Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Proteomic response to cytotoxicity of methylglyoxall

ABSTRACT: Tumor glycolysis is a target for cancer chemotherapy. Methylglyoxal (MG) is a reactive metabolite formed mainly as a by-product in anaerobic glycolysis, metabolized by glyoxalase 1 (Glo1) of the glyoxalase system. MG is increased to cytotoxic levels by clinical anticancer drugs, contributing to their mechanism of action. We investigated the role of the proteomic response to MG in mediating cytotoxicity. The proteomic response to MG-induced cytotoxicity was explored by high mass resolution proteomics of cytoplasmic and other subcellular protein extracts. MG induced decrease of mitochondrial and spliceosomal proteins. Spliceosomal proteins were targets of MG modification. We conclude that MG-mediated cytotoxicity targets the spliceosome.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Kidney Cancer

SUBMITTER: Paul Thornalley

LAB HEAD: Paul J Thornalley

PROVIDER: PXD029315 | Pride | 2021-11-02

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	MS18-194_MC1.dat	Other
	MS18-194_MC2.dat	Other
	MS18-194_MC3.dat	Other
	MS18-194_MIMC1.dat	Other
	MS18-194_MIMC2.dat	Other

Items per page:

1 - 5 of 36

Similar Datasets

Impairment of methylglyoxal detoxification systems causes mitochondrial dysfunction and behavioral deficits

Project description:Methylglyoxal (MG) is a reactive alpha-dicarbonyl by-product of glycolysis. Several bio-defense systems to detoxify the highly toxic MG are equipped in our body, including an enzymatic system by glyoxalase (GLO) 1 and GLO2 and a scavenge system by vitamin B6 (VB6). We have reported that some population of patients with schizophrenia shows impairment of the MG detoxification systems. Although we have evidences showing a link between impairment of MG detoxification systems and development of schizophrenia, the molecular mechanism to connect them remains poorly understood. Here, we generated a novel mouse model for MG detoxification deficits by feeding Glo1 knockout mice with VB6-lacking diets (KO/VB6(-)), and evaluate effects of impaired MG detoxification systems on brain function. KO/VB6(-) mice showed the accumulation of MG in the prefrontal cortex (PFC), hippocampus, and striatum, and displayed schizophrenia-like behavioral deficits, such as social deficits, cognitive impairment, a sensorimotor deficit in the prepulse inhibition test. Furthermore, we found aberrant gene expression related to mitochondria function in the PFC of the KO/VB6(-) mice by RNA-seq and weighted gene correlation network analysis (WGCNA). Finally, we actually demonstrated respiratory deficits in mitochondria isolated from the PFC of KO/VB6(-) mice. These findings suggest that MG detoxification deficits might cause schizophrenia-like behavioral deficits via mitochondrial dysfunction in the PFC.

2021-07-20 | GSE149585 | GEO

Small molecule activation of PKM in cancer cells induces serine auxotrophy

Project description:Proliferating tumor cells use aerobic glycolysis to support their high metabolic demands. Paradoxically, increased glycolysis is often accompanied by expression of the lower activity PKM isoform, effectively constraining lower glycolysis. Here, we report the discovery of novel PKM activators with a unique allosteric binding mode. Characterization of how these compounds impact cancer cells revealed an unanticipated link between glucose and amino acid metabolism. PKM activation resulted in a metabolic rewiring of cancer cells manifested by a profound dependency on the non-essential amino acid serine for continued cell proliferation. Induction of serine auxotrophy by PKM activation was accompanied by reduced carbon flow into the serine biosynthetic pathway and increased expression of high affinity serine transporters. These data support the hypothesis that PKM expression confers metabolic flexibility to cancer cells that allows adaptation to nutrient stress. A549 cancer cells were treated with compound-16 for up to 24 hours in the presence and absence of serine in the media.

