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Archives of Neurology Mar 2009Phosphoglycerate mutase (PGAM) deficiency (glycogen storage disease type X) has been reported in 12 patients of whom 9 were African American.
BACKGROUND
Phosphoglycerate mutase (PGAM) deficiency (glycogen storage disease type X) has been reported in 12 patients of whom 9 were African American.
OBJECTIVE
To describe 2 patients, 1 of Pakistani and 1 of Italian ethnic origin, with typical clinical and biochemical changes of glycogen storage disease type X and novel mutations in the gene encoding the muscle subunit of PGAM (PGAM2).
DESIGN
Clinical, pathological, biochemical, and molecular analyses.
SETTING
Tertiary care university hospitals and academic institutions. Patients A 37-year-old Danish man of Pakistani origin who had exercise-related cramps and myoglobinuria and a 65-year-old Italian man who had exercise intolerance and myalgia but no pigmenturia and had undergone long-term statin therapy.
MAIN OUTCOME MEASURES
Clinical course and biochemical and molecular features.
RESULTS
Biochemical evidence showed severe isolated PGAM deficiency, and molecular studies revealed 2 novel homozygous mutations, a nonsense mutation and a single nucleotide deletion. Pathological studies of muscle showed mild glycogen accumulation but prominent tubular aggregates in both patients.
CONCLUSIONS
We found that glycogen storage disease type X is not confined to the African American population, is often associated with sarcoplasmic reticulum (SR) proliferation, and is genetically heterogeneous.
Topics: Adult; Aged; Creatine Kinase; Glycogen Storage Disease; Humans; Italy; Male; Pakistan; Phosphoglycerate Mutase
PubMed: 19273759
DOI: 10.1001/archneurol.2008.584 -
PLoS Pathogens Jul 2019The ability of Staphylococcus aureus and other pathogens to consume glucose is critical during infection. However, glucose consumption increases the cellular demand for...
The ability of Staphylococcus aureus and other pathogens to consume glucose is critical during infection. However, glucose consumption increases the cellular demand for manganese sensitizing S. aureus to host-imposed manganese starvation. The current investigations were undertaken to elucidate how S. aureus copes with the need to consume glucose when metal-limited by the host. A critical component of host defense is production of the manganese binding protein calprotectin. S. aureus has two variants of phosphoglycerate mutase, one of which is manganese-dependent, GpmI, and another that is manganese-independent, GpmA. Leveraging the ability to impose metal starvation in culture utilizing calprotectin revealed that the loss of GpmA, but not GpmI, sensitized S. aureus to manganese starvation. Metabolite feeding experiments revealed that the growth defect of GpmA when manganese-starved was due to a defect in glycolysis and not gluconeogenesis. Loss of GpmA reduces the ability of S. aureus to cause invasive disease in wild type mice. However, GpmA was dispensable in calprotectin-deficient mice, which have defects in manganese sequestration, indicating that this isozyme contributes to the ability of S. aureus to overcome manganese limitation during infection. Cumulatively, these observations suggest that expressing a metal-independent variant enables S. aureus to consume glucose while mitigating the negative impact that glycolysis has on the cellular demand for manganese. S. aureus is not the only bacterium that expresses manganese-dependent and -independent variants of phosphoglycerate mutase. Similar results were also observed in culture with Salmonella enterica serovar Typhimurium mutants lacking the metal-independent isozyme. These similar observations in both Gram-positive and Gram-negative pathogens suggest that expression of metal-independent glycolytic isozymes is a common strategy employed by bacteria to survive in metal-limited environments, such as the host.
Topics: Animals; Bacterial Proteins; Genetic Variation; Glycolysis; Isoenzymes; Leukocyte L1 Antigen Complex; Manganese; Metals; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphoglycerate Mutase; Staphylococcal Infections; Staphylococcus aureus; Virulence
PubMed: 31344131
DOI: 10.1371/journal.ppat.1007971 -
Metallomics : Integrated Biometal... Dec 2011Production of ATP by the glycolytic pathway in the mammalian pathogenic stage of protists from the genus Trypanosoma is required for the survival of the parasites....
