Browse
Submit Data
Databases
API
Help

Dataset Information

26 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Metabolic Regulation by Lysine Malonylation, Succinylation, and Glutarylation.

ABSTRACT: Protein acetylation is a well-studied regulatory mechanism for several cellular processes, ranging from gene expression to metabolism. Recent discoveries of new post-translational modifications, including malonylation, succinylation, and glutarylation, have expanded our understanding of the types of modifications found on proteins. These three acidic lysine modifications are structurally similar but have the potential to regulate different proteins in different pathways. The deacylase sirtuin 5 (SIRT5) catalyzes the removal of these modifications from a wide range of proteins in different subcellular compartments. Here, we review these new modifications, their regulation by SIRT5, and their emerging role in cellular regulation and diseases.

SUBMITTER: Hirschey MD

PROVIDER: S-EPMC4563717 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Metabolic Regulation by Lysine Malonylation, Succinylation, and Glutarylation.

Hirschey Matthew D MD Zhao Yingming Y

Molecular & cellular proteomics : MCP 20150225 9

Protein acetylation is a well-studied regulatory mechanism for several cellular processes, ranging from gene expression to metabolism. Recent discoveries of new post-translational modifications, including malonylation, succinylation, and glutarylation, have expanded our understanding of the types of modifications found on proteins. These three acidic lysine modifications are structurally similar but have the potential to regulate different proteins in different pathways. The deacylase sirtuin 5 ...[more]

PMID: 25717114

Similar Datasets

Lysine succinylation and lysine malonylation in histones.

Project description:Histone protein post-translational modifications (PTMs) are significant for gene expression and DNA repair. Here we report the identification and validation of a new type of PTM in histones, lysine succinylation. The identified lysine succinylated histone peptides were verified by MS/MS of synthetic peptides, HPLC co-elution, and isotopic labeling. We identified 13, 7, 10, and 7 histone lysine succinylation sites in HeLa, mouse embryonic fibroblast, Drosophila S2, and Saccharomyces cerevisiae cells, respectively. We demonstrated that this histone PTM is present in all eukaryotic cells we examined. Mutagenesis of succinylation sites followed by functional assays implied that histone lysine succinylation can cause unique functional consequences. We also identified one and two histone lysine malonylation sites in HeLa and S. cerevisiae cells, respectively. Our results therefore increase potential combinatorial diversity of histone PTMs and suggest possible new connections between histone biology and metabolism.

| S-EPMC3418837 | biostudies-literature

Protein Succinylation and Malonylation as Potential Biomarkers in Schizophrenia.

Project description:Two protein post-translational modifications, lysine succinylation and malonylation, are implicated in protein regulation, glycolysis, and energy metabolism. The precursors of these modifications, succinyl-CoA and malonyl-CoA, are key players in central metabolic processes. Both modification profiles have been proven to be responsive to metabolic stimuli, such as hypoxia. As mitochondrial dysfunction and metabolic dysregulation are implicated in schizophrenia and other psychiatric illnesses, these modification profiles have the potential to reveal yet another layer of protein regulation and can furthermore represent targets for biomarkers that are indicative of disease as well as its progression and treatment. In this work, data from shotgun mass spectrometry-based quantitative proteomics were compiled and analyzed to probe the succinylome and malonylome of postmortem brain tissue from patients with schizophrenia against controls and the human oligodendrocyte precursor cell line MO3.13 with the dizocilpine chemical model for schizophrenia, three antipsychotics, and co-treatments. Several changes in the succinylome and malonylome were seen in these comparisons, revealing these modifications to be a largely under-studied yet important form of protein regulation with broad potential applications.

| S-EPMC9500613 | biostudies-literature

Functions and Mechanisms of Lysine Glutarylation in Eukaryotes.

Project description:Lysine glutarylation (Kglu) is a newly discovered post-translational modification (PTM), which is considered to be reversible, dynamic, and conserved in prokaryotes and eukaryotes. Recent developments in the identification of Kglu by mass spectrometry have shown that Kglu is mainly involved in the regulation of metabolism, oxidative damage, chromatin dynamics and is associated with various diseases. In this review, we firstly summarize the development history of glutarylation, the biochemical processes of glutarylation and deglutarylation. Then we focus on the pathophysiological functions such as glutaric acidemia 1, asthenospermia, etc. Finally, the current computational tools for predicting glutarylation sites are discussed. These emerging findings point to new functions for lysine glutarylation and related enzymes, and also highlight the mechanisms by which glutarylation regulates diverse cellular processes.

| S-EPMC8264553 | biostudies-literature

Global Insights Into Lysine Acylomes Reveal Crosstalk Between Lysine Acetylation and Succinylation in Streptomyces coelicolor Metabolic Pathways.