2012-12-20 | E-GEOD-40191 | biostudies-arrayexpress

Loss of Glo2 alters the glucose metabolism in zebrafish

Project description:Glyoxalase 2 is the second enzyme of the glyoxalase system, catalyzing the detoxification of methylglyoxal to D-lactate via SD-Lactoylglutathione. Recent studies have suggested Glo2 as a regulator of glycolysis, but the physiological functions of Glo2 in vivo and organ specific functions of the enzyme have not yet been evaluated. Therefore, a CRISPR/Cas9 knockout of glo2 in zebrafish was created and analyzed. Consistent with its function in methylglyoxal detoxification, SD-Lactoylglutathione, but not methylglyoxal accumulated in glo2-/- larvae, with no change in longevity. Adult glo2‑/- livers developed an impaired insulin signaling, indicated by a reduced hepatic P70-S6-kinase activation and reduced hepatic hexose concentration. In contrast, glo2-/- skeletal muscle remained functionally intact, compensating for the dysfunctional liver through increased glucose uptake, thereby maintaining euglycemia and preventing damage of the retina and kidney. In conclusion, the data identified Glo2 to fulfill similar but unique functions compared to Glo1 and established Glo2 as a novel target in diabetes research, regulating hepatic insulin signaling.

2023-03-15 | GSE205085 | GEO

Profiling of Methylglyoxal Blood Metabolism and Advanced Glycation End-Product Proteome using a Chemical Probe

Project description:Methylglyoxal (MG) is a toxic byproduct of the glycolytic pathway and is quantitatively the most important precursor to advanced glycation end-products (AGEs). Insight into which proteins and in particular their individual modification sites are central to understand the involvement of MG and AGE in diabetes and aging related diseases. Here, we present a method to simultaneously monitor protein AGE formation in biological samples by employing an alkyne-labeled methylglyoxal probe. We apply the method to blood and plasma to demonstrate the impact of blood cell glyoxalase activity on plasma protein AGE formation. We move on to isolate proteins modified by the MG probe and accordingly can present the first general inventory of more than 100 proteins and 300 binding sites of the methylglyoxal probe on plasma as well as erythrocytic proteins.

2019-07-31 | PXD011314 | Pride

Esculetin inhibits cancer cell glycolysis by binding tumor PGK2, GPD2, and GPI

Project description:Glycolysis can improve the tolerance of tissue cells to hypoxia, and its intermediates provide raw materials for the synthesis and metabolism of the tumor cells. If it can inhibit the activity of glycolysis-related enzymes and control the energy metabolism of tumor, it can be targeted for the treatment of malignant tumor. The target proteins phosphoglycerate kinase 2 (PGK2), glycerol-3-phosphate dehydrogenase (GPD2) and glucose-6-phosphate isomerase (GPI) were screened by combining transcriptome, proteomics and reverse docking. We detected the binding constant of the active compound using microscale thermophoresis (MST). It was found that esculetin bound well with three potential target proteins. Esculetin significantly inhibited the rate of glycolysis, manifested by differences of cellular lactate production and glucose consumption in HepG2 cells with or without esculetin. It was found that GPD2 bound strongly to GPI, revealing the direct interaction between the two glycolysis-related proteins. Animal tests have further demonstrated that esculetin may have anticancer effects by affecting the activity of PGK2, GPD2 and GPI. The results of this study demonstrated that esculetin can affect the glucose metabolism by binding to glycolytic proteins, thus playing an anti-tumor role, and these proteins which have direct interactions are potential novel targets for tumor treatment by esculetin.

