比利时鲁汶天主教大学Guido T. Bommer等研究人员合作发现，一种假常染色体糖基化紊乱促进多萜醇生物合成的修正。相关论文于2024年5月30日在线发表在《细胞》杂志上。
研究人员表示，多萜醇是一种对N-糖基化至关重要的脂质，是活化糖和新生寡糖的载体。人们通常认为它是由SRD5A3酶直接从多酚生成的。
但研究人员发现，多萜醇的合成需要经过三步迂回，其中涉及额外的代谢物，而SRD5A3只催化第二步反应。第一和第三步由DHRSX完成，其基因位于X和Y染色体的假常染色体区域。因此，研究人员报告了一种假常染色体隐性疾病，在DHRSX（DHRSX-CDG）错义变体患者中表现为先天性糖基化障碍。值得注意的是，DHRSX具有独特的双重底物和辅助因子特异性，使其能够在两个非连续步骤中作为NAD+依赖性脱氢酶和NADPH依赖性还原酶发挥作用。因此，该工作揭示了多萜醇生物合成末端步骤意想不到的复杂性。此外，研究人员还深入了解了胆固醇代谢缺陷导致疾病的机制。
附：英文原文
Title: A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis
Author: Matthew P. Wilson, Takfarinas Kentache, Charlotte R. Althoff, Céline Schulz, Geoffroy de Bettignies, Gisèle Mateu Cabrera, Loreta Cimbalistiene, Birute Burnyte, Grace Yoon, Gregory Costain, Sandrine Vuillaumier-Barrot, David Cheillan, Daisy Rymen, Lucie Rychtarova, Hana Hansikova, Marina Bury, Joseph P. Dewulf, Francesco Caligiore, Jaak Jaeken, Vincent Cantagrel, Emile Van Schaftingen, Gert Matthijs, Franois Foulquier, Guido T. Bommer
Issue&Volume: 2024-05-30
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.
DOI: 10.1016/j.cell.2024.04.041
Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00467-7