Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Folate Pathway Disruption Leads to Critical Depletion of Methionine Derivatives in Mycobacterium tuberculosis

ABSTRACT: In this study, screening efforts identified novel antifolates with potent, targeted activity against whole cell Mycobacterium tuberculosis. Liquid chromatography-mass spectrometry analysis of antifolate-treated cultures revealed unique metabolic disruption, including decreased pools of methionine and S-adenosylmethionine. Transcriptomic analysis highlighted up-regulation genes involved in the biosynthesis and utilization of methionine. Supplementation with amino acids or methionine derivatives was sufficient to rescue cultures from MIC-level antifolate treatment. Instead of the “thymineless death” that characterizes folate pathway inhibition in a wide variety of organisms, these data suggest that M. tuberculosis is vulnerable to a critical disruption of the biosynthesis of methionine-derived compounds.

ORGANISM(S): Mycobacterium tuberculosis H37Rv

PROVIDER: GSE55979 | GEO | 2014/03/19

SECONDARY ACCESSION(S): PRJNA241497

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Folate Pathway Disruption Leads to Critical Depletion of Methionine Derivatives in Mycobacterium tuberculosis

Project description:In this study, screening efforts identified novel antifolates with potent, targeted activity against whole cell Mycobacterium tuberculosis. Liquid chromatography-mass spectrometry analysis of antifolate-treated cultures revealed unique metabolic disruption, including decreased pools of methionine and S-adenosylmethionine. Transcriptomic analysis highlighted up-regulation genes involved in the biosynthesis and utilization of methionine. Supplementation with amino acids or methionine derivatives was sufficient to rescue cultures from MIC-level antifolate treatment. Instead of the “thymineless death” that characterizes folate pathway inhibition in a wide variety of organisms, these data suggest that M. tuberculosis is vulnerable to a critical disruption of the biosynthesis of methionine-derived compounds. These arrays look at the expression profile triggered by exposure to three different anti-folates (WR99210, dimethyl and diethyl methotrexate) in three biological replicates and in a matched set of untreated samples.

2014-03-19 | E-GEOD-55979 | biostudies-arrayexpress

Oxadiazolone derivatives against M. tuberculosis

Project description:Oxadiazolone (OX) derivatives have been investigated for their antimycobacterial activity against three pathogenic slow-growing mycobacteria: Mycobacterium marinum, Mycobacterium bovis BCG and the avirulent Mycobacterium tuberculosis (M. tb) mc26230. The encouraging MIC values obtained prompted us to test them against virulent M. tb H37Rv growth either in broth medium or inside macrophages. The OX compounds displayed a diversity of action and were found to act either on extracellular M. tb growth only with moderated MIC, or both intracellularly on infected macrophages as well as extracellularly on bacterial growth. One OX derivatives, HPOX, was selected and used in a competitive labelling/enrichment assay against the activity-based probe Desthiobiotin-FP in order to identify its putative target(s). This approach, combined with mass spectrometry, identified 18 potential candidates, all being serine or cysteine enzymes involved in M. tb lipid metabolism and/or in cell wall biosynthesis. Among them, Ag85A, CaeA, TesA, KasA and MetA have been reported as essential for in vitro growth of M. tb and/or its survival and persistence inside macrophages. Overall, our findings support the assumption that OX derivatives may represent a novel class of multi-target inhibitors leading to the arrest of M. tb growth through a cumulative inhibition of a large number of Ser- and Cys-containing enzymes involved in various important physiological processes.

2018-09-25 | PXD010255 | Pride

Disulfiram inhbits M. tuberculosis growth by altering methionine pool and redox balance

Project description:Methionine biosynthetic pathway, essential for the growth of Mycobacterium tuberculosis (Mtb) in the host, represents an attractive target for the development of novel anti-tuberculars. Here, we have biochemically characterized homoserine acetyl transferase (HSAT viz. MetA) of Mtb, which catalyses the first committed step of methionine and S-adenosylmethionine (SAM) biosynthesis. High-throughput screening of a 2300 compound library resulted in identification of thiram, an anti-fungal organosulfur compound, as the most potent MetA inhibitor. Further analysis of thiram analogs led to the identification of orally bioavailable disulfiram (DIS, an anti-alcoholism FDA approved drug) as a novel inhibitor of MetA. Both thiram and DIS restricted the growth of drug-sensitive and drug-resistant Mtb strains in a bactericidal manner. ThermoFlour assay demonstrated direct binding of DIS with MetA. Metabolomic and transcriptomic studies showed DIS mediated perturbation of methionine and redox homeostasis, respectively, in Mtb. In concordance, the effect of DIS on Mtb growth was partially rescued by supplementation with either L-methionine as well as N-acetyl cysteine, suggesting a multi-target killing mechanism. In Mtb-infected mice, DIS administration restricted bacterial growth, increased efficacy of isoniazid, ameliorated lung pathology, modulated lung immune cell landscape and protective immune response. Taken together, our results demonstrate that DIS can be repurposed for designing an effective anti-tubercular therapy.

