A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články
PubMed
38821050
PubMed Central
PMC11250103
DOI
10.1016/j.cell.2024.04.041
PII: S0092-8674(24)00467-7
Knihovny.cz E-zdroje
- Klíčová slova
- N-glycosylation, congenital disorders of glycosylation, dolichal, dolichol, lipid droplets, polyisoprenoids, polyprenal, polyprenol, pseudoautosomal region,
- MeSH
- 3-oxo-5-alfa-steroid-4-dehydrogenasa metabolismus genetika MeSH
- dolichol * metabolismus biosyntéza MeSH
- glykosylace MeSH
- lidé MeSH
- membránové proteiny metabolismus genetika MeSH
- missense mutace MeSH
- vrozené poruchy glykosylace metabolismus genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 3-oxo-5-alfa-steroid-4-dehydrogenasa MeSH
- dolichol * MeSH
- membránové proteiny MeSH
- SRD5A3 protein, human MeSH Prohlížeč
Dolichol is a lipid critical for N-glycosylation as a carrier for activated sugars and nascent oligosaccharides. It is commonly thought to be directly produced from polyprenol by the enzyme SRD5A3. Instead, we found that dolichol synthesis requires a three-step detour involving additional metabolites, where SRD5A3 catalyzes only the second reaction. The first and third steps are performed by DHRSX, whose gene resides on the pseudoautosomal regions of the X and Y chromosomes. Accordingly, we report a pseudoautosomal-recessive disease presenting as a congenital disorder of glycosylation in patients with missense variants in DHRSX (DHRSX-CDG). Of note, DHRSX has a unique dual substrate and cofactor specificity, allowing it to act as a NAD+-dependent dehydrogenase and as a NADPH-dependent reductase in two non-consecutive steps. Thus, our work reveals unexpected complexity in the terminal steps of dolichol biosynthesis. Furthermore, we provide insights into the mechanism by which dolichol metabolism defects contribute to disease.
Department of Pediatrics Center for Metabolic Diseases University Hospitals Leuven Leuven Belgium
Institute of Biomedical Sciences Faculty of Medicine Vilnius University Vilnius Lithuania
Laboratory for Molecular Diagnosis Center for Human Genetics KU Leuven Leuven Belgium
Univ Lille CNRS UMR 8576 UGSF Unité de Glycobiologie Structurale et Fonctionnelle 59000 Lille France
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