Project description:Lysine acylations are reversible and ubiquitous post-translational modifications that play critical roles in regulating multiple cellular processes. In the current study, highly abundant and dynamic acetylation, besides succinylation, was uncovered in a soil bacterium, Streptomyces coelicolor. By affinity enrichment using anti-acetyl-lysine antibody and the following LC-MS/MS analysis, a total of 1298 acetylation sites among 601 proteins were identified. Bioinformatics analyses suggested that these acetylated proteins have diverse subcellular localization and were enriched in a wide range of biological functions. Specifically, a majority of the acetylated proteins were also succinylated in the tricarboxylic acid cycle and protein translation pathways, and the bimodification occurred at the same sites in some proteins. The acetylation and succinylation sites were quantified by knocking out either the deacetylase ScCobB1 or the desuccinylase ScCobB2, demonstrating a possible competitive relationship between the two acylations. Moreover, in vitro experiments using synthetically modified peptides confirmed the regulatory crosstalk between the two sirtuins, which may be involved in the collaborative regulation of cell physiology. Collectively, these results provided global insights into the S. coelicolor acylomes and laid a foundation for characterizing the regulatory roles of the crosstalk between lysine acetylation and succinylation in the future.

| S-EPMC8498004 | biostudies-literature

Lysine malonylation is elevated in type 2 diabetic mouse models and enriched in metabolic associated proteins.

Project description:Protein lysine malonylation, a newly identified protein post-translational modification (PTM), has been proved to be evolutionarily conserved and is present in both eukaryotic and prokaryotic cells. However, its potential roles associated with human diseases remain largely unknown. In the present study, we observed an elevated lysine malonylation in a screening of seven lysine acylations in liver tissues of db/db mice, which is a typical model of type 2 diabetes. We also detected an elevated lysine malonylation in ob/ob mice, which is another model of type 2 diabetes. We then performed affinity enrichment coupled with proteomic analysis on liver tissues of both wild-type (wt) and db/db mice and identified a total of 573 malonylated lysine sites from 268 proteins. There were more malonylated lysine sites and proteins in db/db than in wt mice. Five proteins with elevated malonylation were verified by immunoprecipitation coupled with Western blot analysis. Bioinformatic analysis of the proteomic results revealed the enrichment of malonylated proteins in metabolic pathways, especially those involved in glucose and fatty acid metabolism. In addition, the biological role of lysine malonylation was validated in an enzyme of the glycolysis pathway. Together, our findings support a potential role of protein lysine malonylation in type 2 diabetes with possible implications for its therapy in the future.

| S-EPMC4288257 | biostudies-literature

Lysine glutarylation is a protein posttranslational modification regulated by SIRT5.

Project description:We report the identification and characterization of a five-carbon protein posttranslational modification (PTM) called lysine glutarylation (Kglu). This protein modification was detected by immunoblot and mass spectrometry (MS), and then comprehensively validated by chemical and biochemical methods. We demonstrated that the previously annotated deacetylase, sirtuin 5 (SIRT5), is a lysine deglutarylase. Proteome-wide analysis identified 683 Kglu sites in 191 proteins and showed that Kglu is highly enriched on metabolic enzymes and mitochondrial proteins. We validated carbamoyl phosphate synthase 1 (CPS1), the rate-limiting enzyme in urea cycle, as a glutarylated protein and demonstrated that CPS1 is targeted by SIRT5 for deglutarylation. We further showed that glutarylation suppresses CPS1 enzymatic activity in cell lines, mice, and a model of glutaric acidemia type I disease, the last of which has elevated glutaric acid and glutaryl-CoA. This study expands the landscape of lysine acyl modifications and increases our understanding of the deacylase SIRT5.

| S-EPMC4108075 | biostudies-literature

Computational Identification of Lysine Glutarylation Sites Using Positive-Unlabeled Learning.

