-
Life Sciences Sep 2020Phosphoglycerate kinase 1 (PGK1) is the first critical enzyme to produce ATP in the glycolytic pathway. PGK1 is not only a metabolic enzyme but also a protein kinase,... (Review)
Review
Phosphoglycerate kinase 1 (PGK1) is the first critical enzyme to produce ATP in the glycolytic pathway. PGK1 is not only a metabolic enzyme but also a protein kinase, which mediates the tumor growth, migration and invasion through phosphorylation some important substrates. Moreover, PGK1 is associated with poor treatment and prognosis of cancers. This manuscript reviews the structure, functions, post-translational modifications (PTMs) of PGK1 and its relationship with tumors, which demonstrates that PGK1 has indispensable value in the tumor progression. The current review highlights the important role of PGK1 in anticancer treatments.
Topics: Disease Progression; Humans; Neoplasms; Phosphoglycerate Kinase; Phosphorylation; Prognosis; Protein Processing, Post-Translational
PubMed: 32479953
DOI: 10.1016/j.lfs.2020.117863 -
Plant Physiology Oct 2023Autophagy serves as an important recycling route for the growth and survival of eukaryotic organisms in nutrient-deficient conditions. Since starvation induces massive...
Autophagy serves as an important recycling route for the growth and survival of eukaryotic organisms in nutrient-deficient conditions. Since starvation induces massive changes in the metabolic flux that are coordinated by key metabolic enzymes, specific processing steps of autophagy may be linked with metabolic flux-monitoring enzymes. We attempted to identify carbon metabolic genes that modulate autophagy using VIGS screening of 45 glycolysis- and Calvin-Benson cycle-related genes in Arabidopsis (Arabidopsis thaliana). Here, we report that three consecutive triose-phosphate-processing enzymes involved in cytosolic glycolysis, triose-phosphate-isomerase (TPI), glyceraldehyde-3-phosphate dehydrogenase (GAPC), and phosphoglycerate kinase (PGK), designated TGP, negatively regulate autophagy. Depletion of TGP enzymes causes spontaneous autophagy induction and increases AUTOPHAGY-RELATED 1 (ATG1) kinase activity. TGP enzymes interact with ATG101, a regulatory component of the ATG1 kinase complex. Spontaneous autophagy induction and abnormal growth under insufficient sugar in TGP mutants are suppressed by crossing with the atg101 mutant. Considering that triose-phosphates are photosynthates transported to the cytosol from active chloroplasts, the TGP enzymes would be strategically positioned to monitor the flow of photosynthetic sugars and modulate autophagy accordingly. Collectively, these results suggest that TGP enzymes negatively control autophagy acting upstream of the ATG1 complex, which is critical for seedling development.
Topics: Cytosol; Autophagy; Arabidopsis; Glycolysis; Phosphates; Trioses; Glyceraldehyde-3-Phosphate Dehydrogenases
PubMed: 37539947
DOI: 10.1093/plphys/kiad439 -
Communications Biology Sep 2022Unconjugated bilirubin (UCB) confers Th17-cells immunosuppressive features by activating aryl-hydrocarbon-receptor, a modulator of toxin and adaptive immune responses....
Unconjugated bilirubin (UCB) confers Th17-cells immunosuppressive features by activating aryl-hydrocarbon-receptor, a modulator of toxin and adaptive immune responses. In Crohn's disease, Th17-cells fail to acquire regulatory properties in response to UCB, remaining at an inflammatory/pathogenic state. Here we show that UCB modulates Th17-cell metabolism by limiting glycolysis and through downregulation of glycolysis-related genes, namely phosphoglycerate-kinase-1 (PGK1) and aldolase-A (ALDOA). Th17-cells of Crohn's disease patients display heightened PGK1 and ALDOA and defective response to UCB. Silencing of PGK1 or ALDOA restores Th17-cell response to UCB, as reflected by increase in immunoregulatory markers like FOXP3, IL-10 and CD39. In vivo, PGK1 and ALDOA silencing enhances UCB salutary effects in trinitro-benzene-sulfonic-acid-induced colitis in NOD/scid/gamma humanized mice where control over disease activity and enhanced immunoregulatory phenotypes are achieved. PGK1 and/or ALDOA blockade might have therapeutic effects in Crohn's disease by favoring acquisition of regulatory properties by Th17-cells along with control over their pathogenic potential.
