scholarly journals Implications of central carbon metabolism in SARS-CoV-2 replication and disease severity

2021 ◽  
Author(s):  
Shuba Krishnan ◽  
Hampus Nordqvist ◽  
Anoop T. Ambikan ◽  
Soham Gupta ◽  
Maike Sperk ◽  
...  
Keyword(s):  
Amino Acid ◽  
Disease Severity ◽  
Carbon Metabolism ◽  
Metabolic Pathways ◽  
Central Carbon Metabolism ◽  
Lung Epithelial Cells ◽  
Metabolic Adaptation ◽  
Altered Expression ◽  
Central Carbon

AbstractViruses hijack host metabolic pathways for their replicative advantage. Several observational trans-omics analyses associated carbon and amino acid metabolism in coronavirus disease 2019 (COVID-19) severity in patients but lacked mechanistic insights. In this study, using patient- derived multi-omics data and in vitro infection assays, we aimed to understand i) role of key metabolic pathways in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) reproduction and ii) its association with disease severity. Our data suggests that monocytes are key to the altered immune response during COVID-19. COVID-19 infection was associated with increased plasma glutamate levels, while glucose and mannose levels were determinants of the disease severity. Monocytes showed altered expression pattern of carbohydrate and amino acid transporters, GLUT1 and xCT respectively in severe COVID-19. Furthermore, lung epithelial cells (Calu-3) showed a strong acute metabolic adaptation following infection in vitro by modulating central carbon metabolism. We found that glycolysis and glutaminolysis are essential for virus replication and blocking these metabolic pathways caused significant reduction in virus production. Taken together, our study highlights that the virus utilizes and re-wires pathways governing central carbon metabolism leading to metabolic toxicity. Thus, the host metabolic perturbation could be an attractive strategy to limit the viral replication and disease severity.

scholarly journals Characterisation of putative lactate synthetic pathways of Coxiella burnetii

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255925
Author(s):  
Janine Hofmann ◽  
Mebratu A. Bitew ◽  
Miku Kuba ◽  
David P. De Souza ◽  
Hayley J. Newton ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Coxiella Burnetii ◽  
Carbon Metabolism ◽  
Metabolic Pathways ◽  
Malic Enzyme ◽  
Lactate Production ◽  
Central Carbon Metabolism ◽  
Malolactic Enzyme ◽  
Central Carbon

The zoonotic pathogen Coxiella burnetii, the causative agent of the human disease Q fever, is an ever-present danger to global public health. Investigating novel metabolic pathways necessary for C. burnetii to replicate within its unusual intracellular niche may identify new therapeutic targets. Recent studies employing stable isotope labelling established the ability of C. burnetii to synthesize lactate, despite the absence of an annotated synthetic pathway on its genome. A noncanonical lactate synthesis pathway could provide a novel anti-Coxiella target if it is essential for C. burnetii pathogenesis. In this study, two C. burnetii proteins, CBU1241 and CBU0823, were chosen for analysis based on their similarities to known lactate synthesizing enzymes. Recombinant GST-CBU1241, a putative malate dehydrogenase (MDH), did not produce measurable lactate in in vitro lactate dehydrogenase (LDH) activity assays and was confirmed to function as an MDH. Recombinant 6xHis-CBU0823, a putative NAD+-dependent malic enzyme, was shown to have both malic enzyme activity and MDH activity, however, did not produce measurable lactate in either LDH or malolactic enzyme activity assays in vitro. To examine potential lactate production by CBU0823 more directly, [13C]glucose labelling experiments compared label enrichment within metabolic pathways of a cbu0823 transposon mutant and the parent strain. No difference in lactate production was observed, but the loss of CBU0823 significantly reduced 13C-incorporation into glycolytic and TCA cycle intermediates. This disruption to central carbon metabolism did not have any apparent impact on intracellular replication within THP-1 cells. This research provides new information about the mechanism of lactate biosynthesis within C. burnetii, demonstrating that CBU1241 is not multifunctional, at least in vitro, and that CBU0823 also does not synthesize lactate. Although critical for normal central carbon metabolism of C. burnetii, loss of CBU0823 did not significantly impair replication of the bacterium inside cells.

scholarly journals Flor yeasts rewire the central carbon metabolism during wine alcoholic fermentation

2021 ◽  
Author(s):  
Emilien Peltier ◽  
Charlotte Vion ◽  
Omar Abou Saada ◽  
Anne Friedrich ◽  
Joseph Schacherer ◽  
...  
Keyword(s):  
Carbon Metabolism ◽  
Parental Strain ◽  
Tricarboxylic Acid Cycle ◽  
Phenotypic Variability ◽  
Central Carbon Metabolism ◽  
Metabolic Adaptation ◽  
Flor Yeast ◽  
Central Carbon ◽  
Flor Yeasts ◽  
Allelic Variations

