PubMed

Related Articles Effects of a block in cysteine catabolism on energy balance and fat metabolism in mice. Ann N Y Acad Sci. 2016 Jan;1363:99-115 Authors: Niewiadomski J, Zhou JQ, Roman HB, Liu X, Hirschberger LL, Locasale JW, Stipanuk MH Abstract To gain further insights into the effects of elevated cysteine levels on energy metabolism and the possible mechanisms underlying these effects, we conducted studies in cysteine dioxygenase (Cdo1)-null mice. Cysteine dioxygenase (CDO) catalyzes the first step of the major pathway for cysteine catabolism. When CDO is absent, tissue and plasma cysteine levels are elevated, resulting in enhanced flux of cysteine through desulfhydration reactions. When Cdo1-null mice were fed a high-fat diet, they gained more weight than their wild-type controls, regardless of whether the diet was supplemented with taurine. Cdo1-null mice had markedly lower leptin levels, higher feed intakes, and markedly higher abundance of hepatic stearoyl-CoA desaturase 1 (SCD1) compared to wild-type control mice, and these differences were not affected by the fat or taurine content of the diet. Thus, reported associations of elevated cysteine levels with greater weight gain and with elevated hepatic Scd1 expression are also seen in the Cdo1-null mouse model. Hepatic accumulation of acylcarnitines suggests impaired mitochondrial β-oxidation of fatty acids in Cdo1-null mice. The strong associations of elevated cysteine levels with excess H2 S production and impairments in energy metabolism suggest that H2 S signaling could be involved. PMID: 26995761 [PubMed - indexed for MEDLINE]

Related Articles Phenylpropanoid Defences in Nicotiana tabacum Cells: Overlapping Metabolomes Indicate Common Aspects to Priming Responses Induced by Lipopolysaccharides, Chitosan and Flagellin-22. PLoS One. 2016;11(3):e0151350 Authors: Mhlongo MI, Piater LA, Madala NE, Steenkamp PA, Dubery IA Abstract Plants have evolved both constitutive and inducible defence strategies to cope with different biotic stimuli and stresses. Exposure of a plant to a challenging stress can lead to a primed state that allows it to launch a more rapid and stronger defence. Here we applied a metabolomic approach to study and compare the responses induced in Nicotiana tabacum cells by microbe-associated molecular pattern (MAMP) molecules, namely lipopolysaccharides (LPS), chitosan (CHT) and flagellin-22 (FLG22). Early response metabolites, extracted with methanol, were analysed by UHPLC-MS/MS. Using multivariate statistical tools the metabolic profiles induced by these elicitors were analysed. In the metabolic fingerprint of these agents a total of 19 cinnamic acid derivatives conjugated to quinic acids (chlorogenic acids), shikimic acid, tyramine, polyamines or glucose were found as discriminant biomarkers. In addition, treatment with the phytohormones salicylic acid (SA), methyljasmonic acid (MJ) and abscisic acid (ABA) resulted in differentially-induced phenylpropanoid pathway metabolites. The results indicate that the phenylpropanoid pathway is activated by these elicitors while hydroxycinnamic acid derivatives are commonly associated with the metabolic response to the MAMPs, and that the activated responses are modulated by both SA and MJ, with ABA not playing a role. PMID: 26978774 [PubMed - indexed for MEDLINE]

Related Articles Pharmacometabolomics Meets Genetics: A "Natural" Clinical Trial of Statin Effects. J Am Coll Cardiol. 2016 Mar 15;67(10):1211-3 Authors: Voora D, Shah SH PMID: 26965543 [PubMed - indexed for MEDLINE]

