Diversification of phenolic glucosides by two UDP-glucosyltransferases featuring complementary regioselectivity.
Diversification of phenolic glucosides by two UDP-glucosyltransferases featuring complementary regioselectivity.
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DOI：
10.1186/s12934-022-01935-w
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发表时间：
2022-10-10
影响因子：
6.4
通讯作者：
中科院分区：
文献类型：
--
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糖苷类天然产物已显示出巨大的药用价值和潜力。然而，通过植物提取、化学合成和传统的生物转化生产糖苷的方法远远不能满足快速增长的医药需求。微生物合成生物学为植物糖苷的合成和多样化提供了很有前景的策略。本研究对植物来源的两种高效的UDP-葡萄糖转移酶(UGT)(UGT85A1和RrUGT3)进行了体外鉴定，它们能够识别酚苷元。这两种UGT对酚类底物上的醇羟基和酚羟基具有互补的区域选择性。通过将开发的烷基酚生物氧化系统与这些UGT相结合，从容易获得的烷基酚底物酶促合成了24个酚苷。在生物氧化和糖基化系统的基础上，构建了一系列微生物细胞工厂，并将其应用于生物转化，产生了各种植物和植物样O-葡萄糖苷。值得注意的是，由这两种UGT制备的几种非天然O-糖苷显示出比临床上使用的天麻素、红景天苷和螺旋体等糖苷类药物更好的抑制和/或抗炎活性。此外，这两个UGT还能够催化N-和S-葡萄糖苷键的形成，从而生成N-和S-葡萄糖苷。本研究鉴定了两个具有明显区域选择性的高效UGT，UGT85A1和RrUGT3。利用开发的烷基酚生物氧化体系和这两种UGT，通过细胞生物转化，高效地合成了一组植物和类植物糖苷。许多O-糖苷表现出比植物源糖苷类药物更好的PEP抑制或抗炎活性，显示出巨大的糖苷类新药开发潜力。网上版载有补充材料，可在10.1186/s12934-022-01935-w查阅。
Glucoside natural products have been showing great medicinal values and potentials. However, the production of glucosides by plant extraction, chemical synthesis, and traditional biotransformation is insufficient to meet the fast-growing pharmaceutical demands. Microbial synthetic biology offers promising strategies for synthesis and diversification of plant glycosides. In this study, the two efficient UDP-glucosyltransferases (UGTs) (UGT85A1 and RrUGT3) of plant origin, that are capable of recognizing phenolic aglycons, are characterized in vitro. The two UGTs show complementary regioselectivity towards the alcoholic and phenolic hydroxyl groups on phenolic substrates. By combining a developed alkylphenol bio-oxidation system and these UGTs, twenty-four phenolic glucosides are enzymatically synthesized from readily accessible alkylphenol substrates. Based on the bio-oxidation and glycosylation systems, a number of microbial cell factories are constructed and applied to biotransformation, giving rise to a variety of plant and plant-like O-glucosides. Remarkably, several unnatural O-glucosides prepared by the two UGTs demonstrate better prolyl endopeptidase inhibitory and/or anti-inflammatory activities than those of the clinically used glucosidic drugs including gastrodin, salidroside and helicid. Furthermore, the two UGTs are also able to catalyze the formation of N- and S-glucosidic bonds to produce N- and S-glucosides. Two highly efficient UGTs, UGT85A1 and RrUGT3, with distinct regioselectivity were characterized in this study. A group of plant and plant-like glucosides were efficiently synthesized by cell-based biotransformation using a developed alkylphenol bio-oxidation system and these two UGTs. Many of the O-glucosides exhibited better PEP inhibitory or anti-inflammatory activities than plant-origin glucoside drugs, showing significant potentials for new glucosidic drug development. The online version contains supplementary material available at 10.1186/s12934-022-01935-w.
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影响因子：
2.7
作者：
Ati J;Lafite P;Daniellou R
通讯作者：
Daniellou R
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
2.9
作者：
Cifani, Carlo;Di B, Maria Vittoria Micioni;Massi, Maurizio
通讯作者：
Massi, Maurizio
影响因子：
3.3
作者：
Hannula, M. J.;Myohanen, T. T.;Garcia-Horsman, J. A.
通讯作者：
Garcia-Horsman, J. A.
影响因子：
4.6
作者：
Chung DJ;Morrison PR;Bryant HJ;Jung E;Brauner CJ;Schulte PM
通讯作者：
Schulte PM