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ACS Chemical Biology Mar 2020O-Linked N-acetyl glucosamine (O-GlcNAc) is a protein modification found on thousands of nuclear, cytosolic, and mitochondrial proteins. Many O-GlcNAc sites occur in...
O-Linked N-acetyl glucosamine (O-GlcNAc) is a protein modification found on thousands of nuclear, cytosolic, and mitochondrial proteins. Many O-GlcNAc sites occur in proximity to protein sites that are likewise modified by phosphorylation. While several studies have uncovered crosstalk between these two signaling modifications on individual proteins and pathways, an understanding of the role of O-GlcNAc in regulating kinases, the enzymes that install the phosphate modification, is still emerging. Here we review recent methods to profile the O-GlcNAc modification on a global scale that have revealed more than 100 kinases are modified by O-GlcNAc and highlight existing studies about regulation of these kinases by O-GlcNAc. Continuing efforts to profile the O-GlcNAc proteome and understand the role of O-GlcNAc on kinases will reveal new mechanisms of regulation and potential avenues for manipulation of the signaling mechanisms at the intersection of O-GlcNAc and phosphorylation.
Topics: Acetylglucosamine; Amino Acid Sequence; Catalytic Domain; Glycosylation; Phosphorylation; Phosphotransferases; Protein Binding; Protein Conformation; Protein Engineering; Protein Processing, Post-Translational; Proteome; Signal Transduction; Structure-Activity Relationship
PubMed: 32155042
DOI: 10.1021/acschembio.9b01015 -
Journal of Lipid Research Aug 2020The final step of the CDP-ethanolamine pathway is catalyzed by ethanolamine phosphotransferase 1 (EPT1) and choline/EPT1 (CEPT1). These enzymes are likely involved in...
The final step of the CDP-ethanolamine pathway is catalyzed by ethanolamine phosphotransferase 1 (EPT1) and choline/EPT1 (CEPT1). These enzymes are likely involved in the transfer of ethanolamine phosphate from CDP-ethanolamine to lipid acceptors such as 1,2-diacylglycerol (DAG) for PE production and 1-alkyl-2-acyl-glycerol (AAG) for the generation of 1-alkyl-2-acyl-glycerophosphoethanolamine. Here, we investigated the intracellular location and contribution to ethanolamine phospholipid (EP) biosynthesis of EPT1 and CEPT1 in HEK293 cells. Immunohistochemical analyses revealed that EPT1 localizes to the Golgi apparatus and CEPT1 to the ER. We created EPT1-, CEPT1-, and EPTI-CEPT1-deficient cells, and labeling of these cells with radio- or deuterium-labeled ethanolamine disclosed that EPT1 is more important for the de novo biosynthesis of 1-alkenyl-2-acyl-glycerophosphoethanolamine than is CEPT1. EPT1 also contributed to the synthesis of PE species containing the fatty acids 36:1, 36:4, 38:5, 38:4, 38:3, 40:6, 40:5, and 40:4. In contrast, CEPT1 was important for PE formation from shorter fatty acids such as 32:2, 32:1, 34:2, and 34:1. Brefeldin A treatment did not significantly affect the levels of the different PE species, indicating that the subcellular localization of the two enzymes is not responsible for their substrate preferences. In vitro enzymatic analysis revealed that EPT1 prefers AAG 16-20:4 > DAG 18:0-20:4 > DAG 16:0-18:1 = AAG 16-18:1 as lipid acceptors and that CEPT1 greatly prefers DAG 16:0-18:1 to other acceptors. These results suggest that EPT1 and CEPT1 differ in organelle location and are responsible for the biosynthesis of distinct EP species.
