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Bioorganic & Medicinal Chemistry May 2018Phosphoglycerate mutase 1 (PGAM1) is a glycolytic enzyme that dynamically converts 3-phosphoglycerate (3PG) to 2-phosphoglycerate (2PG), which was upregulated to...
Phosphoglycerate mutase 1 (PGAM1) is a glycolytic enzyme that dynamically converts 3-phosphoglycerate (3PG) to 2-phosphoglycerate (2PG), which was upregulated to coordinate glycolysis, pentose phosphate pathway (PPP) and serine biosynthesis to promote cancer cell proliferation and tumor growth in a variety of cancers. However, only a few inhibitors of PGAM1 have been reported with poor molecular or cellular efficacy. In this paper, a series of xanthone derivatives were discovered as novel PGAM1 inhibitors through scaffold hopping and sulfonamide reversal strategy based on the lead compound PGMI-004A. Most xanthone derivatives showed higher potency against PGAM1 than PGMI-004A and exhibited moderate anti-proliferation activity on different cancer cell lines.
Topics: Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; Molecular Docking Simulation; Phosphoglycerate Mutase; Protein Structure, Tertiary; Structure-Activity Relationship; Xanthones
PubMed: 29530347
DOI: 10.1016/j.bmc.2018.02.044 -
The Journal of Biological Chemistry Mar 2022The glycolytic enzyme phosphoglycerate mutase (PGM) is of utmost importance for overall cellular metabolism and has emerged as a novel therapeutic target in cancer...
The glycolytic enzyme phosphoglycerate mutase (PGM) is of utmost importance for overall cellular metabolism and has emerged as a novel therapeutic target in cancer cells. This enzyme is also conserved in the rapidly proliferating malarial parasite Plasmodium falciparum, which have a similar metabolic framework as cancer cells and rely on glycolysis as the sole energy-yielding process during intraerythrocytic development. There is no redundancy among the annotated PGM enzymes in Plasmodium, and PfPGM1 is absolutely required for the parasite survival as evidenced by conditional knockdown in our study. A detailed comparison of PfPGM1 with its counterparts followed by in-depth structure-function analysis revealed unique attributes of this parasitic protein. Here, we report for the first time the importance of oligomerization for the optimal functioning of the enzyme in vivo, as earlier studies in eukaryotes only focused on the effects in vitro. We show that single point mutation of the amino acid residue W68 led to complete loss of tetramerization and diminished catalytic activity in vitro. Additionally, ectopic expression of the WT PfPGM1 protein enhanced parasite growth, whereas the monomeric form of PfPGM1 failed to provide growth advantage. Furthermore, mutation of the evolutionarily conserved residue K100 led to a drastic reduction in enzymatic activity. The indispensable nature of this parasite enzyme highlights the potential of PfPGM1 as a therapeutic target against malaria, and targeting the interfacial residues critical for oligomerization can serve as a focal point for promising drug development strategies that may not be restricted to malaria only.
Topics: Humans; Malaria; Phosphoglycerate Mutase; Plasmodium falciparum
PubMed: 35150741
DOI: 10.1016/j.jbc.2022.101713 -
Zhongguo Xue Xi Chong Bing Fang Zhi Za... Jun 2012Phosphoglycerate mutase (PGAM) is one of glycolytic enzymes, concerning with the transport of carbohydrates, metabolism, catalytic activity and growth development. PGAM... (Review)
Review
Phosphoglycerate mutase (PGAM) is one of glycolytic enzymes, concerning with the transport of carbohydrates, metabolism, catalytic activity and growth development. PGAM was discovered in yeast firstly, and with its amino acid sequence and crystal structure determined, this protein was found in varies organism, such as human, Escherichia coli, Schistosoma japonicum and Toxoplasma gondii. This article reviews the physico-chemical property and research progress of PGAM of vertebrate, invertebrate and protozoa.
