| Phosphomannose isomerase inhibitors improve N-glycosylation in selected phosphomannomutase-deficient fibroblasts. | |
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MedLine Citation:
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PMID: 21949237 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Congenital disorders of glycosylation (CDG) are rare genetic disorders due to impaired glycosylation. The patients with subtypes CDG-Ia and CDG-Ib have mutations in the genes encoding phosphomannomutase 2 (PMM2) and phosphomannose isomerase (MPI or PMI), respectively. PMM2 (mannose 6-phosphate → mannose 1-phosphate) and MPI (mannose 6-phosphate ⇔ fructose 6-phosphate) deficiencies reduce the metabolic flux of mannose 6-phosphate (Man-6-P) into glycosylation, resulting in unoccupied N-glycosylation sites. Both PMM2 and MPI compete for the same substrate, Man-6-P. Daily mannose doses reverse most of the symptoms of MPI-deficient CDG-Ib patients. However, CDG-Ia patients do not benefit from mannose supplementation because >95% Man-6-P is catabolized by MPI. We hypothesized that inhibiting MPI enzymatic activity would provide more Man-6-P for glycosylation and possibly benefit CDG-Ia patients with residual PMM2 activity. Here we show that MLS0315771, a potent MPI inhibitor from the benzoisothiazolone series, diverts Man-6-P toward glycosylation in various cell lines including fibroblasts from CDG-Ia patients and improves N-glycosylation. Finally, we show that MLS0315771 increases mannose metabolic flux toward glycosylation in zebrafish embryos. |
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Authors:
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Vandana Sharma; Mie Ichikawa; Ping He; David A Scott; Yalda Bravo; Russell Dahl; Bobby G Ng; Nicholas D P Cosford; Hudson H Freeze |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-09-26 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 286 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2011 Nov |
Date Detail:
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Created Date: 2011-11-07 Completed Date: 2011-12-27 Revised Date: 2012-03-27 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 39431-8 Citation Subset: IM |
Affiliation:
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Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Congenital Disorders of Glycosylation / drug therapy*, enzymology*, genetics Enzyme Inhibitors / pharmacology*, therapeutic use Fibroblasts / enzymology* Glycosylation / drug effects HeLa Cells Humans Mannose / genetics, metabolism Mannose-6-Phosphate Isomerase / antagonists & inhibitors*, genetics, metabolism Mannosephosphates / genetics, metabolism Mutation Phosphotransferases (Phosphomutases) / genetics* Zebrafish / genetics, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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R01-DK55615/DK/NIDDK NIH HHS; R21-HD062914/HD/NICHD NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Mannosephosphates; 31103-86-3/Mannose; 3672-15-9/mannose-6-phosphate; EC 5.3.1.8/Mannose-6-Phosphate Isomerase; EC 5.4.2.-/Phosphotransferases (Phosphomutases); EC 5.4.2.8/phosphomannomutase 2, human |
| Comments/Corrections | |
Erratum In:
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J Biol Chem. 2011 Dec 16;286(50):43588 Note: Scott, David A [added] |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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