4月18日，Nature Communications 在线发表了中国科学院上海生命科学研究院营养科学研究所向嵩组的最新研究成果“Crystal structure of glycogen debranching enzyme and insights into its catalysis and disease-causing mutations”。该研究揭示了糖原代谢关键酶糖原去支链酶（glycogen debranching enzyme,GDE）的晶体结构、分子机制以及其致病突变的致病机理。
糖原是重要的人体能量存储形式之一，可被降解为葡萄糖提供能量。糖原代谢的紊乱与糖尿病等疾病密切相关，该通路也是一类糖尿病治疗药物的靶点。糖原是一种多分支的链状葡萄糖多聚体，在其降解过程中，GDE催化的糖原去支链是关键步骤。遗传性的GDE功能不足导致糖原存储疾病III型，病人的肝脏、骨骼肌中堆积大量结构异常的糖原，并有低血糖、发育迟缓及肝脏、心脏、骨骼肌等器官的异常。
上海生科院营养所研究员向嵩指导的博士研究生翟丽婷等解析了高分辨率的GDE晶体结构。研究表明，GDE催化一个两步的糖原脱支链反应，研究人员通过对GDE的功能研究定位了其参与糖原脱支链反应的催化位点，阐明了反应进行的机制及催化位点对底物的特异性识别，并揭示了位于GDE表面的若干个参与其底物招募的糖原锚定位点。通过结构分析和对GDE致病突变的功能分析，研究人员还揭示了这些突变导致GDE功能失活的机理。该工作深化了对糖原代谢分子机制及对糖原存储疾病III型的理解，也为开发新的糖尿病治疗手段提供了理论指导。
该工作得到了营养所尹慧勇研究组的帮助，及基金委、科技部的支持。
糖原去支链酶的功能与结构
原文摘要：
Crystal structure of glycogen debranching enzyme and insights into its catalysis and disease-causing mutations
Glycogen is a branched glucose polymer and serves as an important energy store. Its debranching is a critical step in its mobilization. In animals and fungi, the 170 kDa glycogen debranching enzyme (GDE) catalyses this reaction. GDE deficiencies in humans are associated with severe diseases collectively termed glycogen storage disease type III (GSDIII). We report crystal structures of GDE and its complex with oligosaccharides, and structure-guided mutagenesis and biochemical studies to assess the structural observations. These studies reveal that distinct domains in GDE catalyse sequential reactions in glycogen debranching, the mechanism of their catalysis and highly specific substrate recognition. The unique tertiary structure of GDE provides additional contacts to glycogen besides its active sites, and our biochemical experiments indicate that they mediate its recruitment to glycogen and regulate its activity. Combining the understanding of the GDE catalysis and functional characterizations of its disease-causing mutations provides molecular insights into GSDIII.