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.

Dolichol 是一种对 N-糖基化至关重要的脂质，作为活化糖和新生寡糖的载体。通常认为它是由聚戊烯醇通过酶 SRD5A3 直接产生的。相反，我们发现多醇合成需要三步绕道，涉及额外的代谢物，其中SRD5A3仅催化第二个反应。第一步和第三步由 DHRSX 执行，其基因位于 X 和 Y 染色体的假常染色体区域。因此，我们报告了一种假常染色体隐性疾病，表现为 DHRSX 错义变异 (DHRSX-CDG) 患者的先天性糖基化障碍。值得注意的是，DHRSX 具有独特的双重底物和辅因子特异性，使其能够在两个非连续步骤中充当 NAD ⁺ 依赖性脱氢酶和 NADPH 依赖性还原酶。因此，我们的工作揭示了多醇生物合成最终步骤中意想不到的复杂性。此外，我们还深入了解多醇代谢缺陷导致疾病的机制。