joseph F Petrosino, Christiane S Hampe, Nalini Ram, Farook Jahoor, Ashok Balasubramanyam
Background: A-β + ketosis-prone diabetes (KPD) is a subset of type 2 diabetes in which patients have severe but reversible β cell dysfunction of unknown etiology. Plasma metabolomic analysis indicates that abnormal arginine metabolism may be involved. Objective: The objective of this study was to determine the relation between gut microbiome and arginine metabolism and the relation between arginine availability and β cell function in KPD patients compared with control participants...
February 1, 2018: Journal of Nutrition
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