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Cells Jan 2022In non-small-cell lung cancer (NSCLC), concurrent mutations in the oncogene and tumor suppressor (also known as LKB1) confer an aggressive malignant phenotype, an...
In non-small-cell lung cancer (NSCLC), concurrent mutations in the oncogene and tumor suppressor (also known as LKB1) confer an aggressive malignant phenotype, an unfavourability towards immunotherapy, and overall poor prognoses in patients. In a previous study, we showed that murine co-mutant tumors and human co-mutant cancer cells have an enhanced dependence on glutamine-fructose-6-phosphate transaminase 2 (GFPT2), a rate-limiting enzyme in the hexosamine biosynthesis pathway (HBP), which could be targeted to reduce survival of co-mutants. Here, we found that co-mutant cells also exhibit an increased dependence on -acetylglucosamine-phosphate mutase 3 (PGM3), an enzyme downstream of GFPT2. Genetic or pharmacologic suppression of PGM3 reduced co-mutant tumor growth in both in vitro and in vivo settings. Our results define an additional metabolic vulnerability in co-mutant tumors to the HBP and provide a rationale for targeting PGM3 in this aggressive subtype of NSCLC.
Topics: AMP-Activated Protein Kinase Kinases; Animals; Biosynthetic Pathways; Cell Line, Tumor; Cell Proliferation; Cell Survival; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); Glycosylation; Hexosamines; Humans; Lung Neoplasms; Mice; Molecular Targeted Therapy; Phosphoglucomutase; Proto-Oncogene Proteins p21(ras)
PubMed: 35011738
DOI: 10.3390/cells11010176 -
International Journal of Molecular... Jan 2023Hyper-IgE Syndrome (HIES) is a heterogeneous group of primary immune-deficiency disorders characterized by elevated levels of IgE, eczema, and recurrent skin and lung...
Hyper-IgE Syndrome (HIES) is a heterogeneous group of primary immune-deficiency disorders characterized by elevated levels of IgE, eczema, and recurrent skin and lung infections. HIES that is autosomally dominant in the signal transducer and activator of transcription 3 (STAT3), and autosomal recessive mutations in phosphoglucomutase 3 (PGM3) have been reported in humans. An early diagnosis, based on clinical suspicion and immunological assessments, is challenging. Patients' metabolomics, proteomics, and cytokine profiles were compared to DOCK 8-deficient and atopic dermatitis patients. The PGM3 metabolomics profile identified significant dysregulation in hypotaurine, hypoxanthine, uridine, and ribothymidine. The eight proteins involved include bifunctional arginine demethylase and lysyl hydroxylase (JMJD1B), type 1 protein phosphatase inhibitor 4 (PPI 4), and platelet factor 4 which aligned with an increased level of the cytokine GCSF. Patients with STAT3 deficiency, on the other hand, showed significant dysregulation in eight metabolites, including an increase in protocatechuic acid, seven proteins including ceruloplasmin, and a plasma protease C1 inhibitor, in addition to cytokine VEGF being dysregulated. Using multi-omics profiling, we identified the dysregulation of endothelial growth factor (EGFR) and tumor necrosis factor (TNF) signaling pathways in PGM3 and STAT3 patients, respectively. Our findings may serve as a stepping stone for larger prospective HIES clinical cohorts to validate their future use as biomarkers.
Topics: Humans; Immunoglobulin E; Phosphoglucomutase; STAT3 Transcription Factor; Multiomics; Prospective Studies; Job Syndrome; Mutation; Cytokines
PubMed: 36768728
DOI: 10.3390/ijms24032406 -
Biochimica Et Biophysica Acta Dec 2016Citrus canker, caused by bacteria Xanthomonas citri subsp. citri, can affect all economically important varieties of citrus. Studying Xanthomonas genes related to the...
Citrus canker, caused by bacteria Xanthomonas citri subsp. citri, can affect all economically important varieties of citrus. Studying Xanthomonas genes related to the invasive capacity may improve the knowledge on how this works and ultimately use the information to avoid the disease. Some annotated genes from Xanthomonas citri subsp. citri published genome are addressed to an interesting class of genes named "pathogenicity, virulence and adaptation". One of them is xanA, which encodes a predicted phosphoglucomutase. Phosphoglucomutases are ubiquitous enzymes among the living kingdoms that play roles in carbohydrate metabolism, catalyzing the reversible conversion of 1- to 6-phosphoglucose. In Xanthomonas, phosphoglucomutase activity is required to synthesize precursors of the pathogenesis-related polysaccharide xanthan. In this work, a characterization of this gene product is presented by structural and functional studies. Molecular cloning was used for heterologous expression and deletion of xanA. A Michaelis-Menten kinetics model was obtained using the recombinant protein. The protein structure was also determined by X-ray diffraction on the recombinant enzyme substrate-free, bound to glucose-1,6-biphosphate and to glucose-1-phosphate. Deletion of xanA was done with a suicide plasmid construct and the obtained mutant was tested for pathogenic capacity. This study is the first describing the properties of the Xanthomonas citri subsp. citri phosphoglucomutase.
