Functional and structural dissection of glycosyltransferases underlying the glycodiversity of wolfberry-derived bioactive ingredients lycibarbarspermidines

Shao-Yang Li, Gao-Qian Wang, Liang Long, Jia-Ling Gao, Zheng-Qun Zhou, Yong-Heng Wang, Jian-Ming Lv, Guo-Dong Chen, Dan Hu (), Ikuro Abe () and Hao Gao ()
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Shao-Yang Li: Jinan University
Gao-Qian Wang: Jinan University
Liang Long: Jinan University
Jia-Ling Gao: Jinan University
Zheng-Qun Zhou: Jinan University
Yong-Heng Wang: Jinan University
Jian-Ming Lv: Jinan University
Guo-Dong Chen: Jinan University
Dan Hu: Jinan University
Ikuro Abe: the University of Tokyo, 7-3-1 Hongo
Hao Gao: Jinan University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Lycibarbarspermidines are unusual phenolamide glycosides characterized by a dicaffeoylspermidine core with multiple glycosyl substitutions, and serve as a major class of bioactive ingredients in the wolfberry. So far, little is known about the enzymatic basis of the glycosylation of phenolamides including dicaffeoylspermidine. Here, we identify five lycibarbarspermidine glycosyltransferases, LbUGT1-5, which are the first phenolamide-type glycosyltransferases and catalyze regioselective glycosylation of dicaffeoylspermidines to form structurally diverse lycibarbarspermidines in wolfberry. Notably, LbUGT3 acts as a distinctive enzyme that catalyzes a tandem sugar transfer to the ortho-dihydroxy group on the caffeoyl moiety to form the unusual ortho-diglucosylated product, while LbUGT1 accurately discriminates caffeoyl and dihydrocaffeoyl groups to catalyze a site-selective sugar transfer. Crystal structure analysis of the complexes of LbUGT1 and LbUGT3 with UDP, combined with molecular dynamics simulations, revealed the structural basis of the difference in glycosylation selectivity between LbUGT1 and LbUGT3. Site-directed mutagenesis illuminates a conserved tyrosine residue (Y389 in LbUGT1 and Y390 in LbUGT3) in PSPG box that plays a crucial role in regulating the regioselectivity of LbUGT1 and LbUGT3. Our study thus sheds light on the enzymatic underpinnings of the chemical diversity of lycibarbarspermidines in wolfberry, and expands the repertoire of glycosyltransferases in nature.

Date: 2024
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DOI: 10.1038/s41467-024-49010-9

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