Mycobacterium tuberculosis H37Rv
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA241497 | ENA |
REPOSITORIES: ENA
Similar Datasets
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
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.
2014-03-19 | GSE55979 | GEO
Project description:Time-course transcriptional profiling of the methionine auxotroph M. tuberculosis H37Rv ΔmetA during methionine starvation
2015-08-03 | GSE67843 | GEO
Project description:Time-course transcriptional profiling of the methionine auxotroph M. tuberculosis H37Rv ΔthrA during methionine starvation
2018-08-29 | GSE119105 | GEO
Project description:Transcriptional profiling of H37Rv (WT), Mut1 and Comp1 bacteria under aerobic (Aer/0 day, i.e 0 D) and hypoxic conditions (Hyp/5 days standing culture, i.e 5 D). Mut1: H37Rv carrying devR gene disruption by in frame insertion of kanamycin resistance cassette and expressing DevRN-Kan fusion protein. Comp1: Mut1 complemented with low copy number plasmid carrying devR gene expressed from its native constitutive upstream promoter. (Reference: Majumdar et al., 2010, PLoS One 5:e9448). Goal is to compare transcriptional patterns of WT, Mut1 and Comp1 strains under aerobic (0 D) and hypoxic (5 D) conditions in vitro. Two color and One-color experiments,Organism: Mycobacterium tuberculosis, Genotypic Technology designed Custom Mycobacterium tuberculosis H37Rv Whole Genome 8x15k GE Microarray (AMADID-020181)
2011-09-30 | E-GEOD-30264 | biostudies-arrayexpress
Project description:What is known is that methionine-dependency is a feature of some cancers. So far, it was attributed to mutations in genes involved in the methionine de novo or salvage pathways. What is new is that in this work we propose that methionine dependency stems from an altered cellular metabolism. We provide evidence that in U251 glioblastoma cell line, only cancer stem cells -isolated as tumor spheres in non adherent conditions- are methionine dependent and not monolayer cells grown in adherent conditions. Transcriptome wide-sequencing reveals that several genes involved in cytosolic folate cycle are downregulated whereas some transcripts of genes involved in mitochondrial folate cycle are upregulated. Genome wide DNA methylation does not account for these changes in gene expression. Mass spectrometry measurements confirm that tumor spheres display low cytosolic folate cycle unable to produce enough 5-methyltetrahydrofolate to remethylate homocystein to methionine. This decreased 5-methyltetrahydrofolate bioavailability is presumably due to a reprogrammed mitochondrial folate cycle which instead of synthesizing formate, intended to fuel the cytosolic folate cycle, oxidizes the formyl group to CO2 with the attendant reduction of NADP+ to NADPH and release of tetrahydrofolate. The originality of this work resides in that it replaces methionine deprivation as a useful nutritional strategy in cancer growth control since cancer stem cells are much more tumoregenic than their non stem-like counterparts. Second, it reveals that the primary default responsible of the reprogrammation of folate metabolism originates in the mitochondria. Thus, mitochondrial enzymes could be novel and more promising anticancer targets than dihydrofolate reductase (DHFR), the current target of drug therapy linked with folate metabolism.
2019-07-01 | GSE117448 | GEO
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
Project description:Henry2016 Folate pathway model with induced
PanB reaction
This model is described in the article:
Experimental and Metabolic
Modeling Evidence for a Folate-Cleaving Side-Activity of
Ketopantoate Hydroxymethyltransferase (PanB).
Thiaville JJ, Frelin O,
García-Salinas C, Harrison K, Hasnain G, Horenstein NA,
Díaz de la Garza RI, Henry CS, Hanson AD, de
Crécy-Lagard V.
Front Microbiol 2016; 7: 431
Abstract:
Tetrahydrofolate (THF) and its one-carbon derivatives,
collectively termed folates, are essential cofactors, but are
inherently unstable. While it is clear that chemical oxidation
can cleave folates or damage their pterin precursors, very
little is known about enzymatic damage to these molecules or
about whether the folate biosynthesis pathway responds
adaptively to damage to its end-products. The presence of a
duplication of the gene encoding the folate biosynthesis enzyme
6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (FolK) in
many sequenced bacterial genomes combined with a strong
chromosomal clustering of the folK gene with panB, encoding the
5,10-methylene-THF-dependent enzyme ketopantoate
hydroxymethyltransferase, led us to infer that PanB has a side
activity that cleaves 5,10-methylene-THF, yielding a pterin
product that is recycled by FolK. Genetic and metabolic
analyses of Escherichia coli strains showed that overexpression
of PanB leads to accumulation of the likely folate cleavage
product 6-hydroxymethylpterin and other pterins in cells and
medium, and-unexpectedly-to a 46% increase in total folate
content. In silico modeling of the folate biosynthesis pathway
showed that these observations are consistent with the in vivo
cleavage of 5,10-methylene-THF by a side-activity of PanB, with
FolK-mediated recycling of the pterin cleavage product, and
with regulation of folate biosynthesis by folates or their
damage products.
