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Trends in Biochemical Sciences Apr 2018Protein kinases regulate every aspect of cellular activity, whereas metabolic enzymes are responsible for energy production and catabolic and anabolic processes.... (Review)
Review
Protein kinases regulate every aspect of cellular activity, whereas metabolic enzymes are responsible for energy production and catabolic and anabolic processes. Emerging evidence demonstrates that some metabolic enzymes, such as pyruvate kinase M2 (PKM2), phosphoglycerate kinase 1 (PGK1), ketohexokinase (KHK) isoform A (KHK-A), hexokinase (HK), and nucleoside diphosphate kinase 1 and 2 (NME1/2), that phosphorylate soluble metabolites can also function as protein kinases and phosphorylate a variety of protein substrates to regulate the Warburg effect, gene expression, cell cycle progression and proliferation, apoptosis, autophagy, exosome secretion, T cell activation, iron transport, ion channel opening, and many other fundamental cellular functions. The elevated protein kinase functions of these moonlighting metabolic enzymes in tumor development make them promising therapeutic targets for cancer.
Topics: Animals; Humans; Neoplasms; Protein Kinases
PubMed: 29463470
DOI: 10.1016/j.tibs.2018.01.006 -
Bulletin Du Cancer Dec 2022Phosphoglycerate kinase 1 (PGK1) catalyzes the conversion of 1,3-bisphosphoglyceride (1,3-BPG) and ADP into 3-phosphate (3-PG) and ATP, which is a key process of... (Review)
Review
Phosphoglycerate kinase 1 (PGK1) catalyzes the conversion of 1,3-bisphosphoglyceride (1,3-BPG) and ADP into 3-phosphate (3-PG) and ATP, which is a key process of glycolysis. PGK1 is considered a major regulator of various events, including one-carbon metabolism, serine biosynthesis and cell redox regulation. In the past decade, PGK1 has been found to be closely associated with various malignancies, making it a potential therapeutic target. PGK1 is involved in a series of biological processes related to tumorigenesis through post-translational modifications and various signaling pathways. PGK1 not only can participate in glucose metabolism but also acts as a protein kinase to participate in EMT, autophagy, angiogenesis, DNA replication and other processes related to tumor development. However, PGK1 also acts as a disulfide reductase to inhibit tumor by affecting angiogenesis. Exploring the structure, function and posttranslational modification of PGK1 will be helpful in further understanding the effect of metabolism on tumor progression. This manuscript reviews the role and mechanism of PGK1 in human malignancies, providing the theoretical basis for PGK1 as a possible clinical anticancer target.
Topics: Humans; Phosphoglycerate Kinase; Neoplasms; Glycolysis; Carcinogenesis; Signal Transduction
PubMed: 36096942
DOI: 10.1016/j.bulcan.2022.07.004 -
American Journal of Cancer Research 2019Phosphoglycerate kinase 1 (PGK1) is an essential enzyme in the aerobic glycolysis pathway. PGK1 catalyzes the reversible transfer of a phosphate group from... (Review)
Review
Phosphoglycerate kinase 1 (PGK1) is an essential enzyme in the aerobic glycolysis pathway. PGK1 catalyzes the reversible transfer of a phosphate group from 1,3-bisphosphoglycerate to ADP and produces 3-phosphoglycerate and ATP. In addition to cell metabolism regulation, PGK1 is involved in multiple biological activities, including angiogenesis, autophagy and DNA repair. Because of its multi-faceted functions, PGK1's involvement in cancer development is complicated. High intracellular expression of PGK1 leads to tumor cell proliferation. However, high extracellular expression of PGK1 suppresses cancer malignancy through a suppression of angiogenesis. PGK1 is also associated with chemoradiotherapy resistance and poor prognosis of cancer patients. In this manuscript, we summarize the influence of PGK1 and its post-translational modifications on cancer initiation and progression. PGK1-mediated drug resistance and potential small molecule inhibitors targeting PGK1 are discussed for their future clinical applications.
PubMed: 31815035
DOI: No ID Found -
Molecular Cell Mar 2017Autophagy is crucial for maintaining cell homeostasis. However, the precise mechanism underlying autophagy initiation remains to be defined. Here, we demonstrate that...
