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Metabolic flux

Angela Contreras, Magdalena Ribbeck, Guillermo D Gutiérrez, Pablo M Cañon, Sebastián N Mendoza, Eduardo Agosin
The effect of ethanol on the metabolism of Oenococcus oeni , the bacterium responsible for the malolactic fermentation (MLF) of wine, is still scarcely understood. Here, we characterized the global metabolic response in O. oeni PSU-1 to increasing ethanol contents, ranging from 0 to 12% (v/v). We first optimized a wine-like, defined culture medium, MaxOeno, to allow sufficient bacterial growth to be able to quantitate different metabolites in batch cultures of O. oeni . Then, taking advantage of the recently reconstructed genome-scale metabolic model iSM454 for O...
2018: Frontiers in Microbiology
Katia Tarasava, Rongming Liu, Andrew Garst, Ryan T Gill
Optimization of metabolic flux is a difficult and time-consuming process that often involves changing the expression levels of multiple genes simultaneously. While some pathways have a known rate limiting step, more complex metabolic networks can require a trial-and-error approach of tuning the expression of multiple genes to achieve a desired distribution of metabolic resources. Here we present an efficient method for generating expression diversity on a combinatorial scale using CRISPR interference. We use a modified native Escherichia coli Type I-E CRISPR-Cas system and an iterative cloning strategy for construction of guide RNA arrays...
March 14, 2018: Biotechnology and Bioengineering
Monala Jayaprakash Rao, Malathi Srinivasan, Ram Rajasekharan
Cell size and morphology are key adaptive features that influence almost all aspects of cellular physiology such as cell cycle and lipid metabolism. Here we report the role of a transcription factor Suppressor Phenotype of Ty elements insertion 10 (SPT10) of Saccharomyces cerevisiae in regulating cell cycle, cell size and lipid metabolism in concert, in addition to its defined role of histone gene expression. Morphological and biochemical analyses of spt10Δ strain show an abnormal cell size, cell cycle and lipid levels...
March 13, 2018: Current Genetics
Wonsik Lee, Truc Do, Ge Zhang, Daniel Kahne, Timothy C Meredith, Suzanne Walker
Targeted modification of bacterial chromosomes is necessary to understand new drug targets, investigate virulence factors, elucidate cell physiology, and validate results of -omics-based approaches. For some bacteria, reverse genetics remains a major bottleneck to progress in research. Here we describe a compound-centric strategy that combines new negative selection markers with known positive selection markers to achieve simple, efficient one-step genome engineering of bacterial chromosomes. The method was inspired by the observation that certain non-essential metabolic pathways contain essential late steps, suggesting that antibiotics targeting a late step can be used to select for the absence of genes that control flux into the pathway...
March 13, 2018: ACS Infectious Diseases
Yi-Yuan Zheng, Miao Wang, Xiang-Bing Shu, Pei-Yong Zheng, Guang Ji
AIM: To elucidate the potential role of autophagy and the protective effects of Jiang Zhi Granule (JZG) in metabolic stress-induced hepatocyte injury. METHODS: An in vitro and in vivo approach was used in this study. HepG2 cells were incubated in culture medium containing palmitate (PA; 0, 0.1, 0.2, 0.3, 0.4 or 0.5 mmol/L) and treated with or without JZG (100 μg/mL) for 24 h or 48 h, and the progression of autophagy was visualized by stable fluorescence-expressing cell lines LC3 and p62...
March 7, 2018: World Journal of Gastroenterology: WJG
Daniel R Garza, Marcel C van Verk, Martijn A Huynen, Bas E Dutilh
The environmental metabolome and metabolic potential of microorganisms are dominant and essential factors shaping microbial community composition. Recent advances in genome annotation and systems biology now allow us to semiautomatically reconstruct genome-scale metabolic models (GSMMs) of microorganisms based on their genome sequence1 . Next, growth of these models in a defined metabolic environment can be predicted in silico, mechanistically linking the metabolic fluxes of individual microbial populations to the community dynamics...
March 12, 2018: Nature Microbiology
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
Gabriela Segerer, Daria Engelmann, Alexandra Kaestner, Martin Trötzmüller, Harald Köfeler, Christian Stigloher, Christoph Thiele, Elisabeth Jeanclos, Antje Gohla
Mammalian phosphoglycolate phosphatase (PGP, also known as AUM or glycerol-3-phosphate phosphatase) is a small molecule-directed phosphatase important for metabolite repair and lipid metabolism. Although PGP was first characterized as an enzyme involved in epidermal growth factor (EGF) signaling, PGP protein substrates have remained elusive. Here we show that PGP depletion facilitates fatty acid flux through the intracellular triacylglycerol/fatty acid cycle, and that phosphatidylinositol-4,5-bisphosphate (PIP2), produced in a side branch of this cycle, is critical for the impact of PGP activity on EGF-induced signaling...
March 7, 2018: Biochimica et Biophysica Acta
Yasukazu Takanezawa, Ryosuke Nakamura, Yuka Kojima, Yuka Sone, Shimpei Uraguchi, Masako Kiyono
Cancer cells enhance autophagic activity as a survival measure against metabolic and therapeutic stresses. The inhibition of autophagy may represent a valuable sensitizing target for cancer treatment. Recently, we examined the ability of various cytochalasins to inhibit autophagy and demonstrated the potent inhibitory effect of cytochalasin E (CE) on autophagic flux. The present study was conducted to investigate whether CE inhibited autophagosome-lysosome fusion, and to determine whether CE enhanced chemotherapy-induced cell death...
