scholarly journals Boundary conditions for early life converge to an organo-sulfur metabolism

2018 ◽  
Author(s):  
Joshua E. Goldford ◽  
Hyman Hartman ◽  
Robert Marsland ◽  
Daniel Segrè
Keyword(s):  
Boundary Conditions ◽  
Early Life ◽  
Metabolic Networks ◽  
Sulfur Metabolism ◽  
Continuous Production ◽  
Carbon Sources ◽  
Tca Cycle ◽  
Metabolic Model ◽  
Molecular Precursors ◽  
Combine Network

AbstractIt has been suggested that a deep memory of early life is hidden in the architecture of metabolic networks, whose reactions could have been catalyzed by small molecules or minerals prior to genetically encoded enzymes (1–6). A major challenge in unraveling these early steps is assessing the plausibility of a connected, thermodynamically consistent proto-metabolism under different geochemical conditions, which are still surrounded by high uncertainty. Here we combine network-based algorithms (9, 10) with physicochemical constraints on chemical reaction networks to systematically show how different combinations of parameters (temperature, pH, redox potential and availability of molecular precursors) could have affected the evolution of a proto-metabolism. Our analysis of possible trajectories indicates that a subset of boundary conditions converges to an organo-sulfur-based proto-metabolic network fueled by a thioester- and redox-driven variant of the reductive TCA cycle, capable of producing lipids and keto acids. Surprisingly, environmental sources of fixed nitrogen and low-potential electron donors seem not to be necessary for the earliest phases of biochemical evolution. We use one of these networks to build a steady-state dynamical metabolic model of a proto-cell, and find that different combinations of carbon sources and electron acceptors can support the continuous production of a minimal ancient “biomass” composed of putative early biopolymers and fatty acids.

scholarly journals Comprehensive Plasma Metabolomic Profile of Patients with Advanced Neuroendocrine Tumors (NETs). Diagnostic and Biological Relevance

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2634
Author(s):  
Beatriz Soldevilla ◽  
Angeles López-López ◽  
Alberto Lens-Pardo ◽  
Carlos Carretero-Puche ◽  
Angeles Lopez-Gonzalvez ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Metabolic Networks ◽  
Tca Cycle ◽  
Metabolomic Profile ◽  
Diagnostic Potential ◽  
The Tca Cycle ◽  
Novel Biomarkers ◽  
Potential Methods ◽  
Clinical Potential ◽  
First Time

Purpose: High-throughput “-omic” technologies have enabled the detailed analysis of metabolic networks in several cancers, but NETs have not been explored to date. We aim to assess the metabolomic profile of NET patients to understand metabolic deregulation in these tumors and identify novel biomarkers with clinical potential. Methods: Plasma samples from 77 NETs and 68 controls were profiled by GC−MS, CE−MS and LC−MS untargeted metabolomics. OPLS-DA was performed to evaluate metabolomic differences. Related pathways were explored using Metaboanalyst 4.0. Finally, ROC and OPLS-DA analyses were performed to select metabolites with biomarker potential. Results: We identified 155 differential compounds between NETs and controls. We have detected an increase of bile acids, sugars, oxidized lipids and oxidized products from arachidonic acid and a decrease of carnitine levels in NETs. MPA/MSEA identified 32 enriched metabolic pathways in NETs related with the TCA cycle and amino acid metabolism. Finally, OPLS-DA and ROC analysis revealed 48 metabolites with diagnostic potential. Conclusions: This study provides, for the first time, a comprehensive metabolic profile of NET patients and identifies a distinctive metabolic signature in plasma of potential clinical use. A reduced set of metabolites of high diagnostic accuracy has been identified. Additionally, new enriched metabolic pathways annotated may open innovative avenues of clinical research.

scholarly journals Intracellular Fate of Universally Labelled 13C Isotopic Tracers of Glucose and Xylose in Central Metabolic Pathways of Xanthomonas oryzae