Autophagy is crucial for maintaining cell homeostasis. However, the precise mechanism underlying autophagy initiation remains to be defined. Here, we demonstrate that glutamine deprivation and hypoxia result in inhibition of mTOR-mediated acetyl-transferase ARD1 S228 phosphorylation, leading to ARD1-dependent phosphoglycerate kinase 1 (PGK1) K388 acetylation and subsequent PGK1-mediated Beclin1 S30 phosphorylation. This phosphorylation enhances ATG14L-associated class III phosphatidylinositol 3-kinase VPS34 activity by increasing the binding of phosphatidylinositol to VPS34. ARD1-dependent PGK1 acetylation and PGK1-mediated Beclin1 S30 phosphorylation are required for glutamine deprivation- and hypoxia-induced autophagy and brain tumorigenesis. Furthermore, PGK1 K388 acetylation levels correlate with Beclin1 S30 phosphorylation levels and poor prognosis in glioblastoma patients. Our study unearths an important mechanism underlying cellular-stress-induced autophagy initiation in which the protein kinase activity of the metabolic enzyme PGK1 plays an instrumental role and reveals the significance of the mutual regulation of autophagy and cell metabolism in maintaining cell homeostasis.
Topics: Acetylation; Animals; Autophagosomes; Autophagy; Beclin-1; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Class III Phosphatidylinositol 3-Kinases; Female; Glioblastoma; Glutamine; HEK293 Cells; Humans; Mice, Nude; N-Terminal Acetyltransferase A; N-Terminal Acetyltransferase E; Phosphoglycerate Kinase; Phosphorylation; Protein Binding; RNA Interference; Signal Transduction; TOR Serine-Threonine Kinases; Time Factors; Transfection; Tumor Burden; Tumor Hypoxia
PubMed: 28238651
DOI: 10.1016/j.molcel.2017.01.027 -
Advances in Neurobiology 2016Glutamate is an excitatory neurotransmitter widely used in the vertebrate central nervous systems. The synaptic transmission process is characterized by three steps: (1)...
Glutamate is an excitatory neurotransmitter widely used in the vertebrate central nervous systems. The synaptic transmission process is characterized by three steps: (1) presynaptic vesicular transmitter uptake, (2) presynaptic release, and (3) postsynaptic receptor activation. Presynaptic vesicular glutamate uptake plays an initial pivotal role in glutamate transmission by concentrating glutamate in the vesicular lumen prior to its release. This active glutamate transport harnesses energy derived from ATP hydrolysis, and intra- or extravesicular chloride, and is highly specific to glutamate. The uptake system consists of a vesicular glutamate transporter (VGLUT) and v-type proton-pump ATPase, which generates an electrochemical proton gradient, the driving force of the transport. The major source of ATP is likely to be supplied by glycolytic vesicle-bound enzymes, glyceraldehyde 3-phosphate dehydrogenase, and 3-phosphoglycerate kinase, rather than by mitochondrial ATP synthase. The VGLUT substrate glutamate is proposed to be synthesized by vesicle-bound aspartate amino transferase from α-ketoglutarate, not directly from glutamine. VGLUT has three isoforms, and gaged by their distributions they perform different physiological functions. The mechanism and regulation of vesicular glutamate uptake are discussed. The pharmacology of vesicular glutamate uptake is a developing field of inquiry.
Topics: Amino Acid Transport System X-AG; Animals; Biological Transport; Glutamic Acid; Humans; Synaptic Transmission; Synaptic Vesicles; Vacuolar Proton-Translocating ATPases
PubMed: 27885630
DOI: 10.1007/978-3-319-45096-4_7 -
European Journal of Pharmacology Apr 2022Phosphoglycerate kinase 1 (PGK1) is an essential enzyme that catalyzes adenosine 5'-triphosphate (ATP) production in aerobic glycolysis. In addition to regulating cell... (Review)
Review
Phosphoglycerate kinase 1 (PGK1) is an essential enzyme that catalyzes adenosine 5'-triphosphate (ATP) production in aerobic glycolysis. In addition to regulating cell metabolism, PGK1 is involved in multiple biological activities, including angiogenesis, mediated autophagy starting, binding of plasminogen, the DNA replication and repair, the proliferation and metastasis of tumor cells, cell invasion (a part of the flagellar axoneme and viral replication and it occurs mainly in protists), and is also associated with resistance to chemotherapy and prognosis of cancer patients. In this review, we focus on the basic functions of PGK1 and the relationship between PGK1 and different diseases, indicating that PGK1 has a broad application prospect to find a potential biomarker for tumor prognosis and an effective inhibitor.
Topics: Adenosine Triphosphate; Cell Line, Tumor; Glycolysis; Humans; Neoplasms; Phosphoglycerate Kinase; Prognosis
PubMed: 35183535
DOI: 10.1016/j.ejphar.2022.174835 -
Movement Disorders : Official Journal... Oct 2021Preclinical and epidemiological data suggest that phosphoglycerate kinase 1 activators could have neuroprotective properties and prevent PD.
BACKGROUND
Preclinical and epidemiological data suggest that phosphoglycerate kinase 1 activators could have neuroprotective properties and prevent PD.
OBJECTIVES
The objective of this study was to compare the association between increased use of phosphoglycerate kinase 1 activators and increased use of tamsulosin with PD incidence.