Topics: Ethanolamine; Ethanolaminephosphotransferase; HEK293 Cells; Humans; Intracellular Space; Phospholipids; Protein Transport
PubMed: 32576654
DOI: 10.1194/jlr.RA120000898 -
Advances in Biological Regulation Jan 2015The family of phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) is emerging from a comparative backwater in inositide signalling into the mainstream, as is their... (Review)
Review
The family of phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) is emerging from a comparative backwater in inositide signalling into the mainstream, as is their substrate, phosphatidylinositol 5-phosphate (PI5P). Here we review some of the key questions about the PI5P4Ks, their localisation, interaction, and regulation and also we summarise our current understanding of how PI5P is synthesised and what its cellular functions might be. Finally, some of the evidence for the involvement of PI5P4Ks in pathology is discussed.
Topics: Animals; Humans; Phosphatidylinositol Phosphates; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction
PubMed: 25311266
DOI: 10.1016/j.jbior.2014.09.007 -
Biomolecules May 2021Oximes have been studied for decades because of their significant roles as acetylcholinesterase reactivators. Over the last twenty years, a large number of oximes have... (Review)
Review
Oximes have been studied for decades because of their significant roles as acetylcholinesterase reactivators. Over the last twenty years, a large number of oximes have been reported with useful pharmaceutical properties, including compounds with antibacterial, anticancer, anti-arthritis, and anti-stroke activities. Many oximes are kinase inhibitors and have been shown to inhibit over 40 different kinases, including AMP-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K), cyclin-dependent kinase (CDK), serine/threonine kinases glycogen synthase kinase 3 α/β (GSK-3α/β), Aurora A, B-Raf, Chk1, death-associated protein-kinase-related 2 (DRAK2), phosphorylase kinase (PhK), serum and glucocorticoid-regulated kinase (SGK), Janus tyrosine kinase (JAK), and multiple receptor and non-receptor tyrosine kinases. Some oximes are inhibitors of lipoxygenase 5, human neutrophil elastase, and proteinase 3. The oxime group contains two H-bond acceptors (nitrogen and oxygen atoms) and one H-bond donor (OH group), versus only one H-bond acceptor present in carbonyl groups. This feature, together with the high polarity of oxime groups, may lead to a significantly different mode of interaction with receptor binding sites compared to corresponding carbonyl compounds, despite small changes in the total size and shape of the compound. In addition, oximes can generate nitric oxide. This review is focused on oximes as kinase inhibitors with anticancer and anti-inflammatory activities. Oximes with non-kinase targets or mechanisms of anti-inflammatory activity are also discussed.
Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Enzyme Inhibitors; Humans; Neoplasm Proteins; Neoplasms; Oximes; Phosphotransferases
PubMed: 34067242
DOI: 10.3390/biom11060777 -
The FEBS Journal Sep 2018Purine nucleotides are involved in a variety of cellular functions, such as energy storage and transfer, and signalling, in addition to being the precursors of nucleic... (Review)
Review
Purine nucleotides are involved in a variety of cellular functions, such as energy storage and transfer, and signalling, in addition to being the precursors of nucleic acids and cofactors of many biochemical reactions. They can be generated through two separate pathways, the de novo biosynthesis pathway and the salvage pathway. De novo purine biosynthesis leads to the formation of IMP, from which the adenylate and guanylate pools are generated by two additional steps. The salvage pathways utilize hypoxanthine, guanine and adenine to generate the corresponding mononucleotides. Despite several decades of research on the subject, new and surprising findings on purine metabolism are constantly being reported, and some aspects still need to be elucidated. Recently, purine biosynthesis has been linked to the metabolic pathways regulated by AMP-activated protein kinase (AMPK). AMPK is the master regulator of cellular energy homeostasis, and its activity depends on the AMP : ATP ratio. The cellular energy status and AMPK activation are connected by AMP, an allosteric activator of AMPK. Hence, an indirect strategy to affect AMPK activity would be to target the pathways that generate AMP in the cell. Herein, we report an up-to-date review of the interplay between AMPK and adenylate metabolizing enzymes. Some aspects of inborn errors of purine metabolism are also discussed.
