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Ryoikibetsu Shokogun Shirizu 2001
Review
Topics: Diagnosis, Differential; Glycogen Storage Disease Type V; Humans; Mutation; Phosphoglycerate Mutase; Prognosis
PubMed: 11596425
DOI: No ID Found -
The Journal of Cell Biology Feb 2017Glycolytic enzymes are known to play pivotal roles in cancer cell survival, yet their molecular mechanisms remain poorly understood. Phosphoglycerate mutase 1 (PGAM1) is...
Glycolytic enzymes are known to play pivotal roles in cancer cell survival, yet their molecular mechanisms remain poorly understood. Phosphoglycerate mutase 1 (PGAM1) is an important glycolytic enzyme that coordinates glycolysis, pentose phosphate pathway, and serine biosynthesis in cancer cells. Herein, we report that PGAM1 is required for homologous recombination (HR) repair of DNA double-strand breaks (DSBs) caused by DNA-damaging agents. Mechanistically, PGAM1 facilitates DSB end resection by regulating the stability of CTBP-interacting protein (CtIP). Knockdown of PGAM1 in cancer cells accelerates CtIP degradation through deprivation of the intracellular deoxyribonucleotide triphosphate pool and associated activation of the p53/p73 pathway. Enzymatic inhibition of PGAM1 decreases CtIP protein levels, impairs HR repair, and hence sensitizes BRCA1/2-proficient breast cancer to poly(ADP-ribose) polymerase (PARP) inhibitors. Together, this study identifies a metabolically dependent function of PGAM1 in promoting HR repair and reveals a potential therapeutic opportunity for PGAM1 inhibitors in combination with PARP inhibitors.
Topics: A549 Cells; Animals; Apoptosis; BRCA1 Protein; BRCA2 Protein; Carrier Proteins; Cell Cycle; Cell Proliferation; Cell Survival; DNA Breaks, Double-Stranded; Deoxyribonucleotides; Dose-Response Relationship, Drug; Endodeoxyribonucleases; Female; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Mass Spectrometry; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Nuclear Proteins; Phosphoglycerate Mutase; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Protein Stability; Proteomics; RNA Interference; Recombinational DNA Repair; Time Factors; Transfection; Tumor Burden; Tumor Protein p73; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays
PubMed: 28122957
DOI: 10.1083/jcb.201607008 -
Neurochemistry International Jul 2022Phosphoglycerate mutase 5 (PGAM5), a glycolytic enzyme, plays an important role in cell death and regulation of mitochondrial dynamics. In this study, we investigated...
Phosphoglycerate mutase 5 (PGAM5), a glycolytic enzyme, plays an important role in cell death and regulation of mitochondrial dynamics. In this study, we investigated the effects of PGAM5 on oxidative stress in HT22 hippocampal cells and ischemic damage in the gerbil hippocampus to elucidate the role of PGAM5 in oxidative and ischemic stress. Constructs were designed with a PEP-1 expression vector to facilitate the intracellular delivery of PGAM5 proteins. We observed time- and concentration-dependent increases in the intracellular delivery of the PEP-1-PGAM5 protein, but not its control protein (PGAM5), in HT22 cells, and morphologically demonstrated the localization of the transduced protein, which was stably expressed in the cytoplasm after 12 h of PEP-1-PGAM5 treatment. PEP-1-PGAM5 treatment significantly ameliorated cell death, reactive oxygen species formation, DNA fragmentation, and the reduction of cell proliferation induced by HO treatment in HT22 cells. In addition, PEP-1-PGAM5 was effectively delivered to the gerbil hippocampus 8 h after treatment, and ischemia-induced hyperlocomotion and neuronal death in the hippocampal CA1 region were significantly alleviated 1 and 4 days after ischemia, respectively. Ischemia-induced microglial activation was also mitigated by treatment with 1.0 mg/kg PEP-1-PGAM5. At 3 h after ischemia, PEP-1-PGAM5 treatment significantly ameliorated the increase in lipid peroxidation, as assessed by malondialdehyde and hydroperoxide levels, and decreased glutathione levels (increases in glutathione disulfide, the oxidized form of glutathione) in the hippocampus. Two days after ischemia, treatment with PEP-1-PGAM5 significantly alleviated the ischemia-induced reduction in glutathione peroxidase activity and further increased superoxide dismutase activity in the hippocampus. The neuroprotective effects of PEP-1-PGAM5 are partially mediated by a reduction in oxidative stress, such as the formation of reactive oxygen species, and increases in the activity of antioxidants such as glutathione peroxidase and superoxide dismutase.