Related Articles Cellular metabolic network analysis: discovering important reactions in Treponema pallidum. Biomed Res Int. 2015;2015:328568 Authors: Chen X, Zhao M, Qu H Abstract T. pallidum, the syphilis-causing pathogen, performs very differently in metabolism compared with other bacterial pathogens. The desire for safe and effective vaccine of syphilis requests identification of important steps in T. pallidum's metabolism. Here, we apply Flux Balance Analysis to represent the reactions quantitatively. Thus, it is possible to cluster all reactions in T. pallidum. By calculating minimal cut sets and analyzing topological structure for the metabolic network of T. pallidum, critical reactions are identified. As a comparison, we also apply the analytical approaches to the metabolic network of H. pylori to find coregulated drug targets and unique drug targets for different microorganisms. Based on the clustering results, all reactions are further classified into various roles. Therefore, the general picture of their metabolic network is obtained and two types of reactions, both of which are involved in nucleic acid metabolism, are found to be essential for T. pallidum. It is also discovered that both hubs of reactions and the isolated reactions in purine and pyrimidine metabolisms play important roles in T. pallidum. These reactions could be potential drug targets for treating syphilis. PMID: 26495292 [PubMed - indexed for MEDLINE]

Related Articles Metabolomic alterations in human cancer cells by vitamin C-induced oxidative stress. Sci Rep. 2015;5:13896 Authors: Uetaki M, Tabata S, Nakasuka F, Soga T, Tomita M Abstract Intravenous administration of high-dose vitamin C has recently attracted attention as a cancer therapy. High-dose vitamin C induces pro-oxidant effects and selectively kills cancer cells. However, the anticancer mechanisms of vitamin C are not fully understood. Here, we analyzed metabolic changes induced by vitamin C in MCF7 human breast adenocarcinoma and HT29 human colon cancer cells using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). The metabolomic profiles of both cell lines were dramatically altered after exposure to cytotoxic concentrations of vitamin C. Levels of upstream metabolites in the glycolysis pathway and tricarboxylic acid (TCA) cycle were increased in both cell lines following treatment with vitamin C, while adenosine triphosphate (ATP) levels and adenylate energy charges were decreased concentration-dependently. Treatment with N-acetyl cysteine (NAC) and reduced glutathione (GSH) significantly inhibited vitamin C-induced cytotoxicity in MCF7 cells. NAC also suppressed vitamin C-dependent metabolic changes, and NAD treatment prevented vitamin C-induced cell death. Collectively, our data suggests that vitamin C inhibited energy metabolism through NAD depletion, thereby inducing cancer cell death. PMID: 26350063 [PubMed - indexed for MEDLINE]

Related Articles Strain-level bacterial identification by CeO2-catalyzed MALDI-TOF MS fatty acid analysis and comparison to commercial protein-based methods. Sci Rep. 2015;5:10470 Authors: Cox CR, Jensen KR, Saichek NR, Voorhees KJ Abstract Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has emerged as a rapid approach for clinical bacterial identification. However, current protein-based commercial bacterial ID methods fall short when differentiating closely related species/strains. To address this shortcoming, we employed CeO2-catalyzed fragmentation of lipids to produce fatty acids using the energy inherent to the MALDI laser as a novel alternative to protein profiling. Fatty acid profiles collected from Enterobacteriaceae, Acinetobacter, and Listeria using CeO2-catalyzed metal oxide laser ionization (MOLI MS), processed by principal component analysis, and validated by leave-one-out cross-validation (CV), showed 100% correct classification at the species level and 98% at the strain level. In comparison, protein profile data from the same bacteria yielded 32%, 54% and 67% mean species-level accuracy using two MALDI-TOF MS platforms, respectively. In addition, several pathogens were misidentified by protein profiling as non-pathogens and vice versa. These results suggest novel CeO2-catalyzed lipid fragmentation readily produced (i) taxonomically tractable fatty acid profiles by MOLI MS, (ii) highly accurate bacterial classification and (iii) consistent strain-level ID for bacteria that were routinely misidentified by protein-based methods. PMID: 26190224 [PubMed - indexed for MEDLINE]