Metabolites ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 66 ◽  
Author(s):  
Manu Shree ◽  
Shyam K. Masakapalli
Keyword(s):  
Amino Acids ◽  
Metabolic Pathways ◽  
Metabolic Networks ◽  
Tca Cycle ◽  
Xanthomonas Oryzae ◽  
Flux Analysis ◽  
Isotopic Tracers ◽  
Feeding Experiments ◽  
The Tca Cycle ◽  
Metabolic Route

The goal of this study is to map the metabolic pathways of poorly understood bacterial phytopathogen, Xanthomonas oryzae (Xoo) BXO43 fed with plant mimicking media XOM2 containing glutamate, methionine and either 40% [13C5] xylose or 40% [13C6] glucose. The metabolic networks mapped using the KEGG mapper and the mass isotopomer fragments of proteinogenic amino acids derived from GC-MS provided insights into the activities of Xoo central metabolic pathways. The average 13C in histidine, aspartate and other amino acids confirmed the activities of PPP, the TCA cycle and amino acid biosynthetic routes, respectively. The similar labelling patterns of amino acids (His, Ala, Ser, Val and Gly) from glucose and xylose feeding experiments suggests that PPP would be the main metabolic route in Xoo. Owing to the lack of annotated gene phosphoglucoisomerase in BXO43, the 13C incorporation in alanine could not be attributed to the competing pathways and hence warrants additional positional labelling experiments. The negligible presence of 13C incorporation in methionine brings into question its potential role in metabolism and pathogenicity. The extent of the average 13C labelling in several amino acids highlighted the contribution of pre-existing pools that need to be accounted for in 13C-flux analysis studies. This study provided the first qualitative insights into central carbon metabolic pathway activities in Xoo.

scholarly journals Genome-scale reconstructions to assess metabolic phylogeny and organism clustering

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0240953
Author(s):  
Christian Schulz ◽  
Eivind Almaas
Keyword(s):  
Phylogenetic Trees ◽  
Metabolic Networks ◽  
Sulfur Metabolism ◽  
Phylogenetic Analyses ◽  
Tree Of Life ◽  
Significant Heterogeneity ◽  
Metabolic Reaction ◽  
High Quality ◽  
Conserved Genes ◽  
Genome Scale

Approaches for systematizing information of relatedness between organisms is important in biology. Phylogenetic analyses based on sets of highly conserved genes are currently the basis for the Tree of Life. Genome-scale metabolic reconstructions contain high-quality information regarding the metabolic capability of an organism and are typically restricted to metabolically active enzyme-encoding genes. While there are many tools available to generate draft reconstructions, expert-level knowledge is still required to generate and manually curate high-quality genome-scale metabolic models and to fill gaps in their reaction networks. Here, we use the tool AutoKEGGRec to construct 975 genome-scale metabolic draft reconstructions encoded in the KEGG database without further curation. The organisms are selected across all three domains, and their metabolic networks serve as basis for generating phylogenetic trees. We find that using all reactions encoded, these metabolism-based comparisons give rise to a phylogenetic tree with close similarity to the Tree of Life. While this tree is quite robust to reasonable levels of noise in the metabolic reaction content of an organism, we find a significant heterogeneity in how much noise an organism may tolerate before it is incorrectly placed in the tree. Furthermore, by using the protein sequences for particular metabolic functions and pathway sets, such as central carbon-, nitrogen-, and sulfur-metabolism, as basis for the organism comparisons, we generate highly specific phylogenetic trees. We believe the generation of phylogenetic trees based on metabolic reaction content, in particular when focused on specific functions and pathways, could aid the identification of functionally important metabolic enzymes and be of value for genome-scale metabolic modellers and enzyme-engineers.

scholarly journals Investigating the chemolithoautotrophic and formate metabolism of Nitrospira moscoviensis by constraint-based metabolic modeling and 13C-tracer analysis

