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The Metabolic Map into the Pathomechanism and Treatment of PGM1-CDG
S. Radenkovic, MJ. Bird, TL. Emmerzaal, SY. Wong, C. Felgueira, KM. Stiers, L. Sabbagh, N. Himmelreich, G. Poschet, P. Windmolders, J. Verheijen, P. Witters, R. Altassan, T. Honzik, TF. Eminoglu, PM. James, AC. Edmondson, J. Hertecant, T. Kozicz,...
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
T32 GM008638
NIGMS NIH HHS - United States
NV16-31932A
MZ0
CEP - Centrální evidence projektů
Digitální knihovna NLK
Plný text - Článek
NLK
Cell Press Free Archives
od 1997-01-01 do Před 6 měsíci
Free Medical Journals
od 1949 do Před 6 měsíci
PubMed Central
od 1949 do Před 6 měsíci
Europe PubMed Central
od 1949 do Před 6 měsíci
Open Access Digital Library
od 2005-01-01
- MeSH
- fibroblasty účinky léků metabolismus patologie MeSH
- fosfoglukomutasa nedostatek MeSH
- galaktosa aplikace a dávkování MeSH
- glykosylace MeSH
- kohortové studie MeSH
- kultivované buňky MeSH
- lidé MeSH
- uridindifosfátgalaktosa metabolismus MeSH
- uridindifosfátglukosa metabolismus MeSH
- vrozené poruchy glykosylace farmakoterapie metabolismus patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Phosphoglucomutase 1 (PGM1) encodes the metabolic enzyme that interconverts glucose-6-P and glucose-1-P. Mutations in PGM1 cause impairment in glycogen metabolism and glycosylation, the latter manifesting as a congenital disorder of glycosylation (CDG). This unique metabolic defect leads to abnormal N-glycan synthesis in the endoplasmic reticulum (ER) and the Golgi apparatus (GA). On the basis of the decreased galactosylation in glycan chains, galactose was administered to individuals with PGM1-CDG and was shown to markedly reverse most disease-related laboratory abnormalities. The disease and treatment mechanisms, however, have remained largely elusive. Here, we confirm the clinical benefit of galactose supplementation in PGM1-CDG-affected individuals and obtain significant insights into the functional and biochemical regulation of glycosylation. We report here that, by using tracer-based metabolomics, we found that galactose treatment of PGM1-CDG fibroblasts metabolically re-wires their sugar metabolism, and as such replenishes the depleted levels of galactose-1-P, as well as the levels of UDP-glucose and UDP-galactose, the nucleotide sugars that are required for ER- and GA-linked glycosylation, respectively. To this end, we further show that the galactose in UDP-galactose is incorporated into mature, de novo glycans. Our results also allude to the potential of monosaccharide therapy for several other CDG.
Biochemistry Department University of Missouri Columbia MO 65211 USA
Center of Individualized Medicine Department of Clinical Genomics Mayo Clinic Rochester MN 55905 USA
Centre for Organismal Studies University of Heidelberg 69120 Heidelberg Germany
Clinical Department of Laboratory Medicine University Hospitals Leuven 3000 Leuven Belgium
Department of Cardiovascular Sciences Katholieke Universiteit Leuven 3000 Leuven Belgium
Department of Pediatrics United Arab Emirates University Al Ain United Arab Emirates
Hayward Genetics Center Tulane University School of Medicine New Orleans LA 70112 LA USA
Medical Genetics Department Montréal Children's Hospital McGill University Montreal QC H4A3J1 Canada
Metabolic Center University Hospitals Leuven 3000 Leuven Belgium
Citace poskytuje Crossref.org
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