Inhibition of the hepatic vitamin B12-dependent methionine-salvage pathway by trichloroethylene metabolites accounts for the formic aciduria in the rat
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PROVIDER: PRJNA505919 | ENA |
REPOSITORIES: ENA
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Project description:The industrial solvent trichloroethylene (TCE) produces a marked formic aciduria in male and female F344 rats and in male C57Bl mice following single or multiple dosing. The two major metabolites of TCE formed by cytochromes P450 metabolism also produce formic aciduria. The quantity of formic acid excreted was about 2-fold higher following trichloroacetic acid (TCA) compared to trichloroethanol (TCE-OH) or TCE, at similar doses of 16mg/kg/day for 3 days. Prior treatment of male F344 rats with 1-aminobenzotriazole a cytochrome P450 inhibitor, followed by TCE, completely prevented the formic aciduria but had no effect on formic acid excretion produced by TCA, suggesting TCA is the proximate metabolite producing this response. Metabolism of formic acid is largely controlled by the vitamin B12 –dependent methionine salvage pathway. Transcriptomic analysis on the liver of rats dosed with 16mg/kg/day TCE for three days when compared to control liver showed nine differentially expressed genes, of particular interest was the down regulation of LMBRD1 involved in the conversion of vitamin B12 into one of two molecules, methylcobalamin (CH3Cbl) or S-adenosylcobalamin (AdoCbl). Administration of CH3Cbl or hydroxocobalamin for 3 days to rats given a single dose of TCE, lead to a reduction in formic acid in their urine. Similarly, rats given TCE followed by L-methionine for 3 days excreted less formic acid in their urine. These findings suggest an effect on the vitamin B12 –dependent methionine salvage pathway. This was supported by the finding that hepatic methionine synthase, which converts homocysteine to methionine, was inhibited following three large daily dose of TCE. We propose that TCE metabolites interact with the vitamin B12 -dependent methionine salvage pathway leading to tetrahydrofolate deficiency and increased excretion of formic acid in rat urine.
2020-11-20 | GSE122664 | GEO
Project description:Coastal Antarctic marine ecosystems play an important role in carbon cycling due to their highly productive seasonal phytoplankton blooms. Southern Ocean microbes are primarily limited by light and iron (Fe) and can be co-limited by cobalamin (vitamin B12 ). Micronutrient limitation is a key driver of ecosystem dynamics and influences the composition of blooms, which are often dominated by either diatoms or the haptophyte Phaeocystis antarctica, each with varied impacts on carbon cycling. However, the vitamin requirements and ecophysiology of the keystone species P. antarctica remains poorly characterized. Using cultures, physiological analysis, and comparative ’omics we examined the response of P. antarctica to a matrix of Fe-B12 conditions. We show that P. antarctica is not auxotrophic for B12 , as previously suggested, and report new mechanistic insights of its B12 response in cultures of predominantly solitary and colonial cells. Proteomics coupled with proteogenomics detected a B12 -independent methionine synthase fusion protein (MetE-fusion) that is expressed under vitamin limitation and is interreplaced with the B12 -dependent isoform (MetH) in replete conditions. Database searches returned homologs of the MetE-fusion protein in multiple Phaeocystis species and in a wide range of marine microbes, including other photosynthetic eukaryotes with polymorphic life cycles and also bacterioplankton. Furthermore, MetE-fusion homologs were found to be expressed in metaproteomic and metatranscriptomic field samples in polar and more geographically widespread regions. As climate change impacts micronutrient availability in the coastal Southern Ocean, our finding that P. antarctica has a flexible B12 metabolism has implications for its relative fitness compared to B12 -auxotrophic diatoms.
2023-02-27 | PXD031524 | Pride
Project description:Reprogramming in vivo using OCT4, SOX2, KLF4 and MYC (OSKM) triggers cell dedifferentiation, which is considered of relevance for tissue repair and regeneration. However, little is known about the metabolic requirements of this process. We found that antibiotic depletion of the gut microbiota abolished in vivo reprogramming. Analysis of bacterial metagenomes from stool samples of wild type (WT) and OSKM mice treated with doxycycline led us to identify vitamin B12 as a key factor for in vivo reprogramming, which is partly supplied by the microbiome. We report that B12 demand increases during reprogramming due to enhanced expression of enzymes in the methionine cycle, and supplementing B12 levels both in vitro and in vivo enhances the efficiency of OSKM reprogramming.