2021 ◽  
Author(s):  
Christopher E. Lawson ◽  
Aniela B. Mundinger ◽  
Hanna Koch ◽  
Tyler B. Jacobson ◽  
Coty A. Weathersby ◽  
...  
Keyword(s):  
Wastewater Treatment ◽  
Metabolic Networks ◽  
Metabolic Model ◽  
Scale Model ◽  
Nitrifying Bacteria ◽  
Metabolomic Analysis ◽  
A Genome ◽  
Nitrite Oxidizing Bacteria ◽  
Genome Scale ◽  
Nitrospira Moscoviensis

AbstractNitrite-oxidizing bacteria belonging to the genus Nitrospira mediate a key step in nitrification and play important roles in the biogeochemical nitrogen cycle and wastewater treatment. While these organisms have recently been shown to exhibit metabolic flexibility beyond their chemolithoautotrophic lifestyle, including the use of simple organic compounds to fuel their energy metabolism, the metabolic networks controlling their autotrophic and mixotrophic growth remain poorly understood. Here, we reconstructed a genome-scale metabolic model for Nitrospira moscoviensis (iNmo686) and used constraint-based analysis to evaluate the metabolic networks controlling autotrophic and formatotrophic growth on nitrite and formate, respectively. Subsequently, proteomic analysis and 13C-tracer experiments with bicarbonate and formate coupled to metabolomic analysis were performed to experimentally validate model predictions. Our findings support that N. moscoviensis uses the reductive tricarboxylic acid cycle for CO2 fixation. We also show that N. moscoviensis can indirectly use formate as a carbon source by oxidizing it first to CO2 followed by reassimilation, rather than direct incorporation via the reductive glycine pathway. Our study offers the first measurements of Nitrospira’s in vivo central carbon metabolism and provides a quantitative tool that can be used for understanding and predicting their metabolic processes.ImportanceNitrospira are globally abundant nitrifying bacteria in soil and aquatic ecosystems and wastewater treatment plants, where they control the oxidation of nitrite to nitrate. Despite their critical contribution to nitrogen cycling across diverse environments, detailed understanding of their metabolic network and prediction of their function under different environmental conditions remains a major challenge. Here, we provide the first constraint-based metabolic model of N. moscoviensis representing the ubiquitous Nitrospira lineage II and subsequently validate this model using proteomics and 13C-tracers combined with intracellular metabolomic analysis. The resulting genome-scale model will serve as a knowledge base of Nitrospira metabolism and lays the foundation for quantitative systems biology studies of these globally important nitrite- oxidizing bacteria.

scholarly journals Comparative metabolomics of Phialemonium curvatum as an omnipotent fungus cultivated on crude palm oil versus glucose

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Arief Izzairy Zamani ◽  
Susann Barig ◽  
Sarah Ibrahim ◽  
Hirzun Mohd. Yusof ◽  
Julia Ibrahim ◽  
...  
Keyword(s):  
Carbon Source ◽  
Organic Acids ◽  
Vegetable Oil ◽  
Carbon Metabolism ◽  
Sole Carbon Source ◽  
Carbon Sources ◽  
Tca Cycle ◽  
Central Carbon Metabolism ◽  
Targeted Metabolomics ◽  
Central Carbon

