The metabolic map into the pathomechanism and treatment of PGM1-CDG

• Verfasst von: Radenkovic, Silvia [VerfasserIn]
• Verfasst von: Himmelreich, Nastassja [VerfasserIn]
• Verfasst von: Thiel, Christian [VerfasserIn]
• Titel: The metabolic map into the pathomechanism and treatment of PGM1-CDG
• Verf.angabe: Silvia Radenkovic, Matthew J. Bird, Tim L. Emmerzaal, Sunnie Y. Wong, Catarina Felgueira, Kyle M. Stiers, Leila Sabbagh, Nastassja Himmelreich, Gernot Poschet, Petra Windmolders, Jan Verheijen, Peter Witters, Ruqaiah Altassan, Tomas Honzik, Tuba F. Eminoglu, Phillip M. James, Andrew C. Edmondson, Jozef Hertecant, Tamas Kozicz, Christian Thiel, Pieter Vermeersch, David Cassiman, Lesa Beamer, Eva Morava, Bart Ghesquière
• E-Jahr: 2019
• Jahr: April 11, 2019
• Umfang: 12 S.
• Fussnoten: Gesehen am 03.07.2019
• Titel Quelle: Enthalten in: American journal of human genetics
• Ort Quelle: New York, NY [u.a.] : Cell Press, 1949
• Jahr Quelle: 2019
• Band/Heft Quelle: 104(2019), 5, Seite 835-846
• ISSN Quelle: 0002-9297
• DOI: doi:10.1016/j.ajhg.2019.03.003
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: CDG
• Sach-SW: central carbon metabolism
• Sach-SW: galactose
• Sach-SW: glycosylation
• Sach-SW: mitochondria
• Sach-SW: nucleotide sugars
• Sach-SW: PGM1-CDG
• Sach-SW: tracer metabolomics
• K10plus-PPN: 1668442884

Abstract

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.