Topics: Animals; Antioxidants; Gerbillinae; Glutathione; Glutathione Peroxidase; Hippocampus; Hydrogen Peroxide; Ischemia; Neuroprotective Agents; Oxidative Stress; Phosphoglycerate Mutase; Reactive Oxygen Species; Superoxide Dismutase
PubMed: 35513204
DOI: 10.1016/j.neuint.2022.105346 -
Cancer Cell Nov 2012It is unclear how cancer cells coordinate glycolysis and biosynthesis to support rapidly growing tumors. We found that the glycolytic enzyme phosphoglycerate mutase 1...
It is unclear how cancer cells coordinate glycolysis and biosynthesis to support rapidly growing tumors. We found that the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1), commonly upregulated in human cancers due to loss of TP53, contributes to biosynthesis regulation in part by controlling intracellular levels of its substrate, 3-phosphoglycerate (3-PG), and product, 2-phosphoglycerate (2-PG). 3-PG binds to and inhibits 6-phosphogluconate dehydrogenase in the oxidative pentose phosphate pathway (PPP), while 2-PG activates 3-phosphoglycerate dehydrogenase to provide feedback control of 3-PG levels. Inhibition of PGAM1 by shRNA or a small molecule inhibitor PGMI-004A results in increased 3-PG and decreased 2-PG levels in cancer cells, leading to significantly decreased glycolysis, PPP flux and biosynthesis, as well as attenuated cell proliferation and tumor growth.
Topics: Animals; Binding, Competitive; Cell Line, Tumor; Cell Proliferation; Enzyme Activation; Gene Knockdown Techniques; Gluconates; Glucosephosphate Dehydrogenase; Glyceric Acids; Glycolysis; Humans; Mice; Mice, Nude; Models, Molecular; Neoplasms; Phosphoglycerate Mutase
PubMed: 23153533
DOI: 10.1016/j.ccr.2012.09.020 -
The Plant Journal : For Cell and... Sep 2021Phosphoglycerate mutases (PGAMs) catalyse the reversible isomerisation of 3-phosphoglycerate and 2-phosphoglycerate, a step of glycolysis. PGAMs can be sub-divided into...
Phosphoglycerate mutases (PGAMs) catalyse the reversible isomerisation of 3-phosphoglycerate and 2-phosphoglycerate, a step of glycolysis. PGAMs can be sub-divided into 2,3-bisphosphoglycerate-dependent (dPGAM) and -independent (iPGAM) enzymes. In plants, phosphoglycerate isomerisation is carried out by cytosolic iPGAM. Despite its crucial role in catabolism, little is known about post-translational modifications of plant iPGAM. In Arabidopsis thaliana, phosphoproteomics analyses have previously identified an iPGAM phosphopeptide where serine 82 is phosphorylated. Here, we show that this phosphopeptide is less abundant in dark-adapted compared to illuminated Arabidopsis leaves. In silico comparison of iPGAM protein sequences and 3D structural modelling of AtiPGAM2 based on non-plant iPGAM enzymes suggest a role for phosphorylated serine in the catalytic reaction mechanism. This is confirmed by the activity (or the lack thereof) of mutated recombinant Arabidopsis iPGAM2 forms, affected in different steps of the reaction mechanism. We thus propose that the occurrence of the S82-phosphopeptide reflects iPGAM2 steady-state catalysis. Based on this assumption, the metabolic consequences of a higher iPGAM activity in illuminated versus darkened leaves are discussed.
Topics: Arabidopsis; Arabidopsis Proteins; Glyceric Acids; Glycolysis; Models, Structural; Phosphoglycerate Mutase; Phosphorylation; Plant Leaves; Recombinant Proteins; Serine
PubMed: 34174129
DOI: 10.1111/tpj.15395 -
International Journal of Medical... 2024Alcoholic liver disease (ALD) poses a substantial global health challenge, with its pathogenesis deeply rooted in mitochondrial dysfunction. Our study explores the...