Topics: AMP-Activated Protein Kinases; Adenine Nucleotides; Humans; Pentosyltransferases; Phosphotransferases
PubMed: 29775996
DOI: 10.1111/febs.14508 -
Biomedicine & Pharmacotherapy =... Jul 2023PF-543 is a sphingosine kinase 1(SPHK1)inhibitor developed by Pfizer and is currently considered the most potent selective SPHK1 inhibitor. SPHK1 catalyses the... (Review)
Review
PF-543 is a sphingosine kinase 1(SPHK1)inhibitor developed by Pfizer and is currently considered the most potent selective SPHK1 inhibitor. SPHK1 catalyses the production of sphingosine 1-phosphate (S1P) from sphingosine. It is the rate-limiting enzyme of S1P production, and there is substantial evidence to support a very important role for sphingosine kinase in health and disease. This review is the first to summarize the role and mechanisms of PF-543 as an SPHK1 inhibitor in anticancer, antifibrotic, and anti-inflammatory processes, providing new therapeutic leads and ideas for future research and clinical trials.
Topics: Sphingosine; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 37167721
DOI: 10.1016/j.biopha.2023.114401 -
Cellular and Molecular Life Sciences :... Jul 2022Magnesium (Mg) is the most prevalent divalent intracellular cation. As co-factor in many enzymatic reactions, Mg is essential for protein synthesis, energy production,... (Review)
Review
Magnesium (Mg) is the most prevalent divalent intracellular cation. As co-factor in many enzymatic reactions, Mg is essential for protein synthesis, energy production, and DNA stability. Disturbances in intracellular Mg concentrations, therefore, unequivocally result in delayed cell growth and metabolic defects. To maintain physiological Mg levels, all organisms rely on balanced Mg influx and efflux via Mg channels and transporters. This review compares the structure and the function of prokaryotic Mg transporters and their eukaryotic counterparts. In prokaryotes, cellular Mg homeostasis is orchestrated via the CorA, MgtA/B, MgtE, and CorB/C Mg transporters. For CorA, MgtE, and CorB/C, the motifs that form the selectivity pore are conserved during evolution. These findings suggest that CNNM proteins, the vertebrate orthologues of CorB/C, also have Mg transport capacity. Whereas CorA and CorB/C proteins share the gross quaternary structure and functional properties with their respective orthologues, the MgtE channel only shares the selectivity pore with SLC41 Na/Mg transporters. In eukaryotes, TRPM6 and TRPM7 Mg channels provide an additional Mg transport mechanism, consisting of a fusion of channel with a kinase. The unique features these TRP channels allow the integration of hormonal, cellular, and transcriptional regulatory pathways that determine their Mg transport capacity. Our review demonstrates that understanding the structure and function of prokaryotic magnesiotropic proteins aids in our basic understanding of Mg transport.
Topics: Biological Transport; Cations, Divalent; Magnesium; Membrane Transport Proteins; Phosphotransferases
PubMed: 35819535
DOI: 10.1007/s00018-022-04442-8 -
Biochemical Pharmacology Nov 2014Upregulated glycolysis, both in normoxic and hypoxic environments, is a nearly universal trait of cancer cells. The enormous difference in glucose metabolism offers a... (Review)
Review
Upregulated glycolysis, both in normoxic and hypoxic environments, is a nearly universal trait of cancer cells. The enormous difference in glucose metabolism offers a target for therapeutic intervention with a potentially low toxicity profile. The past decade has seen a steep rise in the development and clinical assessment of small molecules that target glycolysis. The enzymes in glycolysis have a highly heterogeneous nature that allows for the different bioenergetic, biosynthetic, and signaling demands needed for various tissue functions. In cancers, these properties enable them to respond to the variable requirements of cell survival, proliferation and adaptation to nutrient availability. Heterogeneity in glycolysis occurs through the expression of different isoforms, posttranslational modifications that affect the kinetic and regulatory properties of the enzyme. In this review, we will explore this vast heterogeneity of glycolysis and discuss how this information might be exploited to better target glucose metabolism and offer possibilities for biomarker development.