Production of ATP by the glycolytic pathway in the mammalian pathogenic stage of protists from the genus Trypanosoma is required for the survival of the parasites. Cofactor-independent phosphoglycerate mutase (iPGAM) is particularly attractive as a drug target because it shows no similarity to the corresponding enzyme in humans, and has also been genetically validated as a target by RNAi experiments. It has previously been shown that trypanosomatid iPGAMs require Co(2+) to reach maximal activity, but the biologically relevant metal has remained unclear. In this paper the metal content in the cytosol of procyclic and bloodstream-form T. brucei (analysed by inductively coupled plasma-optical emission spectroscopy) shows that Mg(2+), Zn(2+) and Fe(2+) were the most abundant, whereas Co(2+) was below the limit of detection (<0.035 μM). The low concentration indicates that Co(2+) is unlikely to be the biologically relevant metal, but that instead, Mg(2+) and/or Zn(2+) may assume this role. Results from metal analysis of purified Leishmania mexicana iPGAM by inductively coupled plasma-mass spectrometry also show high concentrations of Mg(2+) and Zn(2+), and are consistent with this proposal. Our data suggest that in vivo cellular conditions lacking Co(2+) are unable to support the maximal activity of iPGAM, but instead maintain its activity at a relatively low level by using Mg(2+) and/or Zn(2+). The physiological significance of these observations is being pursued by structural, biochemical and biophysical studies.
Topics: Cobalt; Cytosol; Iron; Magnesium; Mass Spectrometry; Models, Molecular; Phosphoglycerate Mutase; Trypanosoma brucei brucei; Zinc
PubMed: 21993954
DOI: 10.1039/c1mt00119a -
Journal of Molecular Microbiology and... 2010The glycolytic enzyme phosphoglycerate mutase (PGM), which catalyzes the conversion of 3-phosphoglycerate to 2-phosphoglycerate, was examined in Lactococcus lactis with...
The glycolytic enzyme phosphoglycerate mutase (PGM), which catalyzes the conversion of 3-phosphoglycerate to 2-phosphoglycerate, was examined in Lactococcus lactis with respect to its function, kinetics and glycolytic flux control. A library of strains with PGM activities ranging between 15-465% of the wild-type level was constructed by replacing the native promoter of pgm with synthetic promoters of varying strengths. The specific growth rate and glucose flux were found to be maximal at the wild-type level at which PGM had no flux control. Low flux control of PGM was found on mixed acid fluxes at highly reduced PGM activities. At the wild-type level PGM operated very far from V(max). Consequently, in a strain with only 15% PGM activity, the catalytic rate of PGM was almost six times higher than in the wild-type. K(m)of PGM for 3-phosphoglycerate was 1.0 mM and k(cat)was 3,200 s(-1). The L. lactis PGM was dependent on 2,3-bisphosphoglyceric acid for activity, which showed that the enzyme is of the dPGM type in accordance with its predicted homology to dPGM enzymes from other organisms. In conclusion, PGM from L. lactis is a highly efficient catalyst, which partially explains why this enzyme has limited control in wild-type L. lactis.
Topics: 2,3-Diphosphoglycerate; Amino Acid Sequence; Bacterial Proteins; Cluster Analysis; Gene Expression Regulation, Bacterial; Glucose; Glyceric Acids; Kinetics; Lactococcus lactis; Molecular Sequence Data; Phosphoglycerate Mutase; Promoter Regions, Genetic; Sequence Alignment
PubMed: 20530968
DOI: 10.1159/000315458 -
Parasitology Research Aug 2022Secretory enzymes from Schistosoma japonicum are promising candidate antigens in the diagnosis of schistosomiasis. Our previous studies have proven that thioredoxin...
Serological evaluation of the schistosome's secretory enzyme phytochelatin synthase and phosphoglycerate mutase for the detection of human Schistosoma japonicum infection.
Secretory enzymes from Schistosoma japonicum are promising candidate antigens in the diagnosis of schistosomiasis. Our previous studies have proven that thioredoxin peroxidase-1 (SjTPx-1) is useful for the detection of this parasitic disease in humans, water buffaloes, and dogs. In this study, we evaluated two more secretory enzymes namely phosphoglycerate mutase (SjPGM) and phytochelatin synthase (SjPCS) with SjTPx-1 as the reference antigen. SjPGM was shown to have good diagnostic potentials in animal samples in previous studies, whereas SjPCS was chosen because of its absence in the mammalian hosts. Serum samples including 96 endemic negative controls, 107 schistosomiasis japonica positive samples, and 31 samples positive for other parasitic trematode infections (Clonorchis sinensis, Opisthorchis viverrini, Paragonimus westermani) were tested with the antigens using enzyme-linked immunosorbent assay. Results showed that SjPCS detected more positive samples and had fewer cross-reactions than SjPGM. With 85.05% sensitivity and 93.55% specificity, SjPCS can therefore be used in the detection of human schistosomiasis.
