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Clinics in Chest Medicine Sep 2016Elevated serum IgE has many etiologies including parasitic infection, allergy and asthma, malignancy, and immune dysregulation. The hyper-IgE syndromes caused by... (Review)
Review
Elevated serum IgE has many etiologies including parasitic infection, allergy and asthma, malignancy, and immune dysregulation. The hyper-IgE syndromes caused by mutations in STAT3, DOCK8, and PGM3 are monogenic primary immunodeficiencies associated with high IgE, eczema, and recurrent infections. These primary immunodeficiencies are associated with recurrent pneumonias leading to bronchiectasis; however, each has unique features and genetic diagnosis is essential in guiding therapy, discussing family planning, and defining prognosis. This article discusses the clinical features of these primary immunodeficiencies with a particular focus on the pulmonary manifestations and discussion of the genetics, pathogenesis, and approaches to therapy.
Topics: Guanine Nucleotide Exchange Factors; Humans; Job Syndrome; Lung Diseases; Mutation; Phosphoglucomutase; STAT3 Transcription Factor
PubMed: 27514600
DOI: 10.1016/j.ccm.2016.04.016 -
Marine Drugs Jul 2022Agar is widely applied across the food, pharmaceutical and biotechnology industries, owing to its various bioactive functions. To better understand the agar biosynthesis...
Agar is widely applied across the food, pharmaceutical and biotechnology industries, owing to its various bioactive functions. To better understand the agar biosynthesis in commercial seaweed , the activities of four enzymes participating in the agar biosynthesis were detected, and phosphoglucomutase (PGM) was confirmed as highly correlated with agar accumulation. Three genes of (, and ) were identified from the genome. The subcellular localization analysis validated that GlPGM1 was located in the chloroplast and GlPGM3 was not significantly distributed in the organelles. Both the GlPGM1 and GlPGM3 protein levels showed a remarkable consistency with the agar variations, and GlPGM3 may participate in the carbon flux between (iso)floridoside, floridean starch and agar synthesis. After treatment with the PGM inhibitor, the agar and floridean starch contents and the activities of floridean starch synthase were significantly decreased; products identified in the Calvin cycle, the pentose phosphate pathway, the Embden-Meyerhof-Parnas pathway and the tricarboxylic acid cycle were depressed; however, lipids, phenolic acids and the intermediate metabolites, fructose-1,6-phosphate were upregulated. These findings reveal the essential role of PGM in regulating the carbon flux between agar and other carbohydrates in , providing a guide for the artificial regulation of agar accumulation.
Topics: Agar; Carbon Cycle; Phosphoglucomutase; Rhodophyta; Starch
PubMed: 35877735
DOI: 10.3390/md20070442 -
Biomolecular NMR Assignments Oct 2019β-Phosphoglucomutase (βPGM) is a magnesium-dependent phosphoryl transfer enzyme that catalyses the reversible isomerisation of β-glucose 1-phosphate and glucose...
β-Phosphoglucomutase (βPGM) is a magnesium-dependent phosphoryl transfer enzyme that catalyses the reversible isomerisation of β-glucose 1-phosphate and glucose 6-phosphate, via two phosphoryl transfer steps and a β-glucose 1,6-bisphosphate intermediate. Substrate-free βPGM is an essential component of the catalytic cycle and an understanding of its dynamics would present significant insights into βPGM functionality, and enzyme catalysed phosphoryl transfer in general. Previously, 30 residues around the active site of substrate-free βPGM were identified as undergoing extensive millisecond dynamics and were unassignable. Here we report H, N and C backbone resonance assignments of the P146A variant (βPGM) in its substrate-free form, where the K145-A146 peptide bond adopts a trans conformation in contrast to all crystal structures of βPGM, where the K145-P146 peptide bond is cis. In βPGM millisecond dynamics are suppressed for all but 17 residues, allowing 92% of backbone resonances to be assigned. Secondary structure predictions using TALOS-N reflect βPGM crystal structures, and a chemical shift comparison between substrate-free βPGM and βPGM confirms that the solution conformations are very similar, except for the D137-A147 loop. Hence, the isomerisation state of the 145-146 peptide bond has little effect on structure but the cis conformation triggers millisecond dynamics in the hinge (V12-T16), the nucleophile (D8) and residues that coordinate the transferring phosphate group (D8 and S114-S116), and the D137-A147 loop (V141-A142 and K145). These millisecond dynamics occur in addition to those for residues involved in coordinating the catalytic Mg ion and the L44-L53 loop responsible for substrate discrimination.
