Biosynthetic pathway of prescription bergenin from Bergenia purpurascens and Ardisia japonica

Xiang-Yu Liu; Yi-Na Wang; Jiang-Shun Du; Bi-Huan Chen; Kun-Yi Liu; Lei Feng; Gui-Sheng Xiang; Shuang-Yan Zhang; Ying-Chun Lu; Sheng-Chao Yang; Guang-Hui Zhang; Bing Hao

doi:10.3389/fpls.2023.1259347

Biosynthetic pathway of prescription bergenin from Bergenia purpurascens and Ardisia japonica

Front Plant Sci. 2024 Jan 4:14:1259347. doi: 10.3389/fpls.2023.1259347. eCollection 2023.

Authors

Xiang-Yu Liu^#^{1

2}, Yi-Na Wang^#^{1

2}, Jiang-Shun Du^#^{1

2}, Bi-Huan Chen^{1

2}, Kun-Yi Liu², Lei Feng^{1

2}, Gui-Sheng Xiang^{1

2}, Shuang-Yan Zhang^{1

2}, Ying-Chun Lu², Sheng-Chao Yang^{1

2}, Guang-Hui Zhang^{1

2}, Bing Hao^{2

3}

Affiliations

¹ College of Agronomy and Biotechnology, National and Local Joint Engineering Research Center on Germplasm Innovation & Utilization of Chinese Medicinal Materials in Southwest China, Key Laboratory of Medicinal Plant Biology of Yunnan Province, Yunnan Agricultural University, Kunming, Yunnan, China.
² Yunnan Characteristic Plant Extraction Laboratory, Kunming, Yunnan, China.
³ College of Tobacco Science, Yunnan Agricultural University, Kunming, Yunnan, China.

^# Contributed equally.

Abstract

Bergenin is a typical carbon glycoside and the primary active ingredient in antitussive drugs widely prescribed for central cough inhibition in China. The bergenin extraction industry relies on the medicinal plant species Bergenia purpurascens and Ardisia japonica as their resources. However, the bergenin biosynthetic pathway in plants remains elusive. In this study, we functionally characterized a shikimate dehydrogenase (SDH), two O-methyltransferases (OMTs), and a C-glycosyltransferase (CGT) involved in bergenin synthesis through bioinformatics analysis, heterologous expression, and enzymatic characterization. We found that BpSDH2 catalyzes the two-step dehydrogenation process of shikimic acid to form gallic acid (GA). BpOMT1 and AjOMT1 facilitate the methylation reaction at the 4-OH position of GA, resulting in the formation of 4-O-methyl gallic acid (4-O-Me-GA). AjCGT1 transfers a glucose moiety to C-2 to generate 2-Glucosyl-4-O-methyl gallic acid (2-Glucosyl-4-O-Me-GA). Bergenin production ultimately occurs in acidic conditions or via dehydration catalyzed by plant dehydratases following a ring-closure reaction. This study for the first time uncovered the biosynthetic pathway of bergenin, paving the way to rational production of bergenin in cell factories via synthetic biology strategies.

Keywords: C-glycosyltransferase; O-methyltransferases; bergenin; biosynthetic pathway; carbon glycosides.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Fundamental Research Project of Yunnan (202101AS070037, 202301BD070001-100, 202201AT070274), Yunnan Characteristic Plant Extraction Laboratory (2022YKZY001), The Major Science and Technique Programs in Yunnan Province (202102AA310048, 202102AE090042-01, 202102AA310045-01), National Natural Science Foundation of China (Grant No. 82160727).