Topics: Aminoacyltransferases; Animals; Antigens, Helminth; Enzyme-Linked Immunosorbent Assay; Humans; Phosphoglycerate Mutase; Schistosoma japonicum; Schistosomiasis japonica; Sensitivity and Specificity
PubMed: 35672537
DOI: 10.1007/s00436-022-07568-7 -
European Journal of Medicinal Chemistry Dec 2022Glycolysis is a preferred metabolic pattern of cancer cells. Phosphoglycerate mutase 1 (PGAM1) is a pivotal glycolytic enzyme that catalyzes the reciprocal conversion... (Review)
Review
Glycolysis is a preferred metabolic pattern of cancer cells. Phosphoglycerate mutase 1 (PGAM1) is a pivotal glycolytic enzyme that catalyzes the reciprocal conversion between 2-phosphoglycerate and 3-phosphoglycerate. It also stimulates anabolic pathways, generates adenosine triphosphate, and keeps redox balance under hypoxic conditions. Mounting evidence supports that PGAM1 is overexpressed in many cancers and promotes their progression. The critical roles of PGAM1 in tumorigenesis make it a promising theranostical target for cancer. The aberrant expression of PGAM1 enables it to become a potential diagnosis gene for several cancers, and its heterogeneous regulations via interacting with its different ligands increase the possibility of it as a target for cancer therapy and discovery of tens of PGAM1 inhibitors, which can provide the potential feasibility for cancer treatment. This review provides insights into structure, function, and regulation of PGAM1, summarizes its mechanism in tumorigenesis, reviews the advanced status of PGAM1 inhibitors in cancer diagnosis and treatment, and finally emphasizes PGAM1 as an appealing theranostical target for cancer.
Topics: Humans; Phosphoglycerate Mutase; Neoplasms; Glycolysis; Carcinogenesis
PubMed: 36215859
DOI: 10.1016/j.ejmech.2022.114798 -
Clinical and Translational Medicine Dec 2023Hepatocellular carcinoma (HCC) cells undergo reprogramming of glucose metabolism to support uncontrolled proliferation, of which the intrinsic mechanism still merits...
BACKGROUND
Hepatocellular carcinoma (HCC) cells undergo reprogramming of glucose metabolism to support uncontrolled proliferation, of which the intrinsic mechanism still merits further investigation. Although regulatory factor X6 (RFX6) is aberrantly expressed in different cancers, its precise role in cancer development remains ambiguous.
METHODS
Microarrays of HCC tissues were employed to investigate the expression of RFX6 in tumour and adjacent non-neoplastic tissues. Functional assays were employed to explore the role of RFX6 in HCC development. Chromatin immunoprecipitation, untargeted metabolome profiling and sequencing were performed to identify potential downstream genes and pathways regulated by RFX6. Metabolic assays were employed to investigate the effect of RFX6 on glycolysis in HCC cells. Bioinformatics databases were used to validate the above findings.
RESULTS
HCC tissues exhibited elevated expression of RFX6. High RFX6 expression represented as an independent hazard factor correlated to poor prognosis in patients with HCC. RFX6 deficiency inhibited HCC development in vitro and in vivo, while its overexpression exerted opposite functions. Mechanistically, RFX6 bound to the promoter area of phosphoglycerate mutase 1 (PGAM1) and upregulated its expression. The increased PGAM1 protein levels enhanced glycolysis and further promoted the development of HCC.
CONCLUSIONS
RFX6 acted as a novel driver for HCC development by promoting aerobic glycolysis, disclosing the potential of the RFX6-PGAM1 axis for therapeutic targeting.
Topics: Humans; Carcinoma, Hepatocellular; Cell Proliferation; Glycolysis; Liver Neoplasms; Phosphoglycerate Mutase
PubMed: 38093528
DOI: 10.1002/ctm2.1511 -
Molecular Oncology Aug 2022Phosphoglycerate mutase 1 (PGAM1) is a crucial glycolytic enzyme, and its expression status has been confirmed to be associated with tumor progression and metastasis....