Abstract Background Sugars and triglycerides are common carbon sources for microorganisms. Nonetheless, a systematic comparative interpretation of metabolic changes upon vegetable oil or glucose as sole carbon source is still lacking. Selected fungi that can grow in acidic mineral salt media (MSM) with vegetable oil had been identified recently. Hence, this study aimed to investigate the overall metabolite changes of an omnipotent fungus and to reveal changes at central carbon metabolism corresponding to both carbon sources. Results Targeted and non-targeted metabolomics for both polar and semi-polar metabolites of Phialemonium curvatum AWO2 (DSM 23903) cultivated in MSM with palm oil (MSM-P) or glucose (MSM-G) as carbon sources were obtained. Targeted metabolomics on central carbon metabolism of tricarboxylic acid (TCA) cycle and glyoxylate cycle were analysed using LC–MS/MS-TripleQ and GC–MS, while untargeted metabolite profiling was performed using LC–MS/MS-QTOF followed by multivariate analysis. Targeted metabolomics analysis showed that glyoxylate pathway and TCA cycle were recruited at central carbon metabolism for triglyceride and glucose catabolism, respectively. Significant differences in organic acids concentration of about 4- to 8-fold were observed for citric acid, succinic acid, malic acid, and oxaloacetic acid. Correlation of organic acids concentration and key enzymes involved in the central carbon metabolism was further determined by enzymatic assays. On the other hand, the untargeted profiling revealed seven metabolites undergoing significant changes between MSM-P and MSM-G cultures. Conclusions Overall, this study has provided insights on the understanding on the effect of triglycerides and sugar as carbon source in fungi global metabolic pathway, which might become important for future optimization of carbon flux engineering in fungi to improve organic acids production when vegetable oil is applied as the sole carbon source.

scholarly journals Hepatic Mitochondrial Oxidative Metabolism and Lipogenesis Synergistically Adapt to Mediate Healthy Embryonic-to-Neonatal Transition in Chicken

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Chaitra Surugihalli ◽  
Tom E. Porter ◽  
Angela Chan ◽  
Linda S. Farley ◽  
Meghan Maguire ◽  
...  
Keyword(s):  
Lipid Oxidation ◽  
Metabolic Networks ◽  
Tca Cycle ◽  
Neonatal Development ◽  
Alcoholic Fatty Liver ◽  
Species Production ◽  
Mitochondrial Oxidative Metabolism ◽  
And Oxidative Stress ◽  
Alcoholic Fatty Liver Disease ◽  
Neonatal Transition

AbstractDuring the normal embryonic-to-neonatal development, the chicken liver is subjected to intense lipid burden from high rates of yolk-lipid oxidation and also from the accumulation of the yolk-derived and newly synthesized lipids from carbohydrates. High rates of hepatic lipid oxidation and lipogenesis are also central features of non-alcoholic fatty liver disease (NAFLD) in both rodents and humans, but is associated with impaired insulin signaling, dysfunctional mitochondrial energetics and oxidative stress. However, these adverse effects are not apparent in the liver of embryonic and neonatal chicken, despite lipid burden. Utilizing comprehensive metabolic profiling, we identify that steady induction of hepatic mitochondrial tricarboxylic acid (TCA) cycle and lipogenesis are central features of embryonic-to-neonatal transition. More importantly, the induction of TCA cycle and lipogenesis occurred together with the downregulation of hepatic β-oxidation and ketogenesis in the neonatal chicken. This synergistic remodeling of hepatic metabolic networks blunted inflammatory onset, prevented accumulation of lipotoxic intermediates (ceramides and diacylglycerols) and reduced reactive oxygen species production during embryonic-to-neonatal development. This dynamic remodeling of hepatic mitochondrial oxidative flux and lipogenesis aids in the healthy embryonic-to-neonatal transition in chicken. This natural physiological system could help identify mechanisms regulating mitochondrial function and lipogenesis, with potential implications towards treatment of NAFLD.

scholarly journals Metabolic and Developmental Effects Resulting from Deletion of the citA Gene Encoding Citrate Synthase in Aspergillus nidulans

2010 ◽  
Vol 9 (4) ◽  
pp. 656-666 ◽  
Author(s):  
Sandra L. Murray ◽  
Michael J. Hynes
Keyword(s):  
Aspergillus Nidulans ◽  
Fluorescent Protein ◽  
Citrate Synthase ◽  
Glyoxylate Cycle ◽  
Single Gene ◽  
Carbon Sources ◽  
Tca Cycle ◽  
Poor Growth ◽  
Content Type ◽  
The Glyoxylate Cycle

