State Key Laboratory of Bioactive Substance and Function of Natural Medicines, CAMS Key Laboratory of Enzyme and Biocatalysis of Natural Drugs, and NHC Key Laboratory of Biosynthesis of Natural Products, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, 100050, Beijing, China.
Nat Commun. 2020 Oct 14;11(1):5162. doi: 10.1038/s41467-020-18990-9.
Bioactive natural C-glycosides are rare and chemical C-glycosylation faces challenges while enzymatic C-glycosylation catalyzed by C-glycosyltransferases provides an alternative way. However, only a small number of C-glycosyltransferases have been found, and most of the discovered C-glycosyltransferases prefer to glycosylate phenols with an acyl side chain. Here, a promiscuous C-glycosyltransferase, AbCGT, which is capable of C-glycosylating scaffolds lacking acyl groups, is identified from Aloe barbadensis. Based on the substrate promiscuity of AbCGT, 16 C-glycosides with inhibitory activity against sodium-dependent glucose transporters 2 are chemo-enzymatically synthesized. The C-glycoside 46a shows hypoglycemic activity in diabetic mice and is biosynthesized with a cumulative yield on the 3.95 g L scale. In addition, the key residues involved in the catalytic selectivity of AbCGT are explored. These findings suggest that AbCGT is a powerful tool in the synthesis of lead compounds for drug discovery and an example for engineering the catalytic selectivity of C-glycosyltransferases.
生物活性天然 C-糖苷罕见，化学 C-糖苷化具有挑战性，而 C-糖基转移酶催化的酶促 C-糖苷化提供了一种替代方法。然而，仅发现了少数 C-糖基转移酶，并且大多数发现的 C-糖基转移酶更喜欢酰基侧链糖化酚。在这里，从 Aloe barbadensis 中鉴定出一种具有混杂性的 C-糖基转移酶 AbCGT，它能够 C-糖苷化缺乏酰基的支架。基于 AbCGT 的底物混杂性，通过化学-酶法合成了 16 种对钠依赖性葡萄糖转运蛋白 2 具有抑制活性的 C-糖苷。C-糖苷 46a 在糖尿病小鼠中表现出降血糖活性，在 3.95 g/L 规模上具有累积产率。此外，还探索了 AbCGT 催化选择性中涉及的关键残基。这些发现表明 AbCGT 是用于药物发现的先导化合物合成的有力工具，也是工程化 C-糖基转移酶催化选择性的范例。
