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Cancer Genomics & Proteomics Dec 2023Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer worldwide, with a high recurrence rate and a low cure rate. Phosphoglycerate kinase 1 (PGK1),...
BACKGROUND/AIM
Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer worldwide, with a high recurrence rate and a low cure rate. Phosphoglycerate kinase 1 (PGK1), an essential enzyme in the aerobic glycolysis pathway, is a prognostic marker for a variety of cancers. However, it remains unclear whether a PGK1-based immune signature can be used as a prognostic biomarker in HNSCC patients.
MATERIALS AND METHODS
We explored the potential oncogenic mechanisms of PGK1 by multiple bioinformatics analyses combined with multiple databases, including the correlation between PGK1 and prognosis, and the infiltration of immune cells in HNSCC. Functional enrichment analyses were further performed to investigate the potential role of PGK1 in HNSCC.
RESULTS
The expression of PGK1 was significantly higher in HNSCC tissues compared to normal tissues. High expression of PGK1 was associated with poor prognosis in HNSCC, and multivariate cox regression analysis showed that PGK1 could be an independent prognostic factor in HNSCC. Pathway analysis revealed that PGK1 may regulate the pathogenesis of HNSCC through the immune signaling pathway. Moreover, PGK1 expression significantly correlated with the infiltration level of 16 types of immune cells.
CONCLUSION
The current study reports that PGK1 expression was increased in HNSCC and that high PGK1 expression was closely associated with poor prognosis and immune cell infiltration, which could serve as a promising independent prognostic biomarker and potential immunotherapeutic target for HNSCC.
Topics: Humans; Biomarkers; Head and Neck Neoplasms; Prognosis; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Phosphoglycerate Kinase
PubMed: 38035710
DOI: 10.21873/cgp.20419 -
FEBS Letters Jun 2013Domain motions are essential to many catalytic mechanisms in enzymes but they are often difficult to study. X-ray crystal structures can provide molecular details of... (Review)
Review
Domain motions are essential to many catalytic mechanisms in enzymes but they are often difficult to study. X-ray crystal structures can provide molecular details of snapshots of catalysis but many states important in the cycle remain inaccessible using this technique. Phosphoglycerate kinase (PGK) undergoes large domain movements in order to catalyse the production of ATP. PGK is the enzyme responsible for the first ATP generating step of glycolysis and has been implicated in oncogenesis and the in vivo activation of l-nucleoside pro-drugs effective against retroviruses. Its mechanism requires considerable hinge bending to bring the substrates into proximity in order for phosphoryl transfer to occur. The enzyme has been the subject of intense study for decades but new crystal structures, methods in solution scattering and modelling techniques are throwing light on the dynamics of catalysis of this archetypal kinase. Here, I argue that Brownian forces acting on the protein are the dominant factor in the catalytic cycle and that the enzyme has evolved measures to harness this force for efficient catalysis.
Topics: Catalytic Domain; Humans; Models, Molecular; Phosphoglycerate Kinase; Phosphorylation; Protein Structure, Secondary; Surface Properties
PubMed: 23684636
DOI: 10.1016/j.febslet.2013.05.012 -
Journal of Inherited Metabolic Disease Sep 2019Phosphoglycerate kinase (PGK) deficiency is a rare X-linked metabolic disorder caused by mutations in the PGK1 gene. Patients usually develop various combinations of... (Observational Study)
Observational Study
Phosphoglycerate kinase (PGK) deficiency is a rare X-linked metabolic disorder caused by mutations in the PGK1 gene. Patients usually develop various combinations of nonspherocytic hemolytic anemia (NSHA), myopathy, and central nervous system disorders. In this national multicenter observational retrospective study, we recorded all known French patients with PGK deficiency, and 3 unrelated patients were identified. Case 1 was a 32-year-old patient with severe chronic axonal sensorimotor polyneuropathy resembling Charcot-Marie-Tooth (CMT) disease, mental retardation, microcephaly, ophthalmoplegia, pes cavus, and the new c.323G > A PGK1 hemizygous mutation. Case 2 was a 71-year-old patient with recurrent exertional rhabdomyolysis, and a c.943G > A PGK1 hemizygous mutation. Case 3 was a 48-year-old patient with NSHA, retinitis pigmentosa, mental retardation, seizures, stroke, parkinsonism, and a c.491A > T PGK1 hemizygous mutation. This study confirms that PGK deficiency is an extremely rare disorder with a wide phenotypic spectrum, and demonstrates for the first time that PGK deficiency may affect the peripheral nervous system and present as a CMT-like disorder.