Topics: Animals; Humans; Phosphoglycerate Mutase; Yeasts
PubMed: 23012968
DOI: No ID Found -
PloS One 2021Glycolytic metabolism is closely involved in physiological homeostasis and pathophysiological states. Among glycolytic enzymes, phosphoglycerate mutase (PGAM) has been...
Glycolytic metabolism is closely involved in physiological homeostasis and pathophysiological states. Among glycolytic enzymes, phosphoglycerate mutase (PGAM) has been reported to exert certain physiological role in vitro, whereas its impact on glucose metabolism in vivo remains unclear. Here, we report the characterization of Pgam1 knockout mice. We observed that homozygous knockout mice of Pgam1 were embryonic lethal. Although we previously reported that both PGAM-1 and -2 affect global glycolytic profile of cancers in vitro, in vivo glucose parameters were less affected both in the heterozygous knockout of Pgam1 and in Pgam2 transgenic mice. Thus, the impact of PGAM on in vivo glucose metabolism is rather complex than expected before.
Topics: Animals; Gene Knockout Techniques; Genes, Lethal; Glucose; Glycolysis; Loss of Heterozygosity; Male; Mice; Mice, Transgenic; Phosphoglycerate Mutase
PubMed: 33914812
DOI: 10.1371/journal.pone.0250856 -
Biochemical and Biophysical Research... Jul 2023Bacillus anthracis Ser/Thr protein kinase PrkC is necessary for phenotypic memory and spore germination, and the loss of PrkC-dependent phosphorylation events affect the...
Bacillus anthracis Ser/Thr protein kinase PrkC is necessary for phenotypic memory and spore germination, and the loss of PrkC-dependent phosphorylation events affect the spore development. During sporulation, Bacillus sp. can store 3-Phosphoglycerate (3-PGA) that will be required at the onset of germination when ATP will be necessary. The Phosphoglycerate mutase (Pgm) catalyzes the isomerization of 2-PGA and 3-PGA and is important for spore germination as a key metabolic enzyme that maintains 3-PGA pool at later events. Therefore, regulation of Pgm is important for an efficient spore germination process and metabolic switching. While the increased expression of Pgm in B. anthracis decreases spore germination efficiency, it remains unexplored if PrkC could directly influence Pgm activity. Here, we report the phosphorylation and regulation of Pgm by PrkC and its impact on Pgm stability and catalytic activity. Mass spectrometry revealed Pgm phosphorylation on seven threonine residues. In silico mutational analysis highlighted the role of Thr residue towards metal and substrate binding. Altogether, we demonstrated that PrkC-mediated Pgm phosphorylation negatively regulates its activity that is essential to maintain Pgm in its apo-like isoform before germination. This study advances the role of Pgm regulation that represents an important switch for B. anthracis resumption of metabolism and spore germination.
Topics: Phosphorylation; Protein Kinases; Bacillus anthracis; Phosphoglycerate Mutase; Threonine; Spores, Bacterial; Bacterial Proteins
PubMed: 37149987
DOI: 10.1016/j.bbrc.2023.04.039 -
Phosphoglycerate mutase deficiency (glycogen storage disease X) caused by a novel variant in PGAM-M.Neuromuscular Disorders : NMD Oct 2016Phosphoglycerate mutase enzyme deficiency in muscle causes a metabolic myopathy (glycogen storage disease X) characterized by exertional muscle contractures, weakness,...
Phosphoglycerate mutase enzyme deficiency in muscle causes a metabolic myopathy (glycogen storage disease X) characterized by exertional muscle contractures, weakness, hyperCKemia, and myoglobinuria. Six different autosomal recessive variants in PGAM-M have been described thus far (Salameh et al., 2013). In this case report, we report a novel disease-causing variant. A 52-year-old African-American woman presented with exertional muscle contractures, myalgias, and weakness since childhood including an episode of rhabdomyolysis. Neurologic examination and EMG were normal. CK was mildly elevated at rest and over 20,000 U/L during her episode of rhabdomyolysis. Muscle biopsy revealed subsarcolemmal collections suggestive of tubular aggregates. Phosphoglycerate mutase activity was 8% of the reference value. PGAM-M sequencing showed compound heterozygous variants: c.233G>A, which has been found only in African-Americans with this disease, and a novel variant, c.278G>A. This case expands the genetic spectrum of phosphoglycerate mutase deficiency.
