Formaldehyde regulates S-adenosylmethionine biosynthesis and one-carbon metabolism
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1012734 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:One-carbon metabolism is an essential branch of cellular metabolism that intersects with epigenetic regulation. Here, we show formaldehyde, a one-carbon unit derived from both endogenous sources and environmental exposure, regulates one-carbon metabolism by inhibiting the biosynthesis of S-adenosylmethionine (SAM), the major methyl donor in cells. Formaldehyde reacts with privileged, hyperreactive cysteine sites in the proteome, including Cys120 in S-adenosylmethionine synthase isoform type-1 (MAT1A). Formaldehyde exposure inhibited MAT1A activity and decreased SAM production with MAT-isoform specificity. A genetic mouse model of chronic formaldehyde overload showed a decrease in SAM and in methylation on selected histones and genes. Epigenetic and transcriptional regulation of Mat1a and related genes function as compensatory mechanisms for formaldehyde-dependent SAM depletion, revealing a biochemical feedback cycle between formaldehyde and SAM one-carbon units.
2023-09-05 | GSE242266 | GEO
Project description:One-carbon metabolism is a universal hub for cellular metabolism and epigenetic regulation.1–3 Here, we report that formaldehyde (FA), a one-carbon unit that organisms produce in substantial quantities through folate metabolism,4 is a regulator of the one-carbon cycle via the biosynthesis of S-adenosyl-L-methionine (SAM), an essential one-carbon building block for synthesis of nucleotides, amino acids, and methylated nucleic acids and proteins.5 Activity-based protein profiling (ABPP) in mouse liver tissue identifies FA-sensitive cysteine sites across the proteome, revealing several one-carbon cycle targets including S-adenosylmethionine synthetase isoform 1 (MAT1A), the terminal enzyme in SAM biosynthesis. Biochemical studies of the formaldehyde-MAT1A interaction establish FA-dependent inhibition of MAT1A activity through a conserved C120 site, as the MAT2A isoform lacking this cysteine is not FA-sensitive. CRISPR knockout-generated HepG2 cell models that predominantly express either MAT1A or MAT2A show that MAT1A-positive cells respond to FA treatment in a dose-dependent manner by decreasing their SAM levels and downstream RNA methylation, whereas the MAT2A-positive cells are not affected by FA. Our findings reveal an unexpected interplay between SAM and FA, two central one-carbon units to influence the overall methylation potential of the cell.
2023-11-02 | PXD018251 | Pride
Project description:The folate-driven one-carbon (1C) cycle is a fundamental metabolic hub in cells that enables the synthesis of nucleotides and amino acids and epigenetic modifications. This cycle might also release formaldehyde, a potent protein and DNA crosslinking agent that organisms produce in substantial quantities. Here we show that supplementation with tetrahydrofolate, the essential cofactor of this cycle, and other oxidation-prone folate derivatives kills human, mouse and chicken cells that cannot detoxify formaldehyde or that lack DNA crosslink repair. Notably, formaldehyde is generated from oxidative decomposition of the folate backbone. Furthermore, we find that formaldehyde detoxification in human cells generates formate, and thereby promotes nucleotide synthesis. This supply of 1C units is sufficient to sustain the growth of cells that are unable to use serine, which is the predominant source of 1C units. These findings identify an unexpected source of formaldehyde and, more generally, indicate that the detoxification of this ubiquitous endogenous genotoxin creates a benign 1C unit that can sustain essential metabolism.
| S-EPMC5714256 | biostudies-literature
Project description:In the McSC lineage in zebrafish, Aldh2 activity is an important source of formate through its metabolism of its substrate formaldehyde. This formate is required as input into the folate cycle, in particular de novo purine biosynthesis. This scRNA-seq experiment was conducted to investigate the global effects of Aldh2 inhibition on the transcriptomes of isolated McSCs.
2022-05-09 | GSE183868 | GEO
Project description:Accessible chromatin landscape allows remodeling of transcription factors and enhancers during development and molecular subtypes of cancer in patient samples. One-tube universal NicE-seq (OuNicE-seq) is an improved accessible chromatin profiling method that negate DNA purification and incorporate sonication free enzymatic fragmentation before library preparation and is suited to a variety of mammalian cells. OuNicE-seq is versatile, capable of profiling 4% formaldehyde fixed chromatin in 25 fixed cells and opens the possibility for automation. Accessible chromatin profile is more efficient on formaldehyde fixed cells using OuNicE-seq compare to Tn5 transposon mediated methods, demonstrating its versatility.
