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

TITLE=Biosynthetic pathway of prescription bergenin from Bergenia purpurascens and Ardisia japonica

JOURNAL=Frontiers in Plant Science

VOLUME=14

YEAR=2024

URL=https://www.frontiersin.org/journals/plant-science/articles/10.3389/fpls.2023.1259347

DOI=10.3389/fpls.2023.1259347

ISSN=1664-462X

ABSTRACT=<p>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 <italic>Bergenia purpurascens</italic> and <italic>Ardisia japonica</italic> as their resources. However, the bergenin biosynthetic pathway in plants remains elusive. In this study, we functionally characterized a shikimate dehydrogenase (SDH), two <italic>O</italic>-methyltransferases (OMTs), and a <italic>C-</italic>glycosyltransferase (CGT) involved in bergenin synthesis through bioinformatics analysis, heterologous expression, and enzymatic characterization. We found that <italic>BpSDH2</italic> catalyzes the two-step dehydrogenation process of shikimic acid to form gallic acid (GA). <italic>BpOMT1</italic> and <italic>AjOMT1</italic> facilitate the methylation reaction at the 4-OH position of GA, resulting in the formation of 4-<italic>O-</italic>methyl gallic acid (4-<italic>O</italic>-Me-GA). <italic>AjCGT1</italic> transfers a glucose moiety to <italic>C-</italic>2 to generate 2-Glucosyl-4-<italic>O</italic>-methyl gallic acid (2-Glucosyl-4-<italic>O</italic>-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.</p>