Topics: Lactococcus lactis; Mutant Proteins; Nuclear Magnetic Resonance, Biomolecular; Phosphoglucomutase
PubMed: 31396843
DOI: 10.1007/s12104-019-09904-y -
BMC Research Notes May 2022Toxoplasma gondii is a ubiquitous parasite of medical and veterinary importance; however, there exists no cure for chronic toxoplasmosis. Metabolic enzymes required for...
OBJECTIVE
Toxoplasma gondii is a ubiquitous parasite of medical and veterinary importance; however, there exists no cure for chronic toxoplasmosis. Metabolic enzymes required for the production and maintenance of tissue cysts represent promising targets for novel therapies. Here, we use reverse genetics to investigate the role of Toxoplasma phosphoglucomutase 1, PGM1, in Toxoplasma growth and cystogenesis.
RESULTS
We found that disruption of pgm1 did not significantly affect Toxoplasma intracellular growth and the lytic cycle. pgm1-defective parasites could differentiate into bradyzoites and produced cysts containing amylopectin in vitro. However, cysts produced in the absence of pgm1 were significantly smaller than wildtype. Together, our findings suggest that PGM1 is dispensable for in vitro growth but contributes to optimal Toxoplasma cyst development in vitro, thereby necessitating further investigation into the function of this enzyme in Toxoplasma persistence in its host.
Topics: Humans; Phosphoglucomutase; Toxoplasma; Toxoplasmosis
PubMed: 35597992
DOI: 10.1186/s13104-022-06073-5 -
Journal of Clinical Pathology.... 1974
Topics: Alleles; Erythrocytes; Heterozygote; Humans; Isoenzymes; Phosphoglucomutase; Polymorphism, Genetic; Protein Conformation
PubMed: 4536358
DOI: No ID Found -
Frontiers in Cellular and Infection... 2022The obligate intracellular bacteria store glycogen in the lumen of the vacuoles in which they grow. Glycogen catabolism generates glucose-1-phosphate (Glc1P), while the...
The obligate intracellular bacteria store glycogen in the lumen of the vacuoles in which they grow. Glycogen catabolism generates glucose-1-phosphate (Glc1P), while the bacteria can take up only glucose-6-phosphate (Glc6P). We tested whether the conversion of Glc1P into Glc6P could be catalyzed by a phosphoglucomutase (PGM) of host or bacterial origin. We found no evidence for the presence of the host PGM in the vacuole. Two proteins, CT295 and CT815, are potential PGMs. By reconstituting the reaction using purified proteins, and by complementing PGM deficient fibroblasts, we demonstrated that only CT295 displayed robust PGM activity. Intriguingly, we showed that glycogen accumulation in the lumen of the vacuole of a subset of species (, , ) correlated with the presence, in CT295 orthologs, of a secretion signal recognized by the type three secretion (T3S) machinery of . and do not accumulate glycogen, and their CT295 orthologs lack T3S signals. In conclusion, we established that the conversion of Glc1P into Glc6P was accomplished by a bacterial PGM, through the acquisition of a T3S signal in a "housekeeping" protein. Acquisition of this signal likely contributed to shaping glycogen metabolism within .
Topics: Chlamydia trachomatis; Glucose-6-Phosphate; Glycogen; Phosphoglucomutase; Vacuoles
PubMed: 35795184
DOI: 10.3389/fcimb.2022.866729 -
Molecular Genetics and Metabolism Aug 2014We recently redefined phosphoglucomutase-1 deficiency not only as an enzyme defect, involved in normal glycogen metabolism, but also an inborn error of protein... (Review)
Review
We recently redefined phosphoglucomutase-1 deficiency not only as an enzyme defect, involved in normal glycogen metabolism, but also an inborn error of protein glycosylation. Phosphoglucomutase-1 is a key enzyme in glycolysis and glycogenesis by catalyzing in the bidirectional transfer of phosphate from position 1 to 6 on glucose. Glucose-1-P and UDP-glucose are closely linked to galactose metabolism. Normal PGM1 activity is important for effective glycolysis during fasting. Activated glucose and galactose are essential for normal protein glycosylation. The complex defect involving abnormal concentrations of activated sugars leads to hypoglycemia and two major phenotypic presentations, one with primary muscle involvement and the other with severe multisystem disease. The multisystem phenotype includes growth delay and malformations, like cleft palate or uvula, and liver, endocrine and heart function with possible cardiomyopathy. The patients have normal intelligence. Decreased transferrin galactosylation is a characteristic finding on mass spectrometry. Previous in vitro studies in patient fibroblasts showed an improvement of glycosylation on galactose supplements. Four patients with PGM1 deficiency have been trialed on d-galactose (compassionate use), and showed improvement of serum transferrin hypoglycosylation. There was a parallel improvement of liver function, endocrine abnormalities and a decrease in the frequency of hypoglycemic episodes. No side effects have been observed. Galactose supplementation didn't seem to resolve all clinical symptoms. Adding complex carbohydrates showed an additional clinical amelioration. Based on the available clinical data we suggest to consider the use of 0.5-1g/kg/day d-galactose and maximum 50 g/day oral galactose therapy in PGM1-CDG. The existing data on galactose therapy have to be viewed as preliminary observations. A prospective multicenter trial is ongoing to evaluate the efficacy and optimal d-galactose dose of galactose supplementation.
