Ji Qiushuang, Liu Yirong, Zhang Huanyu, Gao Yan, Ding Yixin, Ding Yuanyuan, Xie Jing, Zhang Jianyu, Jin Xinghua, Lai Bin, Chen Cheng, Wang Juan, Gao Wenyuan, Mei Kunrong
School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, 300072, China.
Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei, 050017, China.
Adv Sci (Weinh). 2025 Mar;12(11):e2413185. doi: 10.1002/advs.202413185. Epub 2025 Jan 29.
Ginsenosides are a group of tetracyclic triterpenoids with promising health benefits, consisting of ginseng aglycone attached to various glycans. Pq3-O-UGT2, an important UDP-dependent glycosyltransferase (UGT), catalyzes the production of Ginsenoside Rg3 and Rd by extending the glycan chain of Ginsenoside Rh2 and F2, respectively, with higher selectivity for F2. However, the mechanism underlying its substrate recognition remains unclear. In this study, the crystal structures of Pq3-O-UGT2 in complex with its acceptor substrates are solved. The structures revealed a Nα5-oriented acceptor binding pocket in Pq3-O-UGT2, shaped by the unique conformation of the Nα5-Nα6 linker. Hydrophobic interactions play a pivotal role in the recognition of both Rh2 and F2, while hydrogen bonds specifically aid in F2 recognition due to its additional glucose moiety. The hydrophobic nature of the acceptor binding pocket also enables Pq3-O-UGT2 to recognize flavonoids. Overall, this study provides novel insights into the substrate recognition mechanisms of ginsenoside UGTs, advancing the understanding of their function and specificity.
人参皂苷是一类具有潜在健康益处的四环三萜类化合物，由连接各种聚糖的人参苷元组成。Pq3 - O - UGT2是一种重要的尿苷二磷酸依赖性糖基转移酶（UGT），分别通过延长人参皂苷Rh2和F2的聚糖链来催化人参皂苷Rg3和Rd的产生，对F2具有更高的选择性。然而，其底物识别的潜在机制仍不清楚。在本研究中，解析了Pq3 - O - UGT2与其受体底物复合物的晶体结构。这些结构揭示了Pq3 - O - UGT2中一个面向Nα5的受体结合口袋，由Nα5 - Nα6连接子的独特构象形成。疏水相互作用在Rh2和F2的识别中起关键作用，而氢键由于F2额外的葡萄糖部分而特别有助于其识别。受体结合口袋的疏水性也使Pq3 - O - UGT2能够识别黄酮类化合物。总体而言，本研究为人参皂苷UGT的底物识别机制提供了新的见解，推动了对其功能和特异性的理解。
