2. Academic Validation
  3. Diversification of phenolic glucosides by two UDP-glucosyltransferases featuring complementary regioselectivity

Diversification of phenolic glucosides by two UDP-glucosyltransferases featuring complementary regioselectivity

  • Microb Cell Fact. 2022 Oct 10;21(1):208. doi: 10.1186/s12934-022-01935-w.
Fei Guo # 1,  Xingwang Zhang # 1,  Cai You 1 2,  Chengjie Zhang 1,  Fengwei Li 1,  Nan Li 3,  Yuwei Xia 4,  Mingyu Liu 1,  Zetian Qiu 5,  Xianliang Zheng 6,  Li Ma 1,  Gang Zhang 7,  Lianzhong Luo 7,  Fei Cao 8,  Yingang Feng 2,  Guang-Rong Zhao 5,  Wei Zhang 1,  Shengying Li 1 9,  Lei Du 10 11
Affiliations

Affiliations

  • 1 State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, Shandong, China.
  • 2 Shandong Provincial Key Laboratory of Synthetic Biology, CAS Key Laboratory of Biofuels, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, 266101, Shandong, China.
  • 3 College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China.
  • 4 Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, Shandong, China.
  • 5 Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Yaguan Road 135, Jinnan District, Tianjin, 300350, China.
  • 6 Center For Biocatalysis and Enzyme Technology, Angel Yeast Co., LTD, Cheng Dong Avenue, Yichang, 443003, Hubei, China.
  • 7 Fujian Universities and Colleges Engineering Research Center of Marine Biopharmaceutical Resources, Xiamen Medical College, Xiamen, 361023, Fujian, China.
  • 8 College of Pharmaceutical Sciences, Hebei University, Baoding, 071002, China.
  • 9 Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, Shandong, China.
  • 10 State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, Shandong, China. [email protected].
  • 11 Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, 518000, China. [email protected].
  • # Contributed equally.
PMID: 36217200 DOI: 10.1186/s12934-022-01935-w
Abstract

Background: 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.

Results: 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.

Conclusions: 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.

Keywords

Alkylphenol bio-oxidation; Biocatalysis; Phenolic glucosides; UDP-glucosyltransferases.

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