Topics: Animals; Benzene; Bilirubin; Crohn Disease; Forkhead Transcription Factors; Fructose-Bisphosphate Aldolase; Humans; Interleukin-10; Mice; Mice, Inbred NOD; Phosphoglycerate Kinase; Th17 Cells
PubMed: 36131123
DOI: 10.1038/s42003-022-03913-9 -
Pleura and Peritoneum Mar 2019Detachment of cells from the extracellular matrix into the peritoneal cavity initiates a cascade of metabolic alterations, leading usually to cell death by apoptosis,... (Review)
Review
Detachment of cells from the extracellular matrix into the peritoneal cavity initiates a cascade of metabolic alterations, leading usually to cell death by apoptosis, so-called . Glycolytic enzymes enable the switch from oxidative phosphorylation to aerobic glycolysis and allow resistance to anoikis of shed tumour cells. These enzymes also have moonlighting activities as protein kinases and transcription factors. Phosphoglycerate kinase (PGK) and pyruvate kinase are the only glycolytic enzymes generating ATP in the hexokinase pathway. Hypoxia, EGFR activation, expression of K-Ras G12V and B-Raf V600E induce mitochondrial translocation of phosphoglycerate kinase 1 (PGK1). Mitochondrial PGK1 acts as a protein kinase to phosphorylate pyruvate dehydrogenase kinase 1 (PDHK1), reducing mitochondrial pyruvate utilization, suppressing reactive oxygen species production, increasing lactate production and promoting tumourigenesis. PGK1 also plays a role as a transcription factor once transported into the nucleus. Resistance to anoikis is also facilitated by metabolic support provided by cancer-associated fibroblasts (CAFs). Our series of experiments in-vitro and in the animal model showed that PGK1 knock-out or inhibition is effective in controlling development and growth of peritoneal metastasis (PM) of gastric origin, establishing a causal role of PGK1 in this development. PGK1 also increases CXCR4 and CXCL12 expression, which is associated with a metastatic phenotype and plays a role in the metastatic homing of malignant cells. Thus, PGK1, its modulators and target genes may be exploited as therapeutic targets for preventing development of PM and for enhancing cytotoxic effects of conventional systemic chemotherapy.
PubMed: 31198853
DOI: 10.1515/pp-2019-0003 -
Microorganisms Aug 2023Gossypol, generally found in the roots, stems, leaves, and, especially, the seeds of cotton plants, is highly toxic to animals and humans, which inhibits the use of...
Gossypol, generally found in the roots, stems, leaves, and, especially, the seeds of cotton plants, is highly toxic to animals and humans, which inhibits the use of cotton stalks as a feed resource. Here, a promising fungal strain for biodegrading gossypol was successfully isolated from the soil of cotton stalk piles in Xinjiang Province, China, and identified as -YJ01 with the analysis of ITS. Initial gossypol of 250 mg·L could be removed by 97% within 96 h by YJ01, and initial gossypol of 150 mg·L could also be catalyzed by 98% or 99% within 36 h by the intracellular or extracellular crude enzymes of YJ01. Sucrose and sodium nitrate were found to be the optimal carbon and nitrogen sources for the growth of YJ01, and the optimal initial pH and inoculum size for the growth of YJ01 were 6.0 and 1%, respectively. To further elucidate the mechanisms underlying gossypol biodegradation by YJ01, the draft genome of YJ01 was sequenced using Illumina HiSeq, which is 31,566,870 bp in length with a GC content of 52.27% and a total of 9737 genes. Eight genes and enzymes were predicted to be involved in gossypol biodegradation. Among them, phosphoglycerate kinase, citrate synthase, and other enzymes are related to the energy supply process. With sufficient energy, β-1, 4-endo-xylanase may achieve the purpose of biodegrading gossypol. The findings of this study provide valuable insights into both the basic research and the application of -YJ01 in the biodegradation of gossypol in cotton stalks.
PubMed: 37763992
DOI: 10.3390/microorganisms11092148 -
BioRxiv : the Preprint Server For... Oct 2023Phosphoglycerate kinase 1 (PGK1), the first ATP producing glycolytic enzyme, has emerged as a therapeutic target for Parkinson's Disease (PD), since a potential enhancer...
