| Title |
A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis / |
| Authors |
Wilson, Matthew P ; Kentache, Takfarinas ; Althoff, Charlotte R ; Schulz, Celine ; de Bettignies, Geoffroy ; Cabrera, Gisele Mateu ; Cimbalistienė, Loreta ; Burnytė, Birutė ; Yoon, Grace ; Bommer, Guido T |
| DOI |
10.1016/j.cell.2024.04.041 |
| Full Text |
|
| Is Part of |
Cell.. Cambridge, MA : Cell Press. 2024, vol. 187, iss. 14, p. [1-17].. ISSN 0092-8674. eISSN 1097-4172 |
| Keywords [eng] |
dolichol ; polyprenol ; dolichal ; polyprenal ; N-glycosylation ; pseudoautosomal region ; congenital disorders of glycosylation ; lipid droplets ; polyisoprenoids |
| Abstract [eng] |
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. |
| Published |
Cambridge, MA : Cell Press |
| Type |
Journal article |
| Language |
English |
| Publication date |
2024 |
| CC license |
|