METHODS
Our retrospective cohort study included men older than age 66 years newly exposed to phosphoglycerate kinase 1 activators or tamsulosin and compared their PD incidence, using health care administrative data of Ontario, Canada.
RESULTS
Among 265,745 men, each additional year of cumulative use of phosphoglycerate kinase 1 activators or tamsulosin was associated with 6% and 8% reduction, respectively, in the hazard of PD incidence. These hazards were not significantly different (P = 0.2094). A secondary analysis with the observation window starting after 6 months and 1 and 2 years showed similar results.
CONCLUSIONS
Increasing exposure to phosphoglycerate kinase 1 activators and tamsulosin were both associated with small reductions in PD incidence. These results support further investigation of phosphoglycerate kinase 1 activators and tamsulosin for possible PD disease-modifying properties. © 2021 International Parkinson and Movement Disorder Society.
Topics: Aged; Humans; Incidence; Male; Ontario; Parkinson Disease; Phosphoglycerate Kinase; Retrospective Studies
PubMed: 34241922
DOI: 10.1002/mds.28712 -
Cell Cycle (Georgetown, Tex.) Jun 2019Mature human erythrocytes are dependent on anerobic glycolysis, i.e. catabolism (oxidation) of one glucose molecule to produce two ATP and two lactate molecules.... (Review)
Review
Mature human erythrocytes are dependent on anerobic glycolysis, i.e. catabolism (oxidation) of one glucose molecule to produce two ATP and two lactate molecules. Proliferating tumor cells mimick mature human erythrocytes to glycolytically generate two ATP molecules. They deliberately avoid or switch off their respiration, i.e. tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) machinery and consequently dispense with the production of additional 36 ATP molecules from one glucose molecule. This phenomenon is named aerobic glycolysis or Warburg effect. The present review deals with the fate of a glucose molecule after entering a mature human erythrocyte or a proliferating tumor cell and describes why it is useful for a proliferating tumor cell to imitate a mature erythrocyte. Blood consisting of plasma and cellular components (99% of the cells are erythrocytes) may be regarded as a mobile organ, constantly exercising a direct interaction with other organs. Therefore, the use of drugs, which influences the biological activity of erythrocytes, has an immediate effect on the entire organism. : TCA: tricarboxylic acid cycle; OXPHOS: oxidative phosphorylation; GSH: reduced state of glutathione; NFκB: Nuclear factor of kappa B; PKB (Akt): protein kinase B; NOS: nitric oxide synthase; IgG: immune globulin G; HS: hydrogen sulfide; slanDCs: Human 6-sulfo LacNAc-expressing dendritic cells; IL-8: interleukin-8; LPS: lipopolysaccharide; ROS: reactive oxygen species; PPP: pentose phosphate pathway; NADPH: nicotinamide adenine dinucleotide phosphate hydrogen; R5P: ribose-5-phophate; NAD: nicotinamide adenine dinucleotide; FAD: flavin adenine dinucleotide; O: superoxide anion; G6P: glucose 6-phosphate; HbO: Oxyhemoglobin; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GAP: glyceraldehyde-3-phosphate; 1,3-BPG: 1,3-bis-phosphoglycerate; 2,3-BPG: 2,3-bisphosphoglycerte; PGAM1: phosphoglycerate mutase 1; 3-PG: 3-phosphoglycerate; 2-PG: 2-phosphoglycerate; MIPP1: Multiple inositol polyphosphate phosphatase; mTORC1: mammalian target of rapamycin complex 1; Ru5P: ribulose 5-phosphate; ox-PPP: oxidative branch of pentose phosphate pathway; PGK: phosphoglycerate kinase; IFN-γ: interferon-γ; LDH: lactate dehydrogenase; STAT3: signal transducer and activator of transcription 3; Rheb: Ras homolog enriched in Brain; HO: hydrogen peroxide; ROOH: lipid peroxide; SOD: superoxide dismutase; MRC: mitochondrial respiratory chain; MbFe-O: methmyoglobin; RNR: ribonucleotide reductase; PRPP: phosphoribosylpyrophosphate; PP: pyrophosphate; GSSG: oxidized state of glutathione; non-ox-PPP: non-oxidative branch of pentose phosphate pathway; RPI: ribose-5-phosphate isomerase; RPE: ribulose 5-phosphate 3-epimerase; X5P: xylulose 5-phosphate; TK: transketolase; TA: transaldolase; F6P: fructose-6-phosphate; AR2: aldose reductase 2; SD: sorbitol dehydrogenase; HK: hexokinase; MG: mehtylglyoxal; DHAP: dihydroxyacetone phosphate; TILs: tumor-infiltrating lymphocytes; MCTs: monocarboxylate transporters; pHi: intracellular pH; Hif-1α: hypoxia-induced factor 1; NHE1: sodium/H (Na/H) antiporter 1; V-ATPase: vacuolar-type proton ATPase; CAIX: carbonic anhydrase; CO: carbon dioxide; HCO: bicarbonate; NBC: sodium/bicarbonate (Na/HCO) symporter; pHe: extracellular pH; GLUT-1: glucose transporter 1; PGK-1: phosphoglycerate kinase 1.