Phosphoglycerate kinase 1 (PGK1), the first ATP producing glycolytic enzyme, has emerged as a therapeutic target for Parkinson's Disease (PD), since a potential enhancer of its activity was reported to significantly lower PD risk. We carried out a suppressor screen of hypometabolic synaptic deficits and demonstrated that PGK1 is a rate limiting enzyme in nerve terminal ATP production. Increasing PGK1 expression in mid-brain dopamine neurons protected against hydroxy-dopamine driven striatal dopamine nerve terminal dysfunction and modest changes in PGK1 activity dramatically suppressed hypometabolic synapse dysfunction . Furthermore, PGK1 is cross-regulated by PARK7 (DJ-1), a PD associated molecular chaperone, and synaptic deficits driven by PARK20 (Synaptojanin-1) can be reversed by increasing local synaptic PGK1 activity. These data indicate that nerve terminal bioenergetic deficits may underly a spectrum of PD susceptibilities and the identification of PGK1 as the limiting enzyme in axonal glycolysis provides a mechanistic underpinning for therapeutic protection.
PubMed: 37873141
DOI: 10.1101/2023.10.10.561760 -
Aging Oct 2022Phosphoglycerate kinase 1 (PGK1) is a metabolic enzyme that converts 1,3-diphosphoglycerate to 3-phosphoglycerate. In the current study, we synthesized a PEP-1-PGK1...
Phosphoglycerate kinase 1 (PGK1) is a metabolic enzyme that converts 1,3-diphosphoglycerate to 3-phosphoglycerate. In the current study, we synthesized a PEP-1-PGK1 fusion protein that can cross the blood-brain barrier and cell membrane, and the effects of PEP-1-PGK1 against oxidative stress were investigated HT22 cells and ischemic gerbil brain. The PEP-1-PGK1 protein and its control protein (Con-PGK1) were treated and permeability was evaluated HT22 cells. The PEP-1-PGK1 was introduced into HT22 cells depending on its concentration and incubation time and was gradually degraded over 36 h after treatment. PEP-1-PGK1, but not Con-PGK1, significantly ameliorated HO-induced cell damage and reactive oxygen species formation in HT22 cells. Additionally, PEP-1-PGK1, but not Con-PGK1, mitigated ischemia-induced hyperlocomotion 1 d after ischemia and 4 d after ischemia of neuronic cell death. PEP-1-PGK1 treatment significantly alleviated the raised lactate and succinate dehydrogenase activities in the early (15 min to 6 h) and late (4 and 7 d) stages of ischemia, respectively. In addition, PEP-1-PGK1 treatment ameliorated the decrease in ATP and pH levels in the late stage (2-7 d) of ischemia. Nuclear factor erythroid-2-related factor 2 (Nrf2) levels accelerated the ischemia-induced increase in the hippocampus 1 d after ischemia after PEP-1-PGK1 treatment. Neuroprotective and ameliorative effects were prominent at a low concentration (0.1 mg/kg), but not at a high concentration (1 mg/kg), of PEP-1-PGK1. Collectively, low concentrations of PEP-1-PGK1 prevented neuronal stress by increasing energy production.
Topics: Animals; Gerbillinae; Phosphoglycerate Kinase; Hydrogen Peroxide; Hippocampus; Ischemia; Oxidative Stress
PubMed: 36260875
DOI: 10.18632/aging.204343 -
Cellular Signalling Sep 2023As a hallmark for cancer, aerobic glycolysis, also known as the Warburg effect contributes to tumor progression. However, the roles of aerobic glycolysis on cervical...
As a hallmark for cancer, aerobic glycolysis, also known as the Warburg effect contributes to tumor progression. However, the roles of aerobic glycolysis on cervical cancer remain elusive. In this work, we identified transcription factor HOXA1 as a novel regulator of aerobic glycolysis. High expression of HOXA1 is closely associated with poor outcome of patients. And, altered HOXA1 expression enhance or reduce aerobic glycolysis and progression in cervical cancer. Mechanistically, HOXA1 directly regulates the transcriptional activity of ENO1 and PGK1, thus induce glycolysis and promote cancer progression. Moreover, therapeutic knockdown of HOXA1 results in reduce aerobic glycolysis and inhibits cervical cancer progression in vivo and in vitro. In conclusion, these data indicate a therapeutic role of HOXA1 inhibits aerobic glycolysis and cervical cancer progression.
Topics: Transcription Factors; Homeodomain Proteins; Warburg Effect, Oncologic; Uterine Cervical Neoplasms; Humans; HeLa Cells; Mice, Inbred BALB C; Female; Animals; Mice; DNA-Binding Proteins; Phosphopyruvate Hydratase; Biomarkers, Tumor; Tumor Suppressor Proteins; Phosphoglycerate Kinase; Gene Expression Regulation, Neoplastic; Xenograft Model Antitumor Assays
PubMed: 37286120
DOI: 10.1016/j.cellsig.2023.110747 -
Protein Expression and Purification Apr 2017Phosphoglycerate kinase (PGK) is a glycolytic enzyme present in many parasites. It has been reported as a candidate molecule for drug and vaccine developments. In the...