Related Articles Metabolomics to Detect Response of Lettuce (Lactuca sativa) to Cu(OH)2 Nano-pesticides: Oxidative Stress Response and Detoxification Mechanisms. Environ Sci Technol. 2016 Aug 2; Authors: Zhao L, Ortiz C, Adeleye AS, Hu Q, Zhou H, Huang Y, Keller AA Abstract There has been an increasing influx of nanopesticides into agriculture in recent years. Understanding the interaction between nanopesticides and edible plants is crucial in evaluating the potential impact of nanotechnology on the environment and agriculture. Here we exposed lettuce plants to Cu(OH)2 nanopesticides (1050-2100 mg/L) through foliar spray for one month. Inductively coupled plasma-mass spectrometry (ICP-MS) results indicate that 97-99% (1353-2501 mg/kg) of copper was sequestered in the leaves and only a small percentage (1-3%) (17.5-56.9 mg/kg) was translocated to root tissues through phloem loading. Gas Chromatography-Time-of-Flight Mass Spectrometry (GC-TOF-MS) based metabolomics combined with Partial Least Squares-Discriminant Analysis (PLS-DA) multivariate analysis revealed that Cu(OH)2 nanopesticides altered metabolite levels of lettuce leaves. Tricarboxylic (TCA) cycle and a number of amino acid-related biological pathways were disturbed. Some antioxidant levels (cis-caffeic acid, chlorogenic acid, 3,4-dihydroxycinnamic acid, dehydroascorbic acid) were significantly decreased compared to the control, indicating that oxidative stress and a defense response occurred. Nicotianamine, a copper chelator, increased by 12-27 fold compared to the control, which may represent a detoxification mechanism. The up-regulation of polyamines (spermidine and putrescine) and potassium may mitigate oxidative stress and enhance tolerance. The data presented here provide a molecular-scale perspective on the response of plants to copper nanopesticides. PMID: 27483188 [PubMed - as supplied by publisher]

Related Articles Methyl group donors abrogate adaptive responses to dietary restriction in C. elegans. Genes Nutr. 2016;11:4 Authors: Klapper M, Findeis D, Koefeler H, Döring F Abstract BACKGROUND: Almost all animals adapt to dietary restriction through alternative life history traits that affect their growth, reproduction, and survival. Economized management of fat stores is a prevalent type of such adaptations. Because one-carbon metabolism is a critical gauge of food availability, in this study, we used Caenorhabditis elegans to test whether the methyl group donor choline regulates adaptive responses to dietary restriction. We used a modest dietary restriction regimen that prolonged the fecund period without reducing the lifetime production of progeny, which is the best measure of fitness. RESULTS: We found that dietary supplementation with choline abrogate the dietary restriction-induced prolongation of the reproductive period as well as the accumulation and delayed depletion of large lipid droplets and whole-fat stores and increased the survival rate in the cold. By contrast, the life span-prolonging effect of dietary restriction is not affected by choline. Moreover, we found that dietary restriction led to the enlargement of lipid droplets within embryos and enhancement of the cold tolerance of the progeny of dietarily restricted mothers. Both of these transgenerational responses to maternal dietary restriction were abrogated by exposing the parental generation to choline. CONCLUSIONS: In conclusion, supplementation with the methyl group donor choline abrogates distinct responses to dietary restriction related to reproduction, utilization of fat stored in large lipid droplets, cold tolerance, and thrifty phenotypes in C. elegans. PMID: 27482296 [PubMed]

Related Articles S-adenosylmethionine synthetase 3 is important for pollen tube growth. Plant Physiol. 2016 Aug 1; Authors: Chen Y, Zou T, McCormick S Abstract SAM (S-adenosylmethionine) is widely used in variety of biological reactions and participates in the Met (methionine) metabolic pathway. In Arabidopsis, one of the 4 S-adenosyl methionine synthetase (SAMS) genes, MAT3, is highly expressed in pollen. Here we show that mat3 mutants have impaired pollen tube growth and reduced seed set. Metabolomics analyses confirmed that mat3 pollen and pollen tubes over-accumulate methionine and that mat3 pollen has several metabolite profiles, for example, those of polyamine biosynthesis, which are different from those of wild type. Additionally, we showed that disruption of methionine metabolism in mat3 pollen affected tRNA and histone methylation levels. Thus, our results suggest a connection between metabolism and epigenetics. PMID: 27482079 [PubMed - as supplied by publisher]