Topics: Carcinogenesis; Cell Proliferation; Erythrocytes; Glucose; Glycolysis; Humans; Neoplasms
PubMed: 31154896
DOI: 10.1080/15384101.2019.1618125 -
Open Biology Nov 2020Phosphoglycerate kinase (PGK) is a glycolytic enzyme that is well conserved among the three domains of life. PGK is usually a monomeric enzyme of about 45 kDa that... (Review)
Review
Phosphoglycerate kinase (PGK) is a glycolytic enzyme that is well conserved among the three domains of life. PGK is usually a monomeric enzyme of about 45 kDa that catalyses one of the two ATP-producing reactions in the glycolytic pathway, through the conversion of 1,3-bisphosphoglycerate (1,3BPGA) to 3-phosphoglycerate (3PGA). It also participates in gluconeogenesis, catalysing the opposite reaction to produce 1,3BPGA and ADP. Like most other glycolytic enzymes, PGK has also been catalogued as a moonlighting protein, due to its involvement in different functions not associated with energy metabolism, which include pathogenesis, interaction with nucleic acids, tumorigenesis progression, cell death and viral replication. In this review, we have highlighted the overall aspects of this enzyme, such as its structure, reaction kinetics, activity regulation and possible moonlighting functions in different protistan organisms, especially both free-living and parasitic Kinetoplastea. Our analysis of the genomes of different kinetoplastids revealed the presence of open-reading frames (ORFs) for multiple PGK isoforms in several species. Some of these ORFs code for unusually large PGKs. The products appear to contain additional structural domains fused to the PGK domain. A striking aspect is that some of these PGK isoforms are predicted to be catalytically inactive enzymes or 'dead' enzymes. The roles of PGKs in kinetoplastid parasites are analysed, and the apparent significance of the PGK gene duplication that gave rise to the different isoforms and their expression in is discussed.
Topics: Binding Sites; Catalysis; Enzyme Activation; Evolution, Molecular; Gene Expression Regulation, Enzymologic; Humans; Kinetoplastida; Models, Molecular; Phosphoglycerate Kinase; Phylogeny; Protein Binding; Protein Conformation; Structure-Activity Relationship; Substrate Specificity
PubMed: 33234025
DOI: 10.1098/rsob.200302 -
Science China. Life Sciences Feb 2022The changes associated with malignancy are not only in cancer cells but also in environment in which cancer cells live. Metabolic reprogramming supports tumor cell high... (Review)
Review
The changes associated with malignancy are not only in cancer cells but also in environment in which cancer cells live. Metabolic reprogramming supports tumor cell high demand of biogenesis for their rapid proliferation, and helps tumor cell to survive under certain genetic or environmental stresses. Emerging evidence suggests that metabolic alteration is ultimately and tightly associated with genetic changes, in particular the dysregulation of key oncogenic and tumor suppressive signaling pathways. Cancer cells activate HIF signaling even in the presence of oxygen and in the absence of growth factor stimulation. This cancer metabolic phenotype, described firstly by German physiologist Otto Warburg, insures enhanced glycolytic metabolism for the biosynthesis of macromolecules. The conception of metabolite signaling, i.e., metabolites are regulators of cell signaling, provides novel insights into how reactive oxygen species (ROS) and other metabolites deregulation may regulate redox homeostasis, epigenetics, and proliferation of cancer cells. Moreover, the unveiling of noncanonical functions of metabolic enzymes, such as the moonlighting functions of phosphoglycerate kinase 1 (PGK1), reassures the importance of metabolism in cancer development. The metabolic, microRNAs, and ncRNAs alterations in cancer cells can be sorted and delivered either to intercellular matrix or to cancer adjacent cells to shape cancer microenvironment via media such as exosome. Among them, cancer microenvironmental cells are immune cells which exert profound effects on cancer cells. Understanding of all these processes is a prerequisite for the development of a more effective strategy to contain cancers.
Topics: Cancer-Associated Fibroblasts; Disease Progression; Epigenesis, Genetic; Exosomes; Humans; Neoplasms; Oncogenes; Oxidation-Reduction; Phosphoglycerate Kinase; RNA, Untranslated; Signal Transduction; T-Lymphocytes; Tumor Microenvironment; Warburg Effect, Oncologic
PubMed: 34846643
DOI: 10.1007/s11427-021-1999-2