March 7, 2018: Biochemical and Biophysical Research Communications
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
Wangie Yu, Yunyun Chen, Julien Dubrulle, Fabio Stossi, Vasanta Putluri, Arun Sreekumar, Nagireddy Putluri, Dodge Baluya, Stephen Y Lai, Vlad C Sandulache
Cisplatin is commonly utilized in the treatment of solid tumors. Its mechanism of action is complex and multiple mechanisms of resistance have been described. We sought to determine the impact of cisplatin-generated oxidative stress on head and neck squamous cell carcinoma (HNSCC) proliferation, survival and metabolic activity in order to identify a potential metabolic signature associated with cisplatin response. DNA-bound cisplatin represents a small fraction of total intra-cellular cisplatin but generates a robust oxidative stress response...
March 9, 2018: Scientific Reports
Ricarda Höhner, Joaquim V Marques, Tetsuro Ito, Yoshiaki Amakura, Alan D Budgeon, Karl Weitz, Kim K Hixson, Laurence B Davin, Helmut Kirchhoff, Norman G Lewis
Arogenate dehydratase (ADT) catalyzes the final step of phenylalanine (Phe) biosynthesis. Previous work showed that ADT-deficient Arabidopsis thaliana mutants had significantly reduced lignin contents, with stronger reductions in lines that had deficiencies in more ADT isoforms. Here, by analyzing Arabidopsis ADT mutants using our phenomics facility and UPLC-MS based metabolomics, we describe the effects of modulation of ADT on photosynthetic parameters and secondary metabolism. Our data indicate that a reduced carbon flux into Phe biosynthesis in ADT mutants impairs the consumption of photosynthetically produced ATP leading to an increased ATP/ADP ratio, the over-accumulation of transitory starch, and lower electron transport rates...
March 9, 2018: Plant Physiology
Glenn R Bantug, Marco Fischer, Jasmin Grählert, Maria L Balmer, Gunhild Unterstab, Leyla Develioglu, Rebekah Steiner, Lianjun Zhang, Ana S H Costa, Patrick M Gubser, Anne-Valérie Burgener, Ursula Sauder, Jordan Löliger, Réka Belle, Sarah Dimeloe, Jonas Lötscher, Annaïse Jauch, Mike Recher, Gideon Hönger, Michael N Hall, Pedro Romero, Christian Frezza, Christoph Hess
Glycolysis is linked to the rapid response of memory CD8+ T cells, but the molecular and subcellular structural elements enabling enhanced glucose metabolism in nascent activated memory CD8+ T cells are unknown. We found that rapid activation of protein kinase B (PKB or AKT) by mammalian target of rapamycin complex 2 (mTORC2) led to inhibition of glycogen synthase kinase 3β (GSK3β) at mitochondria-endoplasmic reticulum (ER) junctions. This enabled recruitment of hexokinase I (HK-I) to the voltage-dependent anion channel (VDAC) on mitochondria...
March 1, 2018: Immunity
Yuya Nishimura, Terumi Matsui, Jun Ishii, Akihiko Kondo
BACKGROUND: To produce 1-propanol as a potential biofuel, metabolic engineering of microorganisms, such as E. coli, has been studied. However, 1-propanol production using metabolically engineered Saccharomyces cerevisiae, which has an amazing ability to produce ethanol and is thus alcohol-tolerant, has infrequently been reported. Therefore, in this study, we aimed to engineer S. cerevisiae strains capable of producing 1-propanol at high levels. RESULTS: We found that the activity of endogenous 2-keto acid decarboxylase and alcohol/aldehyde dehydrogenase is sufficient to convert 2-ketobutyrate (2 KB) to 500 mg/L 1-propanol in yeast...
March 9, 2018: Microbial Cell Factories
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
Benjamin G Kremkow, Kelvin H Lee
Glyco-Mapper is a novel systems biology product quality prediction tool created using a new framework termed: Discretized Reaction Network Modeling using Fuzzy Parameters (DReaM-zyP). Within Glyco-Mapper, users fix the nutrient feed composition and the glycosylation reaction fluxes to fit the model glycoform to the reference experimental glycoform, enabling cell-line specific glycoform predictions as a result of cell engineering strategies. Glyco-Mapper accurately predicts published genetically altered glycoforms resulting in the appearance or disappearance of one or more glycans between 1999 and 2014 with an accuracy, sensitivity, and specificity of 96%, 85%, and 97%, respectively...
March 6, 2018: Metabolic Engineering
Nana Y D Ankrah, Angela E Douglas
Many symbiotic microorganisms in animals, including insects, have parallels to microbial nutrient factories of biotechnology: just as the metabolism of individual microorganisms and microbial communities is modified by biotechnologists to produce specific nutrients, so the many insect-associated microorganisms synthesize specific nutrients that support the sustained growth and reproduction of their animal host. Three broad metabolic functions are mediated by insect-associated microorganisms: (i)fermentation of dietary constituents, releasing products that contribute to host carbon and energy metabolism; (ii)overproduction of nutrients, notably essential amino acids, required by the host; and (iii)recycling of host waste metabolites...
March 9, 2018: Environmental Microbiology
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