PDF(Pubmed)
Abstract：
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.
摘要：
Dolichol是N-糖基化的关键脂质，可作为活化糖和新生寡糖的载体。通常认为它是通过酶SRD5A3从聚丙炔醇直接产生的。相反，我们发现dolichol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染色体的伪常染色体区域。因此，我们报道了一种在DHRSX错义变异(DHRSX-CDG)患者中表现为先天性糖基化异常的常染色体隐性遗传病.值得注意的是，DHRSX具有独特的双重底物和辅因子特异性，允许它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dolichol生物合成的最终步骤中意想不到的复杂性。此外，我们提供了有关dolichol代谢缺陷导致疾病的机制的见解。