Alcoholic liver disease (ALD) poses a substantial global health challenge, with its pathogenesis deeply rooted in mitochondrial dysfunction. Our study explores the pivotal roles of Phosphoglycerate mutase family member 5 (Pgam5) and Voltage-Dependent Anion Channel 1 (VDAC1) in the progression of ALD, providing novel insights into their interplay and impact on mitochondrial integrity. We demonstrate that Pgam5 silencing preserves hepatocyte viability and attenuates ethanol-induced apoptosis, underscoring its detrimental role in exacerbating hepatocyte dysfunction. Pgam5's influence extends to the regulation of VDAC1 oligomerization, a key process in mitochondrial permeability transition pore (mPTP) opening, mitochondrial swelling, and apoptosis initiation. Notably, the inhibition of VDAC1 oligomerization through Pgam5 silencing or pharmacological intervention (VBIT-12) significantly preserves mitochondrial function, evident in the maintenance of mitochondrial membrane potential and reduced reactive oxygen species (ROS) production. experiments using hepatocyte-specific knockout () and control mice reveal that deficiency mitigates ethanol-induced liver histopathology, inflammation, lipid peroxidation, and metabolic disorder, further supporting its role in ALD progression. Our findings highlight the critical involvement of Pgam5 and VDAC1 in mitochondrial dysfunction in ALD, suggesting potential therapeutic targets. While promising, these findings necessitate further research, including human studies, to validate their clinical applicability and explore broader implications in liver diseases. Overall, our study provides a significant advancement in understanding ALD pathophysiology, paving the way for novel therapeutic strategies targeting mitochondrial pathways in ALD.
Topics: Animals; Humans; Mice; Ethanol; Liver Diseases, Alcoholic; Mitochondria; Mitochondrial Diseases; Phosphoglycerate Mutase; Voltage-Dependent Anion Channel 1
PubMed: 38464835
DOI: 10.7150/ijms.93171 -
British Journal of Cancer 1997We have compared the levels of phosphoglycerate mutase, 2,3-bisphosphoglycerate phosphatase and enolase activities and the distribution of their isoenzymes in normal...
We have compared the levels of phosphoglycerate mutase, 2,3-bisphosphoglycerate phosphatase and enolase activities and the distribution of their isoenzymes in normal colon, liver and lung tissues, and in colon, liver and lung adenocarcinoma, lung squamous cell carcinoma and lung carcinoid. All tumours presented higher phosphoglycerate mutase and enolase activities and lower 2,3-bisphosphoglycerate phosphatase activity than the normal tissues. No changes were observed in the phosphoglycerate mutase isoenzyme patterns analysed by cellulose acetate electrophoresis. All specimens contained mainly type BB isoenzyme, traces of type MB isoenzyme and no type MM isoenzyme. However, the tumours had decreased levels of 2,3-bisphosphoglycerate mutase and 2,3-bisphosphoglycerate mutase-phosphoglycerate mutase hybrid enzyme. Determined by agarose gel electrophoresis, alpha alpha-enolase was the isoenzyme predominant in normal lung, colon and liver tissue, although alpha gamma- and gamma gamma-enolase were also present in all tissues. In colon, liver and non-endocrine lung tumours, the proportions of alpha gamma- and gamma gamma-enolase decreased. In contrast, in carcinoid tumours of the lung, the proportions of these isoenzymes increased.
Topics: Adenocarcinoma; Carcinoma; Carcinoma, Squamous Cell; Colon; Colonic Neoplasms; Humans; Isoenzymes; Liver; Liver Neoplasms; Lung; Lung Neoplasms; Phosphoglycerate Mutase; Phosphopyruvate Hydratase; Phosphoric Monoester Hydrolases
PubMed: 9083331
DOI: 10.1038/bjc.1997.168 -
Chemical Reviews Mar 2001
Comparative Study Review
Comparison of the binuclear metalloenzymes diphosphoglycerate-independent phosphoglycerate mutase and alkaline phosphatase: their mechanism of catalysis via a phosphoserine intermediate.