Topics: Adult; Aged; France; Genetic Diseases, X-Linked; Humans; Male; Metabolism, Inborn Errors; Middle Aged; Mutation; Phosphoglycerate Kinase; Retrospective Studies
PubMed: 30887539
DOI: 10.1002/jimd.12087 -
Ryoikibetsu Shokogun Shirizu 2001
Review
Topics: Diagnosis, Differential; Humans; Intellectual Disability; Muscular Diseases; Mutation; Phosphoglycerate Kinase; Prognosis; X Chromosome
PubMed: 11596414
DOI: No ID Found -
Ryoikibetsu Shokogun Shirizu 1998
Review
Topics: Anemia, Hemolytic; Central Nervous System Diseases; Humans; Muscular Diseases; Mutation; Phosphoglycerate Kinase; Prognosis
PubMed: 9589992
DOI: No ID Found -
Methods in Enzymology 1975
Topics: Amino Acids; Catalysis; Chemical Phenomena; Chemistry; Chloroform; Chromatography; Chromatography, Gel; Crystallization; Erythrocytes; Ethanol; Fractional Precipitation; Hemoglobins; Hemolysis; Humans; Kinetics; Methods; Molecular Weight; Phosphoglycerate Kinase; Spectrophotometry
PubMed: 1134351
DOI: 10.1016/0076-6879(75)42108-5 -
Biochimie 1990Flexibility and folding of phosphoglycerate kinase, a two-domain monomeric enzyme, have been studied using a wide variety of methods including theoretical approaches.... (Review)
Review
Flexibility and folding of phosphoglycerate kinase, a two-domain monomeric enzyme, have been studied using a wide variety of methods including theoretical approaches. Mutants of yeast phosphoglycerate kinase have been prepared in order to introduce cysteinyl residues as local probes throughout the molecule without perturbating significantly the structural or the functional properties of the enzyme. The apparent reactivity of a unique cysteine in each mutant has been used to study the flexibility of PGK. The regions of larger mobility have been found around residue 183 on segment beta F in the N-domain and residue 376 on helix XII in the C-domain. These regions are also parts of the molecule which unfold first. Ligand binding induces conformational motions in the molecule, especially in the regions located in the cleft. Moreover, the results obtained by introducing a fluorescent probe covalently linked to a cysteine are in agreement with the helix scissor motion of helices 7 and 14 assumed by Blake to direct the hinge bending motion of the domains during the catalytic cycle. The folding process of both horse muscle and yeast phosphoglycerate kinases involves intermediates. These intermediates are more stable in the horse muscle than in the yeast enzyme. In both enzymes, domains behave as structural modules capable of folding and stabilizing independently, but in the horse muscle enzyme the C-domain is more stable and refolds prior to the N-domain, contrary to that which has been observed in the yeast enzyme. A direct demonstration of the independence of domains in yeast phosphoglycerate kinase has been provided following the obtention of separated domains by site-directed mutagenesis. These domains have a native-like structure and refold spontaneously after denaturation by guanidine hydrochloride.
Topics: Animals; Binding Sites; Horses; Models, Molecular; Mutagenesis, Site-Directed; Phosphoglycerate Kinase; Protein Conformation; Protein Denaturation; Saccharomyces cerevisiae
PubMed: 2124145
DOI: 10.1016/0300-9084(90)90066-p -
Photosynthesis Research Aug 2022As chloroplast phosphoglycerate kinase (cpPGK) is one of the enzymes which has the highest capacity among the Calvin-Benson cycle enzymes, it has not been regarded as a...
As chloroplast phosphoglycerate kinase (cpPGK) is one of the enzymes which has the highest capacity among the Calvin-Benson cycle enzymes, it has not been regarded as a determinant for photosynthetic capacity. However, it was reported that the rate of CO assimilation decreased under high irradiance and normal [CO] levels in the Arabidopsis cpPGK-knockdown mutant, implying that cpPGK has a control over photosynthetic capacity at a normal [CO] level. In the present study, the contribution of cpPGK to photosynthetic capacity was evaluated in transgenic rice plants with decreased amounts of cpPGK protein under high irradiance and various [CO] levels. The gene encoding cpPGK was suppressed using RNA interference techniques. Two lines of transgenic plants, Pi3 and Pi5, in which the amount of cpPGK protein decreased to 21% and 76% of that in wild-type plants, respectively, were obtained. However, there was no substantial difference in the rates of CO assimilation between wild-type and transgenic plants. The rates of CO assimilation decreased only slightly at elevated [CO] levels in the transgenic line Pi3 and did not differ between wild-type plants and the transgenic line Pi5, irrespective of [CO] level. These results clearly indicate that cpPGK does not have a strong control over photosynthetic capacity at various [CO] levels in rice.
Topics: Arabidopsis; Carbon Dioxide; Chloroplasts; Oryza; Phosphoglycerate Kinase; Photosynthesis; Plant Leaves; Plants, Genetically Modified
PubMed: 35635654
DOI: 10.1007/s11120-022-00923-w -
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 -
Journal of Translational Medicine Feb 2022Long noncoding RNA NEAT1 has been implicated in glioma progression. However, the effect of NEAT1 on glycolysis of glioma cell and the potential mechanism remain unclear.
BACKGROUND
Long noncoding RNA NEAT1 has been implicated in glioma progression. However, the effect of NEAT1 on glycolysis of glioma cell and the potential mechanism remain unclear.
METHODS
In vitro experiments, including CCK-8, colony formation, ECAR, and lactate detection assays were performed to evaluate the effect of NEAT1 on proliferation and glycolysis of glioma cell. RNA pulldown and RIP assays were performed to identify the interaction between NEAT1 and PGK1. Truncated mutation of NEAT1 and PGK1 was used to confirm the specific interactive domains between NEAT1 and PGK1. Animal studies were performed to analyze the effect of NEAT1/PGK1 on glioma progression.
RESULTS
NEAT1 knockdown significantly suppressed the proliferation and glycolysis of glioma cells. NEAT1 could specifically interact with PGK1, which promotes PGK1 stability. Hairpin A of NEAT1 is essential for interaction with M1 domain of PGK1. Depletion of NEAT1 markedly inhibited tumor growth in mice, while PGK1 could reverse this effect. Higher expression of NEAT1 was associated with poor overall survival of GBM patients.
CONCLUSIONS
NEAT1 over expression promotes glioma progression through stabilizing PGK1. NEAT1/PGK1 axis is a candidate therapeutic target for glioma treatment.
Topics: Animals; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Glioma; Humans; Mice; Phosphoglycerate Kinase; RNA, Long Noncoding
PubMed: 35123484
DOI: 10.1186/s12967-022-03273-2