Phosphoglycerate mutase 1 (PGAM1) is a crucial glycolytic enzyme, and its expression status has been confirmed to be associated with tumor progression and metastasis. However, the precise role and other biological functions of PGAM1 remain unclear. Here, we report that PGAM1 expression is upregulated and related to poor prognosis in patients with breast cancer (BC). Functional experiments showed that knockdown of PGAM1 could suppress the proliferation, invasion, migration, and epithelial-mesenchymal transition of BC cells. Through RNA sequencing, we found that argininosuccinate synthase 1 (ASS1) expression was markedly upregulated in BC cells following PGAM1 knockdown, and it is required to suppress the malignant biological behavior of BC cells. Importantly, we demonstrated that PGAM1 negatively regulates ASS1 expression through the cAMP/AMPK/CEBPB axis. In vivo experiments further validated that PGAM1 promoted tumor growth in BC by altering ASS1 expression. Finally, immunohistochemical analysis showed that downregulated ASS1 levels were associated with PGAM1 expression and poor prognosis in patients with BC. Our study provides new insight into the regulatory mechanism of PGAM1-mediated BC progression that might shed new light on potential targets and combination therapeutic strategies for BC treatment.
Topics: AMP-Activated Protein Kinases; Argininosuccinate Synthase; Breast Neoplasms; CCAAT-Enhancer-Binding Protein-beta; Cell Line, Tumor; Cell Proliferation; Female; Humans; Phosphoglycerate Mutase
PubMed: 35674458
DOI: 10.1002/1878-0261.13259 -
Muscle & Nerve Jan 2013Phosphoglycerate mutase deficiency (PGAM) is a rare metabolic myopathy that results in terminal block in glycogenolysis. Clinically, patients with PGAM deficiency are...
INTRODUCTION
Phosphoglycerate mutase deficiency (PGAM) is a rare metabolic myopathy that results in terminal block in glycogenolysis. Clinically, patients with PGAM deficiency are asymptomatic, except when they engage in brief, strenuous efforts, which may trigger myalgias, cramps, muscle necrosis, and myoglobinuria. An unusual pathologic feature of PGAM deficiency is the association with tubular aggregates.
METHODS
We report an African-American patient from Panama with partial deficiency of PGAM who presented with asymptomatic elevation of creatine kinase levels and tubular aggregates on muscle biopsy.
RESULTS
Muscle biopsies showed subsarcolemmal and sarcolemmal tubular aggregates in type 2 fibers. Muscle PGAM enzymatic activity was decreased and gene sequencing revealed a heterozygous mutation in codon 78 of exon 1 of the PGAM2 gene, which is located on the short arm of chromosome 7.
CONCLUSIONS
PGAM deficiency has been reported in 14 patients, 9 of whom were of African-American ethnicity, and in 5 (36%) tubular aggregates were seen on muscle biopsy. Contrary to previously reported cases, our patient was initially asymptomatic. This further expands the PGAM deficiency phenotype.
Topics: Adult; Humans; Male; Muscle Cramp; Muscle Weakness; Muscle, Skeletal; Phosphoglycerate Mutase
PubMed: 23169535
DOI: 10.1002/mus.23527 -
Biotechnology Journal Oct 2010The yeast Saccharomyces cerevisiae is able to adapt its metabolism to grow on different carbon sources and to shift to non-fermentative growth on C2 or C3 carbon sources...
The yeast Saccharomyces cerevisiae is able to adapt its metabolism to grow on different carbon sources and to shift to non-fermentative growth on C2 or C3 carbon sources (ethanol, acetate, or glycerol) through the activation of gluconeogenesis. Here, we studied the response to the deletion of the glycolytic and gluconeogenic gene GPM1, encoding for phosphoglycerate mutase. It was previously shown that a S. cerevisiae strain with non-functional copies of GPM1 can only grow when glycerol and ethanol are both present as carbon sources, whilst addition of glucose was shown to strongly inhibit growth. It was suggested that glycerol is needed to feed gluconeogenesis whilst ethanol is required for respiration. Here, we studied the physiological response of the GPM1 knock-out mutant through fermentation and transcriptome analysis. Furthermore, we compared the physiological results with those obtained through simulations using a genome-scale metabolic model, showing that glycerol is only needed in small amounts for growth. Our findings strongly suggest a severely impaired growth ability of the knock-out mutant, which presents increased transcript levels of genes involved in the pentose phosphate pathway and in the glyoxylate shunt. These results indicate an attempt to compensate for the energy imbalance caused by the deletion of the glycolytic/gluconeogenic gene within the mutant.
Topics: Fungal Proteins; Gene Deletion; Gene Expression Regulation, Fungal; Gene Knockout Techniques; Oligonucleotide Array Sequence Analysis; Phosphoglycerate Mutase; Saccharomyces cerevisiae; Systems Biology
PubMed: 20815084
DOI: 10.1002/biot.201000199