ABSTRACT Citrate synthase is a central activity in carbon metabolism. It is required for the tricarboxylic acid (TCA) cycle, respiration, and the glyoxylate cycle. In Saccharomyces cerevisiae and Arabidopsis thaliana, there are mitochondrial and peroxisomal isoforms encoded by separate genes, while in Aspergillus nidulans, a single gene, citA, encodes a protein with predicted mitochondrial and peroxisomal targeting sequences (PTS). Deletion of citA results in poor growth on glucose but not on derepressing carbon sources, including those requiring the glyoxylate cycle. Growth on glucose is restored by a mutation in the creA carbon catabolite repressor gene. Methylcitrate synthase, required for propionyl-coenzyme A (CoA) metabolism, has previously been shown to have citrate synthase activity. We have been unable to construct the mcsAΔ citAΔ double mutant, and the expression of mcsA is subject to CreA-mediated carbon repression. Therefore, McsA can substitute for the loss of CitA activity. Deletion of citA does not affect conidiation or sexual development but results in delayed conidial germination as well as a complete loss of ascospores in fruiting bodies, which can be attributed to loss of meiosis. These defects are suppressed by the creA204 mutation, indicating that McsA activity can substitute for the loss of CitA. A mutation of the putative PTS1-encoding sequence in citA had no effect on carbon source utilization or development but did result in slower colony extension arising from single conidia or ascospores. CitA-green fluorescent protein (GFP) studies showed mitochondrial localization in conidia, ascospores, and hyphae. Peroxisomal localization was not detected. However, a very low and variable detection of punctate GFP fluorescence was sometimes observed in conidia germinated for 5 h when the mitochondrial targeting sequence was deleted.

scholarly journals Identification of Enzymatic Bottlenecks for the Aerobic Production of Malate from Glycerol by the Systematic Gene Overexpression of Anaplerotic Enzymes in Escherichia coli

2021 ◽  
Vol 22 (5) ◽  
pp. 2266
Author(s):  
Zamira E. Soto-Varela ◽  
Gema Cabrera ◽  
Agustin Romero ◽  
Domingo Cantero ◽  
Antonio Valle ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Anaerobic Fermentation ◽  
Waste Product ◽  
Carbon Sources ◽  
Dicarboxylic Acids ◽  
Tca Cycle ◽  
Biotechnological Production ◽  
Phosphoenol Pyruvate ◽  
Valuable Compounds ◽  
C4 Production

The biotechnological production of dicarboxylic acids (C4) from renewable carbon sources represents an attractive approach for the provision of these valuable compounds by green chemistry means. Glycerol has become a waste product of the biodiesel industry that serves as a highly reduced carbon source for some microorganisms. Escherichia coli is capable of consuming glycerol to produce succinate under anaerobic fermentation, but with the deletion of some tricarboxylic acid (TCA) cycle genes, it is also able to produce succinate and malate in aerobiosis. In this study, we investigate possible rate-limiting enzymes by overexpressing the C-feeding anaplerotic enzymes Ppc, MaeA, MaeB, and Pck in a mutant that lacks the succinate dehydrogenase (Sdh) enzyme. The overexpression of the TCA enzyme Mdh and the activation of the glyoxylate shunt was also examined. Using this unbiased approach, we found that phosphoenol pyruvate carboxylase (Ppc) overexpression enhances an oxidative pathway that leads to increasing succinate, while phosphoenol pyruvate carboxykinase (Pck) favors a more efficient reductive branch that produces mainly malate, at 57.5% of the theoretical maximum molar yield. The optimization of the culture medium revealed the importance of bicarbonate and pH in the production of malate. An additional mutation of the ppc gene highlights its central role in growth and C4 production.

scholarly journals Hierarchical decomposition of metabolic networks using k-modules