Topics: Exons; Female; Heterozygote; Humans; Kidney Diseases; Middle Aged; Muscle, Skeletal; Muscular Diseases; Mutation; Phosphoglycerate Mutase
PubMed: 27612597
DOI: 10.1016/j.nmd.2016.08.002 -
Acta Pharmacologica Sinica Jan 2021Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib, remains a major challenge in the targeted therapy of...
HKB99, an allosteric inhibitor of phosphoglycerate mutase 1, suppresses invasive pseudopodia formation and upregulates plasminogen activator inhibitor-2 in erlotinib-resistant non-small cell lung cancer cells.
Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib, remains a major challenge in the targeted therapy of non-small cell lung cancer (NSCLC). HKB99 is a novel allosteric inhibitor of phosphoglycerate mutase 1 (PGAM1) that preferentially suppresses cell proliferation and induces more apoptosis in acquired erlotinib-resistant HCC827ER cells compared with its parental HCC827 cells. In this study we identified the molecular biomarkers for HKB99 response in erlotinib-resistant HCC827ER cells. We showed that HCC827ER cells displayed enhanced invasive pseudopodia structures as well as downregulated plasminogen activator inhibitor-2 (PAI-2). Meanwhile, PAI-2 knockdown by siPAI-2 candidates decreased the sensitivity of HCC827 parental cells to erlotinib. Moreover, HKB99 (5 μM) preferentially inhibited the invasive pseudopodia formation and increased the level of PAI-2 in HCC827ER cells. Collectively, this study provides new insight into the role of PAI-2 in regulating the sensitivity of erlotinib resistant NSCLC cells to PGAM1 inhibitor. Furthermore, PAI-2 level might be considered as a potential biomarker for predicting the efficacy of the PGAM1 allosteric inhibitor on the erlotinib resistant NSCLC cells.
Topics: Anthracenes; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Enzyme Inhibitors; Erlotinib Hydrochloride; Gene Knockdown Techniques; Humans; Intracellular Signaling Peptides and Proteins; Lung Neoplasms; Phosphoglycerate Mutase; Pseudopodia; Sulfonamides; Up-Regulation
PubMed: 32404981
DOI: 10.1038/s41401-020-0399-1 -
Bioorganic & Medicinal Chemistry Letters Mar 2021Phosphoglycerate mutase 1 (PGAM1) is a promising target for cancer treatment. Herein, we found that α-mangostin and γ-mangostin exhibited moderate PGAM1 inhibitory...
Phosphoglycerate mutase 1 (PGAM1) is a promising target for cancer treatment. Herein, we found that α-mangostin and γ-mangostin exhibited moderate PGAM1 inhibitory activities, with IC of 7.2 μM and 1.2 µM, respectively. Based on α-mangostin, a series of 1,3,6,7-tetrahydroxyxanthone derivatives were designed, synthesized and evaluated in vitro for PGAM1 inhibition. The significant structure-activity relationships (SAR) and a fresh binding mode of this kind of new compounds were also clearly described. This study provides valuable information for further optimization of PGAM1 inhibitors with 1,3,6,7-tetrahydroxyxanthone backbone or de novo design of novel inhibitor.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; Molecular Structure; Phosphoglycerate Mutase; Structure-Activity Relationship; Xanthones
PubMed: 33513389
DOI: 10.1016/j.bmcl.2021.127820 -
Neurology Jun 1982A 52-year-old man complained since adolescence of cramps and pigmenturia after 15 to 30 minutes of intense exercise. There was no family history of neuromuscular...