Topics: Biomarkers; Energy Metabolism; Glucose; Glycolysis; Humans; Neoplasms; Oxygen Consumption; Phosphotransferases; Up-Regulation
PubMed: 25093285
DOI: 10.1016/j.bcp.2014.07.019 -
The Plant Cell Apr 2022The nucleotide-binding, leucine-rich receptor (NLR) protein HOPZ-ACTIVATED RESISTANCE 1 (ZAR1), an immune receptor, interacts with HOPZ-ETI-DEFICIENT 1 (ZED1)-related...
The nucleotide-binding, leucine-rich receptor (NLR) protein HOPZ-ACTIVATED RESISTANCE 1 (ZAR1), an immune receptor, interacts with HOPZ-ETI-DEFICIENT 1 (ZED1)-related kinases (ZRKs) and AVRPPHB SUSCEPTIBLE 1-like proteins to form a pentameric resistosome, triggering immune responses. Here, we show that ZAR1 emerged through gene duplication and that ZRKs were derived from the cell surface immune receptors wall-associated protein kinases (WAKs) through the loss of the extracellular domain before the split of eudicots and monocots during the Jurassic period. Many angiosperm ZAR1 orthologs, but not ZAR1 paralogs, are capable of oligomerization in the presence of AtZRKs and triggering cell death, suggesting that the functional ZAR1 resistosome might have originated during the early evolution of angiosperms. Surprisingly, inter-specific pairing of ZAR1 and AtZRKs sometimes results in the formation of a resistosome in the absence of pathogen stimulation, suggesting within-species compatibility between ZAR1 and ZRKs as a result of co-evolution. Numerous concerted losses of ZAR1 and ZRKs occurred in angiosperms, further supporting the ancient co-evolution between ZAR1 and ZRKs. Our findings provide insights into the origin of new plant immune surveillance networks.
Topics: Arabidopsis; Arabidopsis Proteins; Carrier Proteins; NLR Proteins; Phosphotransferases; Plant Immunity
PubMed: 35166827
DOI: 10.1093/plcell/koac053 -
Nature Communications May 2022Human neurodegenerative disorders often exhibit similar pathologies, suggesting a shared aetiology. Key pathological features of Parkinson's disease (PD) are also...
Human neurodegenerative disorders often exhibit similar pathologies, suggesting a shared aetiology. Key pathological features of Parkinson's disease (PD) are also observed in other neurodegenerative diseases. Pantothenate Kinase-Associated Neurodegeneration (PKAN) is caused by mutations in the human PANK2 gene, which catalyzes the initial step of de novo CoA synthesis. Here, we show that fumble (fbl), the human PANK2 homolog in Drosophila, interacts with PINK1 genetically. fbl and PINK1 mutants display similar mitochondrial abnormalities, and overexpression of mitochondrial Fbl rescues PINK1 loss-of-function (LOF) defects. Dietary vitamin B5 derivatives effectively rescue CoA/acetyl-CoA levels and mitochondrial function, reversing the PINK1 deficiency phenotype. Mechanistically, Fbl regulates Ref(2)P (p62/SQSTM1 homolog) by acetylation to promote mitophagy, whereas PINK1 regulates fbl translation by anchoring mRNA molecules to the outer mitochondrial membrane. In conclusion, Fbl (or PANK2) acts downstream of PINK1, regulating CoA/acetyl-CoA metabolism to promote mitophagy, uncovering a potential therapeutic intervention strategy in PD treatment.
Topics: Acetyl Coenzyme A; Animals; Drosophila; Drosophila Proteins; Mitochondria; Neurodegenerative Diseases; Parkinson Disease; Phosphotransferases (Alcohol Group Acceptor); Protein Kinases; Protein Serine-Threonine Kinases
PubMed: 35504872
DOI: 10.1038/s41467-022-30178-x