2026年8月26日，中国科学院上海药物研究所徐华强等科学家在《自然》发表研究，揭示了灵长类特异性调控人糖鞘脂守门酶UGCG的机制。

糖鞘脂是膜的重要组成成分，它们组织脂质微域并协调细胞信号传导、分化和神经元功能。在人类中，这些功能源于数百种糖鞘脂种类组成的谱系，这些种类通过逐步的糖链延伸而产生。进入这一网络受一个由UDP-葡萄糖神经酰胺葡萄糖基转移酶（UGCG）催化的唯一限速反应所控制，该酶是决定糖鞘脂多样性和规模的守门酶。尽管其在生物学和治疗上具有重要性，但其机制和调控一直未知。在此，研究人员报道了全长人UGCG在八种功能状态下的冷冻电镜结构，分辨率分别为2.9–3.4 Å。UGCG采用一种此前未被识别的三次跨膜架构，将GT-A核心锚定在膜界面，并形成一个结合可溶性底物和膜嵌入底物的双位点活性中心。与典型的GT-A酶不同，UGCG使用由精氨酸网络驱动的金属非依赖性催化机制。研究人员鉴定出一个灵长类特异性立体元件，该元件可调节脂质亲和力和催化周转率，从而调控糖鞘脂的进入。结合临床使用抑制剂的结构揭示了这种架构如何决定其效力和选择性。总之，这些发现定义了一种酶如何通过结构和进化逻辑控制糖鞘脂多样性，并为疾病中膜脂质稳态的精确调控提供了框架。

附：英文原文

Title: Primate-specific regulation of the human glycosphingolipid gatekeeper UGCG

Author: Wu, Canrong, Jin, Sanshan, Xu, Jiuyin, Wang, James Jiqi, Guo, Xiaoqi, Li, Yunhai, Cao, Zhenyu, Jiang, Mengting, Yuan, Qingning, Hu, Wen, Li, Changyao, Xu, Youwei, Wang, Ming-Wei, Jiang, Yi, Xu, H. Eric

Issue&Volume: 2026-08-26

Abstract: Glycosphingolipids are essential membrane components that organize lipid microdomains and orchestrate cellular signalling, differentiation and neuronal function. In humans, these functions arise from a repertoire of several hundred glycosphingolipid species generated through stepwise glycan elaboration. Entry into this network is controlled by a single committed reaction catalysed by UDP-glucose ceramide glucosyltransferase (UGCG), the gatekeeper that dictates the scale and composition of glycosphingolipid diversity. Despite its biological and therapeutic importance, its mechanism and regulation have remained unknown. Here we report cryogenic electron microscopy structures of full-length human UGCG in eight functional states at 2.9–3.4 resolution. UGCG adopts a previously unrecognized triple-pass transmembrane architecture that anchors a GT-A core at the membrane interface and creates a bipartite active site engaging soluble and membrane-embedded substrates. Contrary to canonical GT-A enzymes, UGCG uses a metal-independent catalytic mechanism driven by an arginine network. We identify a primate-specific steric element that tunes lipid affinity and catalytic turnover, modulating glycosphingolipid entry. Structures with clinically used inhibitors reveal how this architecture governs their potency and selectivity. Together, these findings define the structural and evolutionary logic by which one enzyme controls glycosphingolipid diversity and provide a framework for precision modulation of membrane lipid homeostasis in disease.

DOI: 10.1038/s41586-026-10927-4

Source: https://www.nature.com/articles/s41586-026-10927-4