2021-03-08 | GSE168467 | GEO

Disulfiram mediated modulation of lung immune response during M. tuberculosis infection

2021-03-08 | GSE168458 | GEO

Methionine cycle dysregulation mediates REDD1 overexpression-induced muscle atrophy in cancer cachexia

Project description:The essential amino acid methionine plays a pivotal role in one-carbon metabolism, facilitating the production of S-adenosylmethionine (SAMe), a critical supplier for DNA methylation. Here we find the disruption of methionine metabolism by rapid SAMe depletion in skeletal muscle in cancer cachexia, leading to endoplasmic reticulum (ER) stress and the overexpression of regulated in development and DNA damage responses (REDD1). Targeting the DNA methylation process via DNA methyltransferases (DNMTs) and REDD1 knockout can alleviate cancer cachexia-induced skeletal muscle atrophy. Methionine supplementation maintains the DNA methylation of DNA damage-inducible transcript 4 (Ddit4) by DNMT3A, thereby inhibiting activating transcription factor 4 (ATF4)-mediated Ddit4 transcription. Our study suggests that methionine or SAMe supplementation can effectively reverse muscle atrophy in cancer cachexia, providing valuable mechanistic insights and a promising therapeutic strategy for clinical application.

2024-10-11 | GSE275001 | GEO

Pemetrexed alters inflammatory profile in EA.hy 926 cells grown under low-folate conditions.

Project description:Pemetrexed is an antifolate drug used in the treatment of lung cancer. EA.hy 926 cells grown under low (Lo) and normal (Hi) folate conditions were treated with PMX. Microarray analysis was used to examine changes in gene expression due to PMX treatment.

2012-10-03 | GSE31986 | GEO

S-adenosylmethionine decarboxylase-dependent gene expression in planktonic Bacillus subtilis NCIB3610

Project description:The polyamine spermidine is not required for normal planktonic growth of Bacillus subtilis but is essential for robust biofilm formation. In a spermidine-deficient mutant of B. subtilis, the structural analogue norspermidine but not homospermidine restored biofilm formation. Intracellular biosynthesis of another spermidine analogue aminopropylcadaverine from exogenously supplied homoagmatine also restored biofilm formation. The differential ability of C-methylated spermidine analogues to replace the function of spermidine in biofilm formation indicated that the aminopropyl side of spermidine is more sensitive to C-methylation. Together, these data indicate that the aminopropyl side of spermidine is essential for its function in biofilm formation, and that the length and symmetry of the molecule is not critical. Transcriptomic analysis of a spermidine-depleted speD mutant of B. subtilis uncovered a nitrogen, methionine and S-adenosylmethionine sufficiency response, resulting in repression of gene expression related to purine catabolism, methionine and S-adenosylmethionine biosynthesis, methionine salvage, and there were indications that membrane status was altered. Consistent with the requirement for spermidine in biofilm formation, expression of the operons for production of the exopolysaccharide and TasA protein components of the biofilm matrix was reduced, as was expression of regulator SinR antagonist slrR. Single-cell analysis indicated that the effect of spermidine depletion was to decrease the number of cells expressing the biofilm matrix operons. Deletion of sinR or ectopic expression of slrR in the spermidine-deficient ΔspeD background restored biofilm formation, indicating that spermidine is required to promote expression of the biofilm regulator slrR.

2017-03-24 | GSE96942 | GEO

Methionine starvation of M. tuberculosis H37Rv ΔmetA

Project description:Time-course transcriptional profiling of the methionine auxotroph M. tuberculosis H37Rv ΔmetA during methionine starvation

2015-08-03 | GSE67843 | GEO

Transcriptional adaptation during starvation of Mycobacterium tuberculosis H37Rv ∆thrA

Project description:Time-course transcriptional profiling of the methionine auxotroph M. tuberculosis H37Rv ΔthrA during methionine starvation

2018-08-29 | GSE119105 | GEO

RNA-seq in mouse CD8+ T cells cultured with medium with or without methionine

Project description:Abnormal epigenetic patterns correlate with effector T cell malfunction in tumors. However, their causal link is unknown. Here, we show that tumor cells disrupt methionine metabolism in CD8+ T cells, thereby lowering intracellular methionine levels and the methyl donor S-adenosylmethionine (SAM), resulting in loss of H3K79me2. Consequently, loss of H3K79me2 impaired T cell immunity. Our work reveals a novel mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumor microenvironment.

2020-07-30 | GSE150886 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data