Topics: Bacterial Proteins; Catalytic Domain; Citrus; Cloning, Molecular; Crystallography, X-Ray; Genes, Bacterial; Kinetics; Models, Molecular; Mutation; Phosphoglucomutase; Plant Diseases; Polysaccharides, Bacterial; Protein Conformation; Recombinant Proteins; Virulence; Xanthomonas
PubMed: 27567706
DOI: 10.1016/j.bbapap.2016.08.014 -
PLoS Biology Oct 2018Glycogen metabolism commonly altered in cancer is just beginning to be understood. Phosphoglucomutase 1 (PGM1), the first enzyme in glycogenesis that catalyzes the...
Glycogen metabolism commonly altered in cancer is just beginning to be understood. Phosphoglucomutase 1 (PGM1), the first enzyme in glycogenesis that catalyzes the reversible conversion between glucose 1-phosphate (G-1-P) and glucose 6-phosphate (G-6-P), participates in both the breakdown and synthesis of glycogen. Here, we show that PGM1 is down-regulated in hepatocellular carcinoma (HCC), which is associated with the malignancy and poor prognosis of HCC. Decreased PGM1 expression obstructed glycogenesis pathway, which leads to the increased flow of glucose into glycolysis, thereby promoting tumor cell proliferation and HCC development. The loss of forkhead box protein J2 (FOXJ2), at least partly due to low genomic copy number in HCC, releases cellular nucleic acid-binding protein (CNBP), a nucleic acid chaperon, to bind to and promote G-quadruplex formation in PGM1 promoter and therefore decreases PGM1 expression. In addition, integrated analyses of PGM1 and FOXJ2 expression provide a better prediction for the malignance and prognosis of HCC. This study establishes a tumor-suppressive role of PGM1 by regulating glucose trafficking and uncovers a novel regulatory mechanism of PGM1 expression.
Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Disease Progression; Down-Regulation; Female; Forkhead Transcription Factors; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glucose; Glycolysis; Hep G2 Cells; Humans; Liver Neoplasms; Male; Mice; Mice, Nude; Middle Aged; Phosphoglucomutase; Prognosis; Promoter Regions, Genetic; RNA-Binding Proteins
PubMed: 30335765
DOI: 10.1371/journal.pbio.2006483 -
Scientific Reports Mar 2020Human phosphoglucomutase 1 (PGM1) is an evolutionary conserved enzyme that belongs to the ubiquitous and ancient α-D-phosphohexomutases, a large enzyme superfamily with...
Human phosphoglucomutase 1 (PGM1) is an evolutionary conserved enzyme that belongs to the ubiquitous and ancient α-D-phosphohexomutases, a large enzyme superfamily with members in all three domains of life. PGM1 catalyzes the bi-directional interconversion between α-D-glucose 1-phosphate (G1P) and α-D-glucose 6-phosphate (G6P), a reaction that is essential for normal carbohydrate metabolism and also important in the cytoplasmic biosynthesis of nucleotide sugars needed for glycan biosynthesis. Clinical studies have shown that mutations in the PGM1 gene may cause PGM1 deficiency, an inborn error of metabolism previously classified as a glycogen storage disease, and PGM1 deficiency was recently also shown to be a congenital disorder of glycosylation. Here we present three crystal structures of the isoform 2 variant of PGM1, both as a free enzyme and in complex with its substrate and product. The structures show the longer N-terminal of this PGM1 variant, and the ligand complex structures reveal for the first time the detailed structural basis for both G1P substrate and G6P product recognition by human PGM1. We also show that PGM1 and the paralogous gene PGM5 are the results of a gene duplication event in a common ancestor of jawed vertebrates, and, importantly, that both PGM1 isoforms are conserved and of functional significance in all vertebrates. Our finding that PGM1 encodes two equally conserved and functionally important isoforms in the human organism should be taken into account in the evaluation of disease-related missense mutations in patients in the future.
Topics: Animals; Catalytic Domain; Cytoplasm; Glucose-6-Phosphate; Glucosephosphates; Glycogen Storage Disease; Glycosylation; Humans; Ligands; Mutation, Missense; Phosphoglucomutase; Phosphotransferases (Phosphomutases); Protein Isoforms; Vertebrates
PubMed: 32221390
DOI: 10.1038/s41598-020-62548-0 -
Journal of Inherited Metabolic Disease Mar 2015
Topics: Animals; Glycogen Storage Disease; Humans; Mutation, Missense; Phosphoglucomutase
PubMed: 25288126
DOI: 10.1007/s10545-014-9769-5 -
Scientific Reports Oct 2015The practice of Ayurveda, the traditional medicine of India, is based on the concept of three major constitutional types (Vata, Pitta and Kapha) defined as "Prakriti"....