Topics: Alkaline Phosphatase; Amino Acid Sequence; Catalysis; Escherichia coli; Geobacillus stearothermophilus; Glycerophospholipids; Molecular Sequence Data; Phosphoglycerate Mutase; Phosphoserine; Sequence Homology, Amino Acid
PubMed: 11712498
DOI: 10.1021/cr000253a -
International Journal of Molecular... Oct 2022Phosphoglycerate mutase (PGAM) is a glycolytic enzyme converting 3-phosphoglycerate to 2-phosphoglycerate, which in mammalian cells is expressed in two isoforms: brain...
Phosphoglycerate mutase (PGAM) is a glycolytic enzyme converting 3-phosphoglycerate to 2-phosphoglycerate, which in mammalian cells is expressed in two isoforms: brain (PGAM1) and muscle (PGAM2). Recently, it was shown that besides its enzymatic function, PGAM2 can be imported to the cell nucleus where it co-localizes with the nucleoli. It was suggested that it functions there to stabilize the nucleolar structure, maintain mRNA expression, and assist in the assembly of new pre-ribosomal subunits. However, the precise mechanism by which the protein translocates to the nucleus is unknown. In this study, we present the first crystal structure of PGAM2, identify the residues involved in the nuclear localization of the protein and propose that PGAM contains a "quaternary nuclear localization sequence (NLS)", i.e., one that consists of residues from different protein chains. Additionally, we identify potential interaction partners for PGAM2 in the nucleoli and demonstrate that 14-3-3ζ/δ is indeed an interaction partner of PGAM2 in the nucleus. We also present evidence that the insulin/IGF1-PI3K-Akt-mTOR signaling pathway is responsible for the nuclear localization of PGAM2.
Topics: Animals; Phosphoglycerate Mutase; Active Transport, Cell Nucleus; Phosphatidylinositol 3-Kinases; 14-3-3 Proteins; Muscles; Mammals
PubMed: 36361985
DOI: 10.3390/ijms232113198 -
Bone Research Mar 2024Osteoarthritis (OA) is a common degenerative disease worldwide and new therapeutics that target inflammation and the crosstalk between immunocytes and chondrocytes are...
Osteoarthritis (OA) is a common degenerative disease worldwide and new therapeutics that target inflammation and the crosstalk between immunocytes and chondrocytes are being developed to prevent and treat OA. These attempts involve repolarizing pro-inflammatory M1 macrophages into the anti-inflammatory M2 phenotype in synovium. In this study, we found that phosphoglycerate mutase 5 (PGAM5) significantly increased in macrophages in OA synovium compared to controls based on histology of human samples and single-cell RNA sequencing results of mice models. To address the role of PGAM5 in macrophages in OA, we found conditional knockout of PGAM5 in macrophages greatly alleviated OA symptoms and promoted anabolic metabolism of chondrocytes in vitro and in vivo. Mechanistically, we found that PGAM5 enhanced M1 polarization via AKT-mTOR/p38/ERK pathways, whereas inhibited M2 polarization via STAT6-PPARγ pathway in murine bone marrow-derived macrophages. Furthermore, we found that PGAM5 directly dephosphorylated Dishevelled Segment Polarity Protein 2 (DVL2) which resulted in the inhibition of β-catenin and repolarization of M2 macrophages into M1 macrophages. Conditional knockout of both PGAM5 and β-catenin in macrophages significantly exacerbated osteoarthritis compared to PGAM5-deficient mice. Motivated by these findings, we successfully designed mannose modified fluoropolymers combined with siPGAM5 to inhibit PGAM5 specifically in synovial macrophages via intra-articular injection, which possessed desired targeting abilities of synovial macrophages and greatly attenuated murine osteoarthritis. Collectively, these findings defined a key role for PGAM5 in orchestrating macrophage polarization and provides insights into novel macrophage-targeted strategy for treating OA.
Topics: Humans; Animals; Mice; Phosphoglycerate Mutase; beta Catenin; Osteoarthritis; Inflammation; Macrophages; Phosphoprotein Phosphatases; Mitochondrial Proteins
PubMed: 38433252
DOI: 10.1038/s41413-024-00318-8