Related Articles Metabolomics Profiling for Obstructive Sleep Apnea and Simple Snorers. Sci Rep. 2016;6:30958 Authors: Xu H, Zheng X, Qian Y, Guan J, Yi H, Zou J, Wang Y, Meng L, Zhao A, Yin S, Jia W Abstract Few clinical studies have explored altered urinary metabolite levels in patients with obstructive sleep apnea (OSA). Thus, we applied a metabolomics approach to analyze urinary metabolites in three groups of participants: patients with polysomnography (PSG)-confirmed OSA, simple snorers (SS), and normal subjects. Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry and gas chromatography coupled with time-of-flight mass spectrometry were used. A total of 21 and 31 metabolites were differentially expressed in the SS and OSA groups, respectively. Patients with OSA had 18 metabolites different from those with SS. Of the 56 metabolites detected among the 3 groups, 24 were consistently higher or lower. A receiver operator curve analysis revealed that the combination of 4-hydroxypentenoic acid, arabinose, glycochenodeoxycholate-3-sulfate, isoleucine, serine, and xanthine produced a moderate diagnostic score with a sensitivity (specificity) of 75% (78%) for distinguishing OSA from those without OSA. The combination of 4-hydroxypentenoic acid, 5-dihydrotestosterone sulfate, serine, spermine, and xanthine distinguished OSA from SS with a sensitivity of 85% and specificity of 80%. Multiple metabolites and metabolic pathways associated with SS and OSA were identified using the metabolomics approach, and the altered metabolite signatures could potentially serve as an alternative diagnostic method to PSG. PMID: 27480913 [PubMed - in process]

Related Articles Glutamate racemase is the primary target of β-chloro-D-alanine in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2016 Aug 1; Authors: Prosser GA, Rodenburg A, Khoury H, de Chiara C, Howell S, Snijders AP, de Carvalho LP Abstract The increasing global prevalence of drug-resistance amongst many leading human pathogens necessitates both the development of antibiotics with novel mechanisms of action and a better understanding of the physiological activities of pre-existing clinically effective drugs. Inhibition of peptidoglycan (PG) biosynthesis and cross-linking has traditionally enjoyed immense success as antibiotic targets in multiple bacterial pathogens, except in Mycobacterium tuberculosis where it has so far been under-exploited. D-Cycloserine, a clinically-approved anti-tubercular therapeutic, inhibits enzymes within the D-alanine sub-branch of the PG-biosynthetic pathway and has been a focus in our lab for understanding peptidoglycan biosynthesis inhibition and drug development in M. tuberculosis During our studies on alternative inhibitors of the D-alanine pathway we discovered that the canonical alanine racemase (Alr) inhibitor β-chloro-D-alanine (BCDA) is a very poor inhibitor of recombinant M. tuberculosis Alr, despite having potent anti-tubercular activity. Through a combination of enzymology, microbiology, metabolomics and proteomics, we show here that BCDA does not inhibit the D-alanine pathway in intact cells, consistent with its poor in vitro activity, and that instead it is a mechanism-based inactivator of glutamate racemase (MurI), an upstream enzyme in the same early stage of PG biosynthesis. This is the first report to our knowledge of inhibition of MurI in M. tuberculosis and thus provides a valuable tool for studying this essential and enigmatic enzyme and a starting point for future MurI-targeted antibacterial development. PMID: 27480853 [PubMed - as supplied by publisher]

Related Articles In Vitro Assessment of Plants Growing in Cuba Belonging to Solanaceae Family Against Leishmania amazonensis. Phytother Res. 2016 Aug 2; Authors: Monzote L, Jiménez J, Cuesta-Rubio O, Márquez I, Gutiérrez Y, da Rocha CQ, Marchi M, Setzer WN, Vilegas W Abstract In this study, an in vitro antileishmanial assessment of plant extracts from 12 genera and 46 species growing in Cuba belonging to Solanaceae family was performed. A total of 226 extracts were screened against promastigotes of Leishmania amazonensis, and cytotoxicity of active extracts [median inhibitory concentration (IC50 ) promastigotes <100 µg/mL] was determined on peritoneal macrophage from BALB/c mice. Extracts that showed selective index >5 were then assayed against intracellular amastigote. Metabolomics analysis of promissory extracts was performed using chemical profile obtained by ultra performance liquid chromatography. Only 11 extracts (4.9%) from nine plants were selected as potentially actives: Brunfelsia cestroides A. Rich, Capsicum annuum L., Capsicum chinense Jacq., Cestrum nocturnum L., Nicotiana plumbaginifolia Viv., Solanum havanense Jacq., Solanum myriacanthum Dunal, Solanum nudum Dunal and Solanum seaforthianum And., with IC50  < 50 µg/mL and selectivity index >5. Metabolomics analysis demonstrated significant differences in the chemical profiles with an average of 42.8 (range 31-88) compounds from m/z 104 to 1477, which demonstrated the complex mixture of compounds. In addition, no common markers among active extracts were identified. The results demonstrate the importance of the Solanaceae family to search new antileishmanial agents, particularly in unexplored species of this family. Copyright © 2016 John Wiley & Sons, Ltd. PMID: 27480800 [PubMed - as supplied by publisher]