The practice of Ayurveda, the traditional medicine of India, is based on the concept of three major constitutional types (Vata, Pitta and Kapha) defined as "Prakriti". To the best of our knowledge, no study has convincingly correlated genomic variations with the classification of Prakriti. In the present study, we performed genome-wide SNP (single nucleotide polymorphism) analysis (Affymetrix, 6.0) of 262 well-classified male individuals (after screening 3416 subjects) belonging to three Prakritis. We found 52 SNPs (p ≤ 1 × 10(-5)) were significantly different between Prakritis, without any confounding effect of stratification, after 10(6) permutations. Principal component analysis (PCA) of these SNPs classified 262 individuals into their respective groups (Vata, Pitta and Kapha) irrespective of their ancestry, which represent its power in categorization. We further validated our finding with 297 Indian population samples with known ancestry. Subsequently, we found that PGM1 correlates with phenotype of Pitta as described in the ancient text of Caraka Samhita, suggesting that the phenotypic classification of India's traditional medicine has a genetic basis; and its Prakriti-based practice in vogue for many centuries resonates with personalized medicine.
Topics: Female; Genome-Wide Association Study; Humans; Male; Medicine, Ayurvedic; Phosphoglucomutase; Polymorphism, Single Nucleotide
PubMed: 26511157
DOI: 10.1038/srep15786 -
MicrobiologyOpen Feb 2017The agarolytic bacterium Persicobacter sp. CCB-QB2 was isolated from seaweed (genus Ulva) collected from a coastal area of Malaysia. Here, we report a high-quality draft...
The agarolytic bacterium Persicobacter sp. CCB-QB2 was isolated from seaweed (genus Ulva) collected from a coastal area of Malaysia. Here, we report a high-quality draft genome sequence for QB2. The Rapid Annotation using Subsystem Technology (RAST) annotation server identified four β-agarases (PdAgaA, PdAgaB, PdAgaC, and PdAgaD) as well as galK, galE, and phosphoglucomutase, which are related to the Leloir pathway. Interestingly, QB2 exhibited a diauxic growth in the presence of two kinds of nutrients, such as tryptone and agar. In cells grown with agar, the profiles of agarase activity and growth rate were very similar. galK, galE, and phosphoglucomutase genes were highly expressed in the second growth phase of diauxic growth, indicating that QB2 cells use galactose hydrolyzed from agar by its agarases and exhibit nutrient prioritization. This is the first report describing diauxic growth for agarolytic bacteria. QB2 is a potential novel model organism for studying diauxic growth in environmental bacteria.
Topics: Agar; Bacteroidetes; Base Sequence; DNA, Bacterial; Energy Metabolism; Galactose; Genome, Bacterial; Glycoside Hydrolases; Malaysia; Phosphoglucomutase; Seaweed; Sequence Analysis, DNA
PubMed: 27987272
DOI: 10.1002/mbo3.405 -
PloS One 2014Phosphoglucomutase (PGM) catalyses the interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P) and exists as plastidial (pPGM) and cytosolic (cPGM)...
Phosphoglucomutase (PGM) catalyses the interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P) and exists as plastidial (pPGM) and cytosolic (cPGM) isoforms. The plastidial isoform is essential for transitory starch synthesis in chloroplasts of leaves, whereas the cytosolic counterpart is essential for glucose phosphate partitioning and, therefore, for syntheses of sucrose and cell wall components. In Arabidopsis two cytosolic isoforms (PGM2 and PGM3) exist. Both PGM2 and PGM3 are redundant in function as single mutants reveal only small or no alterations compared to wild type with respect to plant primary metabolism. So far, there are no reports of Arabidopsis plants lacking the entire cPGM or total PGM activity, respectively. Therefore, amiRNA transgenic plants were generated and used for analyses of various parameters such as growth, development, and starch metabolism. The lack of the entire cPGM activity resulted in a strongly reduced growth revealed by decreased rosette fresh weight, shorter roots, and reduced seed production compared to wild type. By contrast content of starch, sucrose, maltose and cell wall components were significantly increased. The lack of both cPGM and pPGM activities in Arabidopsis resulted in dwarf growth, prematurely die off, and inability to develop a functional inflorescence. The combined results are discussed in comparison to potato, the only described mutant with lack of total PGM activity.
Topics: Arabidopsis; Carbohydrate Metabolism; Cytosol; Enzyme Activation; Isoenzymes; Metabolome; Metabolomics; Phenotype; Phosphoglucomutase; Plant Roots; Plants, Genetically Modified; Seeds; Starch
PubMed: 25401493
DOI: 10.1371/journal.pone.0112468 -
Journal of Dairy Science Aug 1971
Review
Topics: Albumins; Animals; Female; Glucose; Glycoproteins; Guinea Pigs; Hexokinase; Isomerases; Lactation; Lactose; Mammary Glands, Animal; Nucleotidyltransferases; Phosphoglucomutase; Pregnancy; Rats
PubMed: 4938533
DOI: 10.3168/jds.S0022-0302(71)86007-1