2023-08-07 | GSE154149 | GEO
Project description:Elucidation of new roles for vitamin B12 in regulation of folate, ubiquinone, and methionine metabolism
2018-10-22 | PXD005723 | Pride
Project description:Vitamin B12 is an essential micronutrient that functions in two metabolic pathways: the canonical propionate breakdown pathway and the methionine/S-adenosylmethionine (Met/SAM) cycle. In Caenorhabditis elegans, low vitamin B12, or genetic perturbation of the canonical propionate breakdown pathway results in propionate accumulation and the transcriptional activation of a propionate shunt pathway. This propionate-dependent mechanism requires nhr-10 and is referred to as “B12-mechanism-I”. Here, we report that vitamin B12 represses the expression of Met/SAM cycle genes by a propionate-independent mechanism we refer to as “B12-mechanism-II”. This mechanism is activated by perturbations in the Met/SAM cycle, genetically or due to low dietary vitamin B12. B12-mechanism-II requires nhr-114 to activate Met/SAM cycle gene expression, the vitamin B12 transporter, pmp-5, and adjust influx and efflux of the cycle by activating msra-1 and repressing cbs-1, respectively. Taken together, Met/SAM cycle activity is sensed and transcriptionally adjusted to be in a tight metabolic regime.
2020-06-05 | GSE151847 | GEO
Project description:Vitamin B12 is an essential micronutrient that functions in two metabolic pathways: the canonical propionate breakdown pathway and the methionine/S-adenosylmethionine (Met/SAM) cycle. In Caenorhabditis elegans, low vitamin B12, or genetic perturbation of the canonical propionate breakdown pathway results in propionate accumulation and the transcriptional activation of a propionate shunt pathway. This propionate-dependent mechanism requires nhr-10 and is referred to as “B12-mechanism-I”. Here, we report that vitamin B12 represses the expression of Met/SAM cycle genes by a propionate-independent mechanism we refer to as “B12-mechanism-II”. This mechanism is activated by perturbations in the Met/SAM cycle, genetically or due to low dietary vitamin B12. B12-mechanism-II requires nhr-114 to activate Met/SAM cycle gene expression, the vitamin B12 transporter, pmp-5, and adjust influx and efflux of the cycle by activating msra-1 and repressing cbs-1, respectively. Taken together, Met/SAM cycle activity is sensed and transcriptionally adjusted to be in a tight metabolic regime.
2020-06-05 | GSE151846 | GEO
Project description:To examine the protective effect of B12 on myocardial ischemia/reperfusion injury and figure out the mechanism of B12.
2024-01-01 | GSE225105 | GEO
Project description:De novo cobalamin biosynthesis, corrinoid salvage and cobalamin-dependent regulation of methionine biosynthesis in Mycobacterium smegmatis
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Project description:Astrocytes express a vitamin B12 uptake receptor, CD320/TCblR, that is regulated by S1P1 signaling. In search of genes controlled under B12 deficiency in astrocytes, we employed RNA-seq using RNA of astrocytes cultured in normal or B12 deficient media.
2022-05-17 | GSE99113 | GEO
Project description:Recent functional genomics and genome-scale modeling approaches indicated that B12 production in Lactobacillus reuteri could be improved by medium optimization. Here we show that a series of systematic single amino acid omissions could significantly modulate the production of B12 from nearly undetectable levels (by isoleucine omission) to 20-fold higher than previously reported through omission of cysteine. We analyzed by cDNA microarray experiments the transcriptional response of L. reuteri to the medium lacking cysteine. These results supported the observed high B12 production and provided new avenues for future improvement of production of vitamin B12. Keywords: cell type comparison
2008-10-31 | GSE13391 | GEO