Related Articles Generation and Functional Evaluation of Designer Monoterpene Synthases. Methods Enzymol. 2016;576:147-65 Authors: Srividya N, Lange I, Lange BM Abstract Monoterpene synthases are highly versatile enzymes that catalyze the first committed step in the pathways toward terpenoids, the structurally most diverse class of plant natural products. Recent advancements in our understanding of the reaction mechanism have enabled engineering approaches to develop mutant monoterpene synthases that produce specific monoterpenes. In this chapter, we are describing protocols to introduce targeted mutations, express mutant enzyme catalysts in heterologous hosts, and assess their catalytic properties. Mutant monoterpene synthases have the potential to contribute significantly to synthetic biology efforts aimed at producing larger amounts of commercially attractive monoterpenes. PMID: 27480686 [PubMed - in process]

Related Articles A Workflow for Studying Specialized Metabolism in Nonmodel Eukaryotic Organisms. Methods Enzymol. 2016;576:69-97 Authors: Torrens-Spence MP, Fallon TR, Weng JK Abstract Eukaryotes contain a diverse tapestry of specialized metabolites, many of which are of significant pharmaceutical and industrial importance to humans. Nevertheless, exploration of specialized metabolic pathways underlying specific chemical traits in nonmodel eukaryotic organisms has been technically challenging and historically lagged behind that of the bacterial systems. Recent advances in genomics, metabolomics, phylogenomics, and synthetic biology now enable a new workflow for interrogating unknown specialized metabolic systems in nonmodel eukaryotic hosts with greater efficiency and mechanistic depth. This chapter delineates such workflow by providing a collection of state-of-the-art approaches and tools, ranging from multiomics-guided candidate gene identification to in vitro and in vivo functional and structural characterization of specialized metabolic enzymes. As already demonstrated by several recent studies, this new workflow opens up a gateway into the largely untapped world of natural product biochemistry in eukaryotes. PMID: 27480683 [PubMed - in process]

Related Articles Metabolomics evaluation of the impact of smokeless tobacco exposure on the oral bacterium Capnocytophaga sputigena. Toxicol In Vitro. 2016 Jul 29; Authors: Sun J, Jin J, Beger RD, Cerniglia CE, Yang M, Chen H Abstract The association between exposure to smokeless tobacco products (STP) and oral diseases is partially due to the physiological and pathological changes in the composition of the oral microbiome and its metabolic profile.However, it is not clear how STPs affect the physiology and ecology of oral microbiota. A UPLC/QTof-MS-based metabolomics study was employed to analyze metabolic alterations in oral bacterium, Capnocytophaga sputigena as a result of smokeless tobacco exposure and to assess the capability of the bacterium to metabolize nicotine.Pathway analysis of the metabolome profiles indicated that smokeless tobacco extracts caused oxidative stress in the bacterium.The metabolomics data also showed that the arginine-nitric oxide pathway was perturbed by the smokeless tobacco treatment.Results also showed that LC/MS was useful in identifying STP constituents and additives, including caffeine and many flavoring compounds.No significant changes in levels of nicotine and its major metabolites were found when C. sputigena was cultured in a nutrient rich medium, although hydroxylnicotine and cotinine N-oxide were detected in the bacterial metabolites suggesting that nicotine metabolism might be present as a minor degradation pathway in the bacterium. Study results provide new insights regarding the physiological and toxicological effects of smokeless tobacco on oral bacterium C. sputigena and associated oral health as well as measuring the ability of the oral bacterium to metabolize nicotine. PMID: 27480511 [PubMed - as supplied by publisher]