Topics: Congenital Disorders of Glycosylation; Galactose; Humans; Hypoglycemia; Muscular Diseases; Phenotype; Phosphoglucomutase
PubMed: 24997537
DOI: 10.1016/j.ymgme.2014.06.002 -
Journal of Experimental Botany Mar 2023This article comments on: . 2023. Stress response requires an efficient glycogen and central carbon metabolism connection by phosphoglucomutases in cyanobacteria....
This article comments on: . 2023. Stress response requires an efficient glycogen and central carbon metabolism connection by phosphoglucomutases in cyanobacteria. Journal of Experimental Botany , 1532–1550
Topics: Phosphoglucomutase; Synechocystis; Bacterial Proteins
PubMed: 36913621
DOI: 10.1093/jxb/erac513 -
The Journal of Biological Chemistry Jun 2022Aspergillus fumigatus is the causative agent of invasive aspergillosis, an infection with mortality rates of up to 50%. The glucan-rich cell wall of A. fumigatus is a...
Aspergillus fumigatus is the causative agent of invasive aspergillosis, an infection with mortality rates of up to 50%. The glucan-rich cell wall of A. fumigatus is a protective structure that is absent from human cells and is a potential target for antifungal treatments. Glucan is synthesized from the donor uridine diphosphate glucose, with the conversion of glucose-6-phosphate to glucose-1-phosphate by the enzyme phosphoglucomutase (PGM) representing a key step in its biosynthesis. Here, we explore the possibility of selectively targeting A. fumigatus PGM (AfPGM) as an antifungal treatment strategy. Using a promoter replacement strategy, we constructed a conditional pgm mutant and revealed that pgm is required for A. fumigatus growth and cell wall integrity. In addition, using a fragment screen, we identified the thiol-reactive compound isothiazolone fragment of PGM as targeting a cysteine residue not conserved in the human ortholog. Furthermore, through scaffold exploration, we synthesized a para-aryl derivative (ISFP10) and demonstrated that it inhibits AfPGM with an IC of 2 μM and exhibits 50-fold selectivity over the human enzyme. Taken together, our data provide genetic validation of PGM as a therapeutic target and suggest new avenues for inhibiting AfPGM using covalent inhibitors that could serve as tools for chemical validation.
Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Glucans; Humans; Phosphoglucomutase
PubMed: 35504355
DOI: 10.1016/j.jbc.2022.102003 -
FEMS Microbiology Reviews Mar 2008The biosynthesis of bacterial cell wall peptidoglycan is a complex process that involves enzyme reactions that take place in the cytoplasm (synthesis of the nucleotide... (Review)
Review
The biosynthesis of bacterial cell wall peptidoglycan is a complex process that involves enzyme reactions that take place in the cytoplasm (synthesis of the nucleotide precursors) and on the inner side (synthesis of lipid-linked intermediates) and outer side (polymerization reactions) of the cytoplasmic membrane. This review deals with the cytoplasmic steps of peptidoglycan biosynthesis, which can be divided into four sets of reactions that lead to the syntheses of (1) UDP-N-acetylglucosamine from fructose 6-phosphate, (2) UDP-N-acetylmuramic acid from UDP-N-acetylglucosamine, (3) UDP-N-acetylmuramyl-pentapeptide from UDP-N-acetylmuramic acid and (4) D-glutamic acid and dipeptide D-alanyl-D-alanine. Recent data concerning the different enzymes involved are presented. Moreover, special attention is given to (1) the chemical and enzymatic synthesis of the nucleotide precursor substrates that are not commercially available and (2) the search for specific inhibitors that could act as antibacterial compounds.
Topics: Bacteria; Bacterial Proteins; Biosynthetic Pathways; Cytoplasm; Escherichia coli Proteins; Multienzyme Complexes; Peptidoglycan; Phosphoglucomutase; Uridine Diphosphate N-Acetylglucosamine
PubMed: 18266853
DOI: 10.1111/j.1574-6976.2008.00104.x