Phosphoglycerate kinase (PGK) is a glycolytic enzyme present in many parasites. It has been reported as a candidate molecule for drug and vaccine developments. In the present study, a full-length cDNA encoding the Brugia malayi 3-phosphoglycerate kinase (BmPGK) with an open reading frame of 1.3 kb was isolated and PCR amplified and cloned. The exact size of the BmPGK's ORF is 1377 bps. The BmPGK gene was subcloned into pET-28a (+) expression vector, the expressed enzyme was purified by affinity column and characterized. The SDS-PAGE analysis revealed native molecular weight of recombinant Brugia malayi 3-phosphoglycerate kinase (rBmPGK) to be ∼45 kDa. The enzyme was found sensitive to temperature and pH, it showed maximum activity at 25 °C and pH 8.5. The K values for PGA and ATP were 1.77 and 0.967 mM, respectively. The PGK inhibitor, clorsulon and antifilarial drugs albendazole and ivermectin inhibited the enzyme. The specific inhibitor of PGK, clorsulon, competitively inhibited enzyme with K value 1.88 μM. Albendazole also inhibited PGK competitively with K value 35.39 μM. Further these inhibitory studies were confirmed by docking and molecular simulation of drugs with enzyme. Clorsulon interacted with substrate binding site with glutamine 37 as well as in hinge regions with aspartic acid 385 and valine 387 at ADP binding site. On the other hand albendazole interacted with asparagine 335 residues. These effects were in good association with binding interactions. Thus current study might help in designing and synthesis of effective inhibitors for this novel drug target and understanding their mode of interaction with the potent anthelmintic drugs.
Topics: Animals; Brugia malayi; Cloning, Molecular; Escherichia coli; Gene Expression; Helminth Proteins; Open Reading Frames; Phosphoglycerate Kinase; Recombinant Proteins
PubMed: 28192198
DOI: 10.1016/j.pep.2017.02.005 -
Neuroscience Aug 2023Understanding the role and mechanism of astrocytes in inflammation and oxidative response is crucial for developing therapeutic strategies to reduce inflammation and...
Downregulated Phosphoglycerate Kinase 1 Attenuates Cerebral Ischemia-Reperfusion Injury by Reversing Neuroinflammation and Oxidative Stress through the Nuclear Factor Erythroid 2 Related Factor 2/ARE Pathway.
Understanding the role and mechanism of astrocytes in inflammation and oxidative response is crucial for developing therapeutic strategies to reduce inflammation and oxidative injury in cerebral ischemia-reperfusion injury (CIRI). In this study, we investigated the regulatory effects of phosphoglycerate kinase 1 (PGK1) on inflammation and oxidative response after CIRI in male adult Sprague-Dawley (SD) rats and using primary astrocytes obtained from neonatal SD rats, and explored its related mechanisms. We established a rat model of middle cerebral artery occlusion-reperfusion (MCAO/R) by suture occlusion, and an oxygen-glucose deprivation/reoxygenation model of astrocytes using oxygen-free, glucose-free, and serum-free cultures. AAV8-PGK1-GFP was injected into the left ventricle 24 h before modeling. Real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, co-immunoprecipitation (CoIP) assay, fluorescence in situ hybridization (FISH), and western blotting were used to elucidate the in-depth mechanisms of PGK1 in CIRI. PGK1 overexpression significantly exacerbated neurological deficits, increased cerebral infarct volume, and aggravated nerve cell injury in rats after MCAO/R. Using FISH and CoIP assays, we verified the localization of PGK1 and Nrf2 in primary astrocytes. Further rescue experiments showed that Nrf2 knockdown eliminated the protective effect of CBR-470-1 (a PGK1 inhibitor) on CIRI. Lastly, we confirmed that PGK1 aggravates CIRI by inhibiting the Nrf2/ARE pathway. In conclusion, our findings suggest that inhibiting PGK1 attenuates CIRI by reducing the release of inflammatory and oxidative factors from astrocytes by activating the Nrf2/ARE signaling pathway.
Topics: Rats; Male; Animals; Rats, Sprague-Dawley; Phosphoglycerate Kinase; Neuroinflammatory Diseases; NF-E2-Related Factor 2; In Situ Hybridization, Fluorescence; Oxidative Stress; Infarction, Middle Cerebral Artery; Reperfusion Injury; Brain Ischemia
PubMed: 37295596
DOI: 10.1016/j.neuroscience.2023.05.019