Related Articles Gas Chromatography/Mass Spectrometry-Based Metabolomic Profiling Reveals Alterations in Mouse Plasma and Liver in Response to Fava Beans. PLoS One. 2016;11(3):e0151103 Authors: Xiao M, Du G, Zhong G, Yan D, Zeng H, Cai W Abstract Favism is a life-threatening hemolytic anemia resulting from the intake of fava beans by susceptible individuals with low erythrocytic glucose 6-phosphate dehydrogenase (G6PD) activity. However, little is known about the metabolomic changes in plasma and liver after the intake of fava beans in G6PD normal and deficient states. In this study, gas chromatography/mass spectrometry was used to analyze the plasma and liver metabolic alterations underlying the effects of fava beans in C3H- and G6PD-deficient (G6PDx) mice, and to find potential biomarkers and metabolic changes associated with favism. Our results showed that fava beans induced oxidative stress in both C3H and G6PDx mice. Significantly, metabolomic differences were observed in plasma and liver between the control and fava bean treated groups of both C3H and G6PDx mice. The levels of 7 and 21 metabolites in plasma showed significant differences between C3H-control (C3H-C)- and C3H fava beans-treated (C3H-FB) mice, and G6PDx-control (G6PDx-C)- and G6PDx fava beans-treated (G6PDx-FB) mice, respectively. Similarly, the levels of 7 and 25 metabolites in the liver showed significant differences between C3H and C3H-FB, and G6PDx and G6PDx-FB, respectively. The levels of oleic acid, linoleic acid, and creatinine were significantly increased in the plasma of both C3H-FB and G6PDx-FB mice. In the liver, more metabolic alterations were observed in G6PDx-FB mice than in C3H-FB mice, and were involved in a sugar, fatty acids, amino acids, cholesterol biosynthesis, the urea cycle, and the nucleotide metabolic pathway. These findings suggest that oleic acid, linoleic acid, and creatinine may be potential biomarkers of the response to fava beans in C3H and G6PDx mice and therefore that oleic acid and linoleic acid may be involved in oxidative stress induced by fava beans. This study demonstrates that G6PD activity in mice can affect their metabolic pathways in response to fava beans. PMID: 26981882 [PubMed - indexed for MEDLINE]

Related Articles A Comparison of the ATP Generating Pathways Used by S. Typhimurium to Fuel Replication within Human and Murine Macrophage and Epithelial Cell Lines. PLoS One. 2016;11(3):e0150687 Authors: Garcia-Gutierrez E, Chidlaw AC, Le Gall G, Bowden SD, Tedin K, Kelly DJ, Thompson A Abstract The metabolism of S. Typhimurium within infected host cells plays a fundamental role in virulence since it enables intracellular proliferation and dissemination and affects the innate immune response. An essential requirement for the intracellular replication of S. Typhimurium is the need to regenerate ATP. The metabolic route used to fulfil this requirement is the subject of the present study. For infection models we used human and murine epithelial and macrophage cell lines. The epithelial cell lines were mICc12, a transimmortalised murine colon enterocyte cell line that shows many of the characteristics of a primary epithelial cell line, and HeLa cells. The model macrophage cell lines were THP-1A human monocyte/macrophages and RAW 264.7 murine macrophages. Using a mutational approach combined with an exometabolomic analysis, we showed that neither fermentative metabolism nor anaerobic respiration play major roles in energy generation in any of the cell lines studied. Rather, we identified overflow metabolism to acetate and lactate as the foremost route by which S. Typhimurium fulfils its energy requirements. PMID: 26930214 [PubMed - indexed for MEDLINE]