2021-12-01 | GSE175651 | GEO
Project description:P. putida is equipped with functions related to one-carbon (C1) compounds (e.g. methanol, formaldehyde and formate) oxidation—yet pathways to assimilate these carbon sources are largely absent. In this work, we adopted a systems-level approach to study the genetic and molecular basis of C1 metabolism in P. putida (both in EM42 and a double mutant of the characterized formate dehydrogenases in this organism.
2023-04-19 | GSE229763 | GEO
Project description:Rapid adaptation to grow within the physiological conditions found in the host environment is an essential but poorly understood virulence requirement for systemic pathogens such as Streptococcus pneumoniae. We have now demonstrated an essential role for the one-carbon metabolism pathway and a conditional role depending on strain background for proline biosynthesis for S. pneumoniae growth in serum or CSF and therefore for systemic virulence. RNAseq data demonstrated that loss of one carbon metabolism or proline biosynthesis both have profound but differing effects on S. pneumoniae metabolism in human serum, identifying the metabolic processes dependent on each pathway during systemic infection. These data provide a more detailed understanding of the adaptations required by systemic bacterial pathogens in order to cause infection, and demonstrate that the requirement for some of these adaptations vary between strains from the same species and could therefore underpin strain variations in virulence potential.
2023-09-10 | E-MTAB-13289 | biostudies-arrayexpress
Project description:In order for bacteria to thrive, they must be well-adapted to their environmental niche, which may involve specialized metabolism, timely adaptation to shifting environments, and/or the ability to mitigate numerous stressors. These attributes are highly dependent on cellular machinery that can sense both the external and intracellular environment. Methylorubrum extorquens is an extensively studied facultative methylotroph, an organism that can use single-carbon compounds as their sole source of carbon and energy. In methylotrophic metabolism, carbon flows through formaldehyde as a central metabolite; thus, formaldehyde is both an obligate metabolite and a metabolic stressor. Via the one-carbon dissimilation pathway, free formaldehyde is rapidly incorporated by formaldehyde activating enzyme (Fae), which is constitutively expressed at high levels. In the presence of elevated formaldehyde levels, a recently identified formaldehyde-sensing protein, EfgA, induces growth arrest. Herein, we describe TtmR, a formaldehyde-responsive transcription factor that, like EfgA, modulates formaldehyde resistance. It is a member of the MarR family of transcription factors and impacts the expression of 75 genes distributed throughout the genome, many of which are themselves transcription factors and/or involved in stress response, including efgA. Notably, when M. extorquens is adapting its metabolic network during the transition to methylotrophy, efgA and ttmR mutants experience an imbalance in formaldehyde production and a notable growth delay. Although methylotrophy necessitates that M. extorquens maintain a relatively high level of formaldehyde tolerance, this work reveals a tradeoff between formaldehyde resistance and the efficient transition to methylotrophic growth and suggests that TtmR and EfgA play a pivotal role in maintaining this balance.
2021-03-11 | GSE159711 | GEO
Project description:Bao XR, Ong SE, Goldberger O, Peng J, Sharma R, Thompson DA, Vafai SB, Cox A, Marutani E, Ichinose F, Goessling W, Regev A, Carr SA, Clish CB, Mootha VK. eLife 2016. Mitochondrial dysfunction is associated with a spectrum of human disorders, ranging from rare, inborn errors of metabolism to common, age-associated diseases such as neurodegeneration. How these lesions give rise to diverse pathology is not well understood, partly because their proximal consequences have not been well-studied in mammalian cells. Here we provide two lines of evidence that mitochondrial respiratory chain dysfunction leads to alterations in one-carbon metabolism pathways. First, using hypothesis-generating metabolic, proteomic, and transcriptional profiling, followed by confirmatory experiments, we report that mtDNA depletion leads to an ATF4-mediated increase in serine biosynthesis and transsulfuration. Second, we show that lesioning the respiratory chain impairs mitochondrial production of formate from serine, and that in some cells, respiratory chain inhibition leads to growth defects upon serine withdrawal that are rescuable with purine or formate supplementation. Our work underscores the connection between the respiratory chain and one-carbon metabolism with implications for understanding mitochondrial pathogenesis.
2016-06-02 | MSV000079791 | MassIVE
Project description:Chromosomal instability causes sensitivity to polyamines and one-carbon metabolism
| PRJNA966989 | ENA