重新审视路径

IF 12.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Nature chemical biology Pub Date : 2024-08-20 DOI:10.1038/s41589-024-01724-z

Gene Chong

引用次数: 0

摘要

蛋白质糖基化和糖代谢缺陷会导致先天性糖基化紊乱（CDGs）。N-糖基化的一个关键步骤涉及脂质多立醇，它的磷酸化形式是将糖转移到蛋白质上的载体。以前，人们认为多立醇是由 SRD5A3 酶直接从聚肾上腺素合成的。Wilson 等人现在报告了对这一途径的修正，发现了从多烯醇到多立醇的三步转换。这种转换涉及到另一种酶 DHRSX，它也被发现与 CDGs 有关。这一发现首先源于发现了四名出现 CDG 症状的患者。他们的血清糖蛋白分析显示糖基化异常，全基因组或外显子组测序发现了 DHRSX 基因的错义变异。DHRSX 以前被注释为一种功能不明的 NADPH 依赖性氧化还原酶。在患者身上发现的突变映射到 DHRSX 的 AlphaFold2 模型中预测的 NADP+ 结合位点附近的疏水核心。Wilson 等人发现，DHRSX 在多戊烯醇和 NADP+ 的存在下产生脂质多戊烯醛，SRD5A3 催化多戊烯醛到多利西醛的下一个反应。有趣的是，DHRSX 还能在有 NADPH 存在的情况下催化从多利查尔到多利可醇的最后反应，在体内，涉及 DHRSX 的这两个反应可同时发生，第一个反应使用 NAD+，最后一步使用 NADPH。缺乏 DHRSX 会导致聚肾酚磷酸盐的积累，而聚肾酚磷酸盐是比多立醇磷酸盐更差的底物，从而破坏了糖基转移酶的活性。这项研究说明了对四名 CDG 患者的检查如何揭示了 DHRSX 在将多烯醇代谢为多羟基化合物的过程中独特的双重功能，而多烯醇对 N-糖基化途径的启动至关重要：细胞 187, 3585-3601.e22 (2024)

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A pathway revisited

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来源期刊

Nature chemical biology 生物-生化与分子生物学

CiteScore

23.90

自引率

1.40%

发文量

238

审稿时长

12 months

期刊介绍： Nature Chemical Biology stands as an esteemed international monthly journal, offering a prominent platform for the chemical biology community to showcase top-tier original research and commentary. Operating at the crossroads of chemistry, biology, and related disciplines, chemical biology utilizes scientific ideas and approaches to comprehend and manipulate biological systems with molecular precision. The journal embraces contributions from the growing community of chemical biologists, encompassing insights from chemists applying principles and tools to biological inquiries and biologists striving to comprehend and control molecular-level biological processes. We prioritize studies unveiling significant conceptual or practical advancements in areas where chemistry and biology intersect, emphasizing basic research, especially those reporting novel chemical or biological tools and offering profound molecular-level insights into underlying biological mechanisms. Nature Chemical Biology also welcomes manuscripts describing applied molecular studies at the chemistry-biology interface due to the broad utility of chemical biology approaches in manipulating or engineering biological systems. Irrespective of scientific focus, we actively seek submissions that creatively blend chemistry and biology, particularly those providing substantial conceptual or methodological breakthroughs with the potential to open innovative research avenues. The journal maintains a robust and impartial review process, emphasizing thorough chemical and biological characterization.