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 for Child and Adolescent Medicine Department 1 University of Heidelberg 69120 Heidelberg Germany

Center of Individualized Medicine Department of Clinical Genomics Mayo Clinic Rochester MN 55905 USA

Center of Individualized Medicine Department of Clinical Genomics Mayo Clinic Rochester MN 55905 USA; Metabolic Center University Hospitals Leuven 3000 Leuven Belgium

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 Anatomy Radboud University Medical Centre Donders Institute for Brain Cognition and Behaviour 6535 HR Nijmegen the Netherlands

Department of Anatomy Radboud University Medical Centre Donders Institute for Brain Cognition and Behaviour 6535 HR Nijmegen the Netherlands; Hayward Genetics Center Tulane University School of Medicine New Orleans LA 70112 LA USA; Center of Individualized Medicine Department of Clinical Genomics Mayo Clinic Rochester MN 55905 USA

Department of Pediatric Metabolism and Nutrition Ankara University School of Medicine 06560 Ankara Turkey

Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague 12108 Prague Czech Republic

Department of Pediatrics United Arab Emirates University Al Ain United Arab Emirates

Division of Human Genetics Department of Pediatrics the Children's Hospital of Philadelphia Philadelphia PA 19104 USA

Hayward Genetics Center Tulane University School of Medicine New Orleans LA 70112 LA USA

Laboratory of Hepatology Department of Chronic Diseases Metabolism and Aging Katholieke Universiteit Leuven 3000 Leuven Belgium

Laboratory of Hepatology Department of Chronic Diseases Metabolism and Aging Katholieke Universiteit Leuven 3000 Leuven Belgium; Metabolic Center University Hospitals Leuven 3000 Leuven Belgium

Metabolic Center University Hospitals Leuven 3000 Leuven Belgium

Metabolic Center University Hospitals Leuven 3000 Leuven Belgium; Medical Genetics Department Montréal Children's Hospital McGill University Montreal QC H4A3J1 Canada

Metabolomics Expertise Center Center for Cancer Biology VIB Center for Cancer Biology 3000 Leuven Belgium; Laboratory of Hepatology Department of Chronic Diseases Metabolism and Aging Katholieke Universiteit Leuven 3000 Leuven Belgium; Metabolomics Expertise Center Department of Oncology Katholieke Universiteit Leuven 3000 Leuven Belgium

Metabolomics Expertise Center Center for Cancer Biology VIB Center for Cancer Biology 3000 Leuven Belgium; Laboratory of Hepatology Department of Chronic Diseases Metabolism and Aging Katholieke Universiteit Leuven 3000 Leuven Belgium; Metabolomics Expertise Center Department of Oncology Katholieke Universiteit Leuven 3000 Leuven Belgium; Clinical Department of Laboratory Medicine University Hospitals Leuven 3000 Leuven Belgium

Metabolomics Expertise Center Center for Cancer Biology VIB Center for Cancer Biology 3000 Leuven Belgium; Metabolomics Expertise Center Department of Oncology Katholieke Universiteit Leuven 3000 Leuven Belgium

Phoenix Children's Medical Group Genetics and Metabolism Phoenix Children's Hospital Phoenix AZ 85016 USA

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