Related Articles Phototransduction Influences Metabolic Flux and Nucleotide Metabolism in Mouse Retina. J Biol Chem. 2016 Feb 26;291(9):4698-710 Authors: Du J, Rountree A, Cleghorn WM, Contreras L, Lindsay KJ, Sadilek M, Gu H, Djukovic D, Raftery D, Satrústegui J, Kanow M, Chan L, Tsang SH, Sweet IR, Hurley JB Abstract Production of energy in a cell must keep pace with demand. Photoreceptors use ATP to maintain ion gradients in darkness, whereas in light they use it to support phototransduction. Matching production with consumption can be accomplished by coupling production directly to consumption. Alternatively, production can be set by a signal that anticipates demand. In this report we investigate the hypothesis that signaling through phototransduction controls production of energy in mouse retinas. We found that respiration in mouse retinas is not coupled tightly to ATP consumption. By analyzing metabolic flux in mouse retinas, we also found that phototransduction slows metabolic flux through glycolysis and through intermediates of the citric acid cycle. We also evaluated the relative contributions of regulation of the activities of α-ketoglutarate dehydrogenase and the aspartate-glutamate carrier 1. In addition, a comprehensive analysis of the retinal metabolome showed that phototransduction also influences steady-state concentrations of 5'-GMP, ribose-5-phosphate, ketone bodies, and purines. PMID: 26677218 [PubMed - indexed for MEDLINE]

Revealing disease-associated pathways by network integration of untargeted metabolomics. Nat Methods. 2016 Aug 1; Authors: Pirhaji L, Milani P, Leidl M, Curran T, Avila-Pacheco J, Clish CB, White FM, Saghatelian A, Fraenkel E Abstract Uncovering the molecular context of dysregulated metabolites is crucial to understand pathogenic pathways. However, their system-level analysis has been limited owing to challenges in global metabolite identification. Most metabolite features detected by untargeted metabolomics carried out by liquid-chromatography-mass spectrometry cannot be uniquely identified without additional, time-consuming experiments. We report a network-based approach, prize-collecting Steiner forest algorithm for integrative analysis of untargeted metabolomics (PIUMet), that infers molecular pathways and components via integrative analysis of metabolite features, without requiring their identification. We demonstrated PIUMet by analyzing changes in metabolism of sphingolipids, fatty acids and steroids in a Huntington's disease model. Additionally, PIUMet enabled us to elucidate putative identities of altered metabolite features in diseased cells, and infer experimentally undetected, disease-associated metabolites and dysregulated proteins. Finally, we established PIUMet's ability for integrative analysis of untargeted metabolomics data with proteomics data, demonstrating that this approach elicits disease-associated metabolites and proteins that cannot be inferred by individual analysis of these data. PMID: 27479327 [PubMed - as supplied by publisher]

Intracellular metabolic changes of Clostridium acetobutylicum and promotion to butanol tolerance during biobutanol fermentation. Int J Biochem Cell Biol. 2016 Jul 28; Authors: Wang YF, Tian J, Ji ZH, Song MY, Li H Abstract During the fermentation process, Clostridium acetobutylicum cells are often inhibited by the accumulated butanol. However, the mechanism underlying response of C. acetobutylicum to butanol stress remains poorly understood. This study was performed to clarify such mechanism through investigating the butanol stress-associated intracellular biochemical changes at acidogenesis phase (i.e., middle exponential phase) and solventogenesis phase (i.e., early stationary phase) by a gas chromatography-mass spectrometry-based metabolomics strategy. With the aid of partial least-squares-discriminant analysis, a pairwise discrimination between control group and butanol-treated groups was revealed, and 27 metabolites with variable importance in the projection value greater than 1 were identified. Under butanol stress, the glycolysis might be inhibited while TCA cycle might be promoted. Moreover, changes of lipids and fatty acids compositions, amino acid metabolism and osmoregulator concentrations might be the key factors involved in C. acetobutylicum metabolic response to butanol stress. It was suggested that C. acetobutylicum cells might change the levels of long acyl chain saturated fatty acids and branched-chain amino acids to maintain the integrity of cell membrane through adjusting membrane fluidity under butanol stress. The increased level of glycerol was considered to be correlated with osmoregulation and regulating redox balance. In addition, increased levels of some amino acids (i.e., threonine, glycine, alanine, phenylalanine, tyrosine, tryptophan, aspartate and glutamate) might also confer butanol tolerance to C. acetobutylicum. These results highlighted our knowledge about the response or adaptation of C. acetobutylicum to butanol stress, and would contribute to the construction of feasible butanologenic strains with higher butanol tolerance. PMID: 27477314 [PubMed - as supplied by publisher]