Document Detail

Phosphomannose isomerase inhibitors improve N-glycosylation in selected phosphomannomutase-deficient fibroblasts.
MedLine Citation:
PMID:  21949237     Owner:  NLM     Status:  MEDLINE    
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.
Vandana Sharma; Mie Ichikawa; Ping He; David A Scott; Yalda Bravo; Russell Dahl; Bobby G Ng; Nicholas D P Cosford; Hudson H Freeze
Related Documents :
9458387 - Value of fluorescence in situ hybridization for detecting the bcr/abl gene fusion in in...
8807107 - Allogeneic bone marrow transplantation for acute leukaemia--igci experience. internatio...
19291297 - Discovery and identification of potential biomarkers of pediatric acute lymphoblastic l...
9552087 - Comparison of referring and tertiary cancer center physician's diagnoses in patients wi...
10886317 - Assessment of corticodiaphragmatic pathway and pulmonary function in acute ischemic str...
20057157 - Does obesity attenuate the effect of metabolic syndrome on chronic kidney disease in pa...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-09-26
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-07     Completed Date:  2011-12-27     Revised Date:  2013-10-28    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  39431-8     Citation Subset:  IM    
Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Congenital Disorders of Glycosylation / drug therapy*,  enzymology*,  genetics
Enzyme Inhibitors / pharmacology*,  therapeutic use
Fibroblasts / enzymology*
Glycosylation / drug effects
HeLa Cells
Mannose / genetics,  metabolism
Mannose-6-Phosphate Isomerase / antagonists & inhibitors*,  genetics,  metabolism
Mannosephosphates / genetics,  metabolism
Phosphotransferases (Phosphomutases) / genetics*
Zebrafish / genetics,  metabolism
Grant Support
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Mannosephosphates; 31103-86-3/Mannose; 3672-15-9/mannose-6-phosphate; EC Isomerase; EC 5.4.2.-/Phosphotransferases (Phosphomutases); EC 2, human
Erratum In:
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

Previous Document:  The expression profile of de-N-acetyl polysialic acid (NeuPSA) in normal and diseased human tissue.
Next Document:  Binding to syntenin-1 protein defines a new mode of ubiquitin-based interactions regulated by phosph...