2015 ◽  
Vol 43 (6) ◽  
pp. 1146-1150 ◽  
Author(s):  
Arne C. Reimers
Keyword(s):  
Metabolic Networks ◽  
Null Space ◽  
Tca Cycle ◽  
Primary Objective ◽  
Hierarchical Decomposition ◽  
Matroid Theory ◽  
Optimal Solutions ◽  
Algorithmic Problems ◽  
Branch Decompositions

The optimal solutions obtained by flux balance analysis (FBA) are typically not unique. Flux modules have recently been shown to be a very useful tool to simplify and decompose the space of FBA-optimal solutions. Since yield-maximization is sometimes not the primary objective encountered in vivo, we are also interested in understanding the space of sub-optimal solutions. Unfortunately, the flux modules are too restrictive and not suited for this task. We present a generalization, called k-module, which compensates the limited applicability of flux modules to the space of sub-optimal solutions. Intuitively, a k-module is a sub-network with low connectivity to the rest of the network. Recursive application of k-modules yields a hierarchical decomposition of the metabolic network, which is also known as branch decomposition in matroid theory. In particular, decompositions computed by existing methods, like the null-space-based approach, introduced by Poolman et al. [(2007) J. Theor. Biol. 249, 691–705] can be interpreted as branch decompositions. With k-modules we can now compare alternative decompositions of metabolic networks to the classical sub-systems of glycolysis, tricarboxylic acid (TCA) cycle, etc. They can be used to speed up algorithmic problems [theoretically shown for elementary flux modes (EFM) enumeration] and have the potential to present computational solutions in a more intuitive way independently from the classical sub-systems.

scholarly journals Regulation of the acuF Gene, Encoding Phosphoenolpyruvate Carboxykinase in the Filamentous Fungus Aspergillus nidulans

2002 ◽  
Vol 184 (1) ◽  
pp. 183-190 ◽  
Author(s):  
Michael J. Hynes ◽  
Oliver W. Draht ◽  
Meryl A. Davis
Keyword(s):  
Carbon Source ◽  
Aspergillus Nidulans ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Carbon Sources ◽  
Tca Cycle ◽  
Northern Blotting ◽  
Gene Encoding ◽  
The Tca Cycle ◽  
Key Enzyme ◽  
Acetate Utilization

ABSTRACT Phosphoenolpyruvate carboxykinase (PEPCK) is a key enzyme required for gluconeogenesis when microorganisms grow on carbon sources metabolized via the tricarboxylic acid (TCA) cycle. Aspergillus nidulans acuF mutants isolated by their inability to use acetate as a carbon source specifically lack PEPCK. The acuF gene has been cloned and shown to encode a protein with high similarity to PEPCK from bacteria, plants, and fungi. The regulation of acuF expression has been studied by Northern blotting and by the construction of lacZ fusion reporters. Induction by acetate is abolished in mutants unable to metabolize acetate via the TCA cycle, and induction by amino acids metabolized via 2-oxoglutarate is lost in mutants unable to form 2-oxoglutarate. Induction by acetate and proline is not additive, consistent with a single mechanism of induction. Malate and succinate result in induction, and it is proposed that PEPCK is controlled by a novel mechanism of induction by a TCA cycle intermediate or derivative, thereby allowing gluconeogenesis to occur during growth on any carbon source metabolized via the TCA cycle. It has been shown that the facB gene, which mediates acetate induction of enzymes specifically required for acetate utilization, is not directly involved in PEPCK induction. This is in contrast to Saccharomyces cerevisiae, where Cat8p and Sip4p, homologs of FacB, regulate PEPCK as well as the expression of other genes necessary for growth on nonfermentable carbon sources in response to the carbon source present. This difference in the control of gluconeogenesis reflects the ability of A. nidulans and other filamentous fungi to use a wide variety of carbon sources in comparison with S. cerevisiae. The acuF gene was also found to be subject to activation by the CCAAT binding protein AnCF, a protein homologous to the S. cerevisiae Hap complex and the mammalian NFY complex.

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