This model is hosted on
BioModels Database
and identified by:
MODEL1602280002.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000689 | BioModels
Project description:Henry2016 Folate pathway model with induced
PanB reaction
This model is described in the article:
Experimental and Metabolic
Modeling Evidence for a Folate-Cleaving Side-Activity of
Ketopantoate Hydroxymethyltransferase (PanB).
Thiaville JJ, Frelin O,
García-Salinas C, Harrison K, Hasnain G, Horenstein NA,
Díaz de la Garza RI, Henry CS, Hanson AD, de
Crécy-Lagard V.
Front Microbiol 2016; 7: 431
Abstract:
Tetrahydrofolate (THF) and its one-carbon derivatives,
collectively termed folates, are essential cofactors, but are
inherently unstable. While it is clear that chemical oxidation
can cleave folates or damage their pterin precursors, very
little is known about enzymatic damage to these molecules or
about whether the folate biosynthesis pathway responds
adaptively to damage to its end-products. The presence of a
duplication of the gene encoding the folate biosynthesis enzyme
6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (FolK) in
many sequenced bacterial genomes combined with a strong
chromosomal clustering of the folK gene with panB, encoding the
5,10-methylene-THF-dependent enzyme ketopantoate
hydroxymethyltransferase, led us to infer that PanB has a side
activity that cleaves 5,10-methylene-THF, yielding a pterin
product that is recycled by FolK. Genetic and metabolic
analyses of Escherichia coli strains showed that overexpression
of PanB leads to accumulation of the likely folate cleavage
product 6-hydroxymethylpterin and other pterins in cells and
medium, and-unexpectedly-to a 46% increase in total folate
content. In silico modeling of the folate biosynthesis pathway
showed that these observations are consistent with the in vivo
cleavage of 5,10-methylene-THF by a side-activity of PanB, with
FolK-mediated recycling of the pterin cleavage product, and
with regulation of folate biosynthesis by folates or their
damage products.
This model is hosted on
BioModels Database
and identified by:
MODEL1602280002.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000690 | BioModels
Project description:Thiaville2016 - Wild type folate pathway
model with proposed PanB reaction
This is a wild type E. coli model, and
is one amongst the three models described in the paper. The other
two models are MODEL1602280002 (wild type with PanB over
expression) and MODEL1602280003 (wild type with PanB over
expression and THF regulation).
This model is described in the article:
Experimental and Metabolic
Modeling Evidence for a Folate-Cleaving Side-Activity of
Ketopantoate Hydroxymethyltransferase (PanB).
Thiaville JJ, Frelin O,
García-Salinas C, Harrison K, Hasnain G, Horenstein NA,
Díaz de la Garza RI, Henry CS, Hanson AD, de
Crécy-Lagard V.
Front Microbiol 2016; 7: 431
Abstract:
Tetrahydrofolate (THF) and its one-carbon derivatives,
collectively termed folates, are essential cofactors, but are
inherently unstable. While it is clear that chemical oxidation
can cleave folates or damage their pterin precursors, very
little is known about enzymatic damage to these molecules or
about whether the folate biosynthesis pathway responds
adaptively to damage to its end-products. The presence of a
duplication of the gene encoding the folate biosynthesis enzyme
6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (FolK) in
many sequenced bacterial genomes combined with a strong
chromosomal clustering of the folK gene with panB, encoding the
5,10-methylene-THF-dependent enzyme ketopantoate
hydroxymethyltransferase, led us to infer that PanB has a side
activity that cleaves 5,10-methylene-THF, yielding a pterin
product that is recycled by FolK. Genetic and metabolic
analyses of Escherichia coli strains showed that overexpression
of PanB leads to accumulation of the likely folate cleavage
product 6-hydroxymethylpterin and other pterins in cells and
medium, and-unexpectedly-to a 46% increase in total folate
content. In silico modeling of the folate biosynthesis pathway
showed that these observations are consistent with the in vivo
cleavage of 5,10-methylene-THF by a side-activity of PanB, with
FolK-mediated recycling of the pterin cleavage product, and
with regulation of folate biosynthesis by folates or their
damage products.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000639.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000639 | BioModels