2020-03-03 | PXD017819 | Pride

Global Lysine Acetylome Analysis of LPS-Stimulated HepG2 Cells Identifies Hyperacetylation of PKM2 as a Metabolic Reg-ulator in Sepsis

Project description:Sepsis-induced liver dysfunction is a frequent event and is strongly associated with mortality. Establishing a causative link between protein post-translational modification (PTM) and diseases is challenging. We studied the relationship among the lysine acetylation (Kac), the sirtuin (SIRTs), and their interactors carefully selected in sepsis-induced liver dysfunction (SILD), per-formed on LPS-stimulated HepG2 cells. Protein hyperacetylation was observed according to SIRTs reduction after LPS treatment for 24 h. We identified 1,449 Kac sites based on comparative acetylome analysis, and quantified 1,086 Kac sites on 410 proteins for acetylation. Interestingly, the up-regulated Kac proteins are enriched in glycolysis/gluconeogenesis pathways in the KEGG category. Among the proteins in the glycolysis pathway, hyperacetylation, a key regulator of lactate level in sepsis, was observed in three pyruvate kinase M2 (PKM2) sites. Hyperacetylation of PKM2 induced an increase in its activity, increasing the lactate concentration as a result. In conclusion, this study is the first to conduct global profiling of Kac, suggesting the Kac mecha-nism of PKM2 in glycolysis of sepsis. Moreover, it helps further understand the systematical in-formation of hyperacetylation during the sepsis process.

2024-01-30 | PXD027496 | Pride

Integrative transcriptome and proteome revealed high-yielding mechanisms of epsilon-poly-L-lysine by Streptomyces albulus

Project description:ε-poly-L-lysine (ε-PL) is a high value, widely used natural antimicrobial peptide additive for foods and cosmetic products that is mainly produced by S. albulus. In previous work, we developed the high-yield industrial strain S. albulus WG-608 through successive rounds of engineering. Here, we use integrated physiological, transcriptomic, and proteomics association analysis to resolve the complex mechanisms underlying high ε-PL production by comparing WG-608 with the progenitor strain M-Z18. Our results show that key genes in the glycolysis, glyoxylate, and L-lysine biosynthesis pathways are differentially upregulated in WG-608, while genes in the biosynthetic pathways for fatty acids, various branched amino acids, and secondary metabolite by-products are downregulated. This regulatory pattern results in the introduction of more carbon atoms into L-lysine biosynthesis and ε-PL production. Furthermore, transcriptional and translational upregulation of genes involved in the tricarboxylic acid cycle, oxidative phosphorylation, and pentose phosphate pathway also increase the pools of available NADH, ATP, and NADPH. In addition, significant changes in the regulation of DNA replication, transcription, and translation, two component systems, and quorum sensing may facilitate the adaptability to environmental pressure, thus further regulating the ε-PL biosynthesis. This study enables comprehensive understanding of the biosynthetic mechanisms of ε-PL in S. albulus WG-608, while providing a theoretical foundation development of advanced Streptomycetaceae microbial cell factories.

2023-07-20 | PXD036099 | Pride

Proteomics sequencing analysis revealed the pathogenesis of arterial dissection caused by hypertension

Project description:Aortic dissection (AD) is a devastating disease with rapid progression and high mortality, and hypertension is a leading cause for AD. The aim of this study was to compare the protein expression profiles of aortas from patients with and without AD, screen vital proteins and explore their potential roles to grasp a further understanding of the pathogenesis mechanism of AD. The results of Tandem Mass Tag (TMT) sequencing revealed the different protein expression profiles between AD and control groups. 131 proteins were significantly upregulated and 239 proteins were prominently downregulated in AD. Upon further enrichment analysis of differential proteins, we found that 5 signaling pathways changed significantly in AD such as glycolysis, ECM and the other three pathways. Moreover, PPI networks were constructed to locate nodal proteins that may be essential points for AD. Our observation demonstrates for the first time that the protein expression in AD was notably changed compared to the control. Our results present evidences that glycolysis and ECM signaling pathway may present a promising approach for the etiology of AD.

2020-09-14 | PXD020841 | Pride

Proteomics sequencing analysis revealed the pathogenesis of arterial dissection caused by hypertension

2020-09-14 | PXD020769 | Pride

Proteomics sequencing analysis revealed the pathogenesis of arterial dissection caused by hypertension

2020-09-14 | PXD020765 | Pride