A 52-year-old man complained since adolescence of cramps and pigmenturia after 15 to 30 minutes of intense exercise. There was no family history of neuromuscular diseases, and strength was normal. The rise of venous lactate after forearm ischemic exercise was abnormally low. Histochemical and ultrastructural studies of a muscle biopsy showed mild increase of glycogen, which was confirmed by biochemical analysis. Studies of anaerobic glycolysis in vitro showed decrease lactate formation with glycogen and with all hexosephosphate glycolytic intermediates, suggesting a defect below the phosphofructokinase reaction. Muscle phosphoglycerate mutase (PGAM) activity was 5.7% of the lowest control, while all other enzymes of glycolysis had normal activities. Electrophoretic, heat lability, and mercury inhibition studies showed that the small residual activity of PGAM in the patient's muscle was represented by the brain (BB) isoenzyme, suggesting a genetic defect of the M subunit that predominates in normal muscle. The prevalence of the BB isoenzyme in other tissues, including muscle culture, may explain why symptoms were confined to muscle.
Topics: Adult; Brain; Glycogen; Glycolysis; Humans; Male; Middle Aged; Muscles; Myoglobinuria; Phosphoglycerate Mutase; Phosphotransferases
PubMed: 6283419
DOI: 10.1212/wnl.32.6.584 -
Cardiovascular Drugs and Therapy Feb 2019Necroptosis is an important form of cell death following myocardial ischemia/reperfusion (I/R) and phosphoglycerate mutase 5 (PGAM5) functions as the convergent point...
PURPOSE
Necroptosis is an important form of cell death following myocardial ischemia/reperfusion (I/R) and phosphoglycerate mutase 5 (PGAM5) functions as the convergent point for multiple necrosis pathways. This study aims to investigate whether inhibition of PGAM5 could reduce I/R-induced myocardial necroptosis and the underlying mechanisms.
METHODS
The SD rat hearts (or H9c2 cells) were subjected to 1-h ischemia (or 10-h hypoxia) plus 3-h reperfusion (or 4-h reoxygenation) to establish the I/R (or H/R) injury model. The myocardial injury was assessed by the methods of biochemistry, H&E (hematoxylin and eosin), and PI/DAPI (propidium iodide/4',6-diamidino-2-phenylindole) staining, respectively. Drug interventions or gene knockdown was used to verify the role of PGAM5 in I/R (or H/R)-induced myocardial necroptosis and possible mechanisms.
RESULTS
The I/R-treated heart showed the injuries (increase in infarct size and creatine kinase release), upregulation of PGAM5, dynamin-related protein 1 (Drp1), p-Drp1-S616, and necroptosis-relevant proteins (RIPK1/RIPK3, receptor-interacting protein kinase 1/3; MLKL, mixed lineage kinase domain-like); these phenomena were attenuated by inhibition of PGAM5 or RIPK1. In H9c2 cells, H/R treatment elevated the levels of PGAM5, RIPK1, RIPK3, MLKL, Drp1, and p-Drp1-S616 and induced mitochondrial dysfunctions (elevation in mitochondrial membrane potential and ROS level) and cellular necrosis (increase in LDH release and the ratio of PI/DAPI cells); these effects were blocked by inhibition or knockdown of PGAM5.
CONCLUSIONS
Inhibition of PGAM5 can reduce necroptosis in I/R-treated rat hearts through suppression of Drp1; there is a positive feedback between RIPK1 and PGAM5, and PGAM5 might serve as a novel therapeutic target for prevention of myocardial I/R injury.
Topics: Animals; Cell Death; Cell Line; DNA (Cytosine-5-)-Methyltransferase 1; Disease Models, Animal; Down-Regulation; Enzyme Inhibitors; Glycolates; Male; Mitochondrial Proteins; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Phosphoglycerate Mutase; Phosphoprotein Phosphatases; Protein Serine-Threonine Kinases; Rats, Sprague-Dawley; Receptor-Interacting Protein Serine-Threonine Kinases; Signal Transduction
PubMed: 30637549
DOI: 10.1007/s10557-018-06848-8