Project description:BackgroundAs a new type of protein acylation modification, lysine glutarylation has been found to play a crucial role in metabolic processes and mitochondrial functions. To further explore the biological mechanisms and functions of glutarylation, it is significant to predict the potential glutarylation sites. In the existing glutarylation site predictors, experimentally verified glutarylation sites are treated as positive samples and non-verified lysine sites as the negative samples to train predictors. However, the non-verified lysine sites may contain some glutarylation sites which have not been experimentally identified yet.MethodsIn this study, experimentally verified glutarylation sites are treated as the positive samples, whereas the remaining non-verified lysine sites are treated as unlabeled samples. A bioinformatics tool named PUL-GLU was developed to identify glutarylation sites using a positive-unlabeled learning algorithm.ResultsExperimental results show that PUL-GLU significantly outperforms the current glutarylation site predictors. Therefore, PUL-GLU can be a powerful tool for accurate identification of protein glutarylation sites.ConclusionA user-friendly web-server for PUL-GLU is available at http://bioinform.cn/pul_glu/.

| S-EPMC7521029 | biostudies-literature

Global Proteomic Analysis of Lysine Malonylation in Toxoplasma gondii.

Project description:Lysine malonylation (Kmal) is a new post-translational modification (PTM), which has been reported in several prokaryotic and eukaryotic species. Although Kmal can regulate many and diverse biological processes in various organisms, knowledge about this important PTM in the apicomplexan parasite Toxoplasma gondii is limited. In this study, we performed the first global profiling of malonylated proteins in T. gondii tachyzoites using affinity enrichment and Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Three experiments performed in tandem revealed 294, 345, 352 Kmal sites on 203, 236, 230 malonylated proteins, respectively. Computational analysis showed the identified malonylated proteins to be localized in various subcellular compartments and involved in many cellular functions, particularly mitochondrial function. Additionally, one conserved Kmal motif with a strong bias for cysteine was detected. Taken together, these findings provide the first report of Kmal profile in T. gondii and should be an important resource for studying the physiological roles of Kmal in this parasite.

| S-EPMC7198775 | biostudies-literature

Identification of lysine succinylation substrates and the succinylation regulatory enzyme CobB in Escherichia coli.

Project description:Lysine succinylation is a newly identified protein post-translational modification pathway present in both prokaryotic and eukaryotic cells. However, succinylation substrates and regulatory enzyme(s) remain largely unknown, hindering the biological study of this modification. Here we report the identification of 2,580 bacterial lysine succinylation sites in 670 proteins and 2,803 lysine acetylation (Kac) sites in 782 proteins, representing the first lysine succinylation dataset and the largest Kac dataset in wild-type E. coli. We quantified dynamic changes of the lysine succinylation and Kac substrates in response to high glucose. Our data showed that high-glucose conditions led to more lysine-succinylated proteins and enhanced the abundance of succinyllysine peptides more significantly than Kac peptides, suggesting that glucose has a more profound effect on succinylation than on acetylation. We further identified CobB, a known Sir2-like bacterial lysine deacetylase, as the first prokaryotic desuccinylation enzyme. The identification of bacterial CobB as a bifunctional enzyme with lysine desuccinylation and deacetylation activities suggests that the eukaryotic Kac-regulatory enzymes may have enzymatic activities on various lysine acylations with very different structures. In addition, it is highly likely that lysine succinylation could have unique and more profound regulatory roles in cellular metabolism relative to lysine acetylation under some physiological conditions.

| S-EPMC3861704 | biostudies-literature

Lysine malonylation and propionylation are prevalent in human lens proteins.

Project description:Acylated lysine residues represent major chemical modifications in proteins. We investigated the malonylation and propionylation of lysine residues (MalK, PropK) in the proteins of aging human lenses. Western blot results showed that the two modifications are present in human lens proteins. Liquid chromatography-mass spectrometry (LC-MS/MS) results showed 4-18 and 4-32?pmol/mg protein of MalK and PropK, respectively, in human lens proteins with no apparent changes related to aging. Mass spectrometry results revealed that MalK- and PropK-modified lysine residues are present in all major crystallins, other cytosolic proteins, and membrane and cytoskeletal proteins of the lens. Several mitochondrial and cytosolic proteins in cultured human lens epithelial cells showed MalK and PropK modifications. Sirtuin 3 (SIRT3) and sirtuin 5 (SIRT5) were present in human lens epithelial and fiber cells. Moreover, lens epithelial cell lysate deacylated propionylated and malonylated lysozyme. The absence of SIRT3 and SIRT5 led to higher PropK and MalK levels in mouse lenses. Together, these data suggest that MalK and PropK are widespread modifications in lens and SIRT3 and SIRT5 could regulate their levels in lens epithelial cells.

| S-EPMC6957740 | biostudies-literature

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