AbstractThe identification of natural allelic variations controlling quantitative traits could contribute to decipher metabolic adaptation mechanisms within different populations of the same species. Such variations could result from man-mediated selection pressures and participate to the domestication. In this study, the genetic causes of the phenotypic variability of the central carbon metabolism Saccharomyces cerevisiae were investigated in the context of the enological fermentation. Carbon dioxide and glycerol production as well as malic acid consumption modulate the fermentation yield revealing a high level of genetic complexity. Their genetic determinism was found out by a multi environment QTL mapping approach allowing the identification of 14 quantitative trait loci from which 8 of them were validated down to the gene level by genetic engineering. Most of the validated genes had allelic variations involving flor yeast specific alleles. Those alleles were brought in the offspring by one parental strain that is closely related to the flor yeast genetic group while the second parental strain is part of the wine group. The causative genes identified are functionally linked to quantitative proteomic variations that would explain divergent metabolic features of wine and flor yeasts involving the tricarboxylic acid cycle (TCA), the glyoxylate shunt and the homeostasis of proton and redox cofactors. Overall, this work led to the identification of genetic factors that are hallmarks of adaptive divergence between flor yeast and wine yeast in the wine biotope. These alleles can also be used in the context of yeast selection to improve oenological traits linked to fermentation yield.

scholarly journals Immunosuppressive activity enhances central carbon metabolism and bioenergetics in myeloid-derived suppressor cells in vitro models

2012 ◽  
Vol 13 (1) ◽  
pp. 18 ◽  
Author(s):  
Ines Hammami ◽  
Jingkui Chen ◽  
Frederic Murschel ◽  
Vincenzo Bronte ◽  
Gregory De Crescenzo ◽  
...  
Keyword(s):  
Carbon Metabolism ◽  
Suppressor Cells ◽  
Central Carbon Metabolism ◽  
In Vitro Models ◽  
Myeloid Derived Suppressor Cells ◽  
Immunosuppressive Activity ◽  
Central Carbon

scholarly journals Transcriptomic Analysis of the Influence of Methanol Assimilation on the Gene Expression in the Recombinant Pichia pastoris Producing Hirudin Variant 3

Genes ◽  
2019 ◽  
Vol 10 (8) ◽  
pp. 606 ◽  
Author(s):  
Li ◽  
Ma ◽  
Xu ◽  
Wang ◽  
Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Amino Acid ◽  
Pichia Pastoris ◽  
Carbon Metabolism ◽  
Fermentation Broth ◽  
Alcohol Oxidase ◽  
Central Carbon Metabolism ◽  
Recombinant Pichia Pastoris ◽  
Central Carbon ◽  
Almost All

Hirudin and its variants, as strong inhibitors against thrombin, are present in the saliva of leeches and are recognized as potent anticoagulants. However, their yield is far from the clinical requirement up to now. In this study, the production of hirudin variant 3 (HV3) was successfully realized by cultivating the recombinant Pichia pastoris GS115/pPIC9K-hv3 under the regulation of the promoter of AOX1 encoding alcohol oxidase (AOX). The antithrombin activity in the fermentation broth reached the maximum value of 5000 ATU/mL. To explore an effective strategy for improving HV3 production in the future, we investigated the influence of methanol assimilation on the general gene expression in this recombinant by transcriptomic study. The results showed that methanol was partially oxidized into CO2, and the rest was converted into glycerone-P which subsequently entered into central carbon metabolism, energy metabolism, and amino acid biosynthesis. However, the later metabolic processes were almost all down-regulated. Therefore, we propose that the up-regulated central carbon metabolism, energy, and amino acid metabolism should be beneficial for methanol assimilation, which would accordingly improve the production of HV3.

scholarly journals Biochemical unity revisited: microbial central carbon metabolism holds new discoveries, multi-tasking pathways, and redundancies with a reason

2020 ◽  
Vol 401 (12) ◽  
pp. 1429-1441
Author(s):  
Lennart Schada von Borzyskowski ◽  
Iria Bernhardsgrütter ◽  
Tobias J. Erb
Keyword(s):  
Carbon Metabolism ◽  
Metabolic Pathways ◽  
Central Carbon Metabolism ◽  
Genetic Redundancy ◽  
Acetyl Coa ◽  
Central Carbon ◽  
Long Time ◽  
Biochemical Research ◽  
Biochemical Diversity ◽  
Central Reaction

AbstractFor a long time, our understanding of metabolism has been dominated by the idea of biochemical unity, i.e., that the central reaction sequences in metabolism are universally conserved between all forms of life. However, biochemical research in the last decades has revealed a surprising diversity in the central carbon metabolism of different microorganisms. Here, we will embrace this biochemical diversity and explain how genetic redundancy and functional degeneracy cause the diversity observed in central metabolic pathways, such as glycolysis, autotrophic CO2 fixation, and acetyl-CoA assimilation. We conclude that this diversity is not the exception, but rather the standard in microbiology.

Sign in / Sign up

Export Citation Format

Share Document