Pathway-specific enzymes from bamboo and crop leaves biosynthesize anti-nociceptive C-glycosylated flavones

Yuwei Sun,Yong Wang,Zhuo Chen,Yulian Zhang,Shiyi Li,Qian Zhang,Ying Zhang,Jingya Yang,Ishmael Mutanda

doi:10.1038/s42003-020-0834-3

Abstract

C-glycosylated flavones (CGFs) are promising candidates as anti-nociceptive compounds. The leaves of bamboo and related crops in the grass family are a largely unexploited bioresource with a wide array of CGFs. We report here pathway-specific enzymes including C-glycosyltransferases (CGTs) and P450 hydroxylases from cereal crops and bamboo species accumulating abundant CGFs. Mining of CGTs and engineering of P450s that decorate the flavonoid skeleton allowed the production of desired CGFs (with yield of 20–40 mg/L) in an Escherichia coli cell factory. We further explored the antinociceptive activity of major CGFs in mice models and identified isoorientin as the most potent, with both neuroanalgesic and anti-inflammatory effects superior to clinical drugs such as rotundine and aspirin. Our discovery of the pain-alleviating flavonoids elicited from bamboo and crop leaves establishes this previously underutilized source, and sheds light on the pathway and pharmacological mechanisms of the compounds.

Highlights

C-glycosylated flavones (CGFs) are promising candidates as anti-nociceptive compounds
Even though ancient Chinese did believe that some folk medicine or herbal tea made from bamboo leaves could help remove “toxic heat”, resulting in the alleviation of inflammation and pain[14], a poor understanding of both the biosynthetic machinery of CGFs in bamboos and the inadequately defined pharmacological mechanisms severely hindered effective and extensive use of bamboo leaves as analgesics
While CGFs are widely spread among monocot plants (Fig. 2a), especially in the leaves of the grass family[28], a full picture of the CGF diverse spectrum still remains obscure

Summary

Introduction

C-glycosylated flavones (CGFs) are promising candidates as anti-nociceptive compounds. Our discovery of the pain-alleviating flavonoids elicited from bamboo and crop leaves establishes this previously underutilized source, and sheds light on the pathway and pharmacological mechanisms of the compounds. Previous and ongoing work with plant extracts has identified some promising antinociceptive compounds, for example, C-glycosylated flavones (CGFs) that have been shown to exhibit analgesic activity in both partially pure extracts[1,2] and purified forms[3,4]. Compared to other flavone classes and closely related Oglycosylated flavonoids, less is known on C-glycosylated flavonoids in terms of their distribution pattern in the plant kingdom, the evolutionary history of pathway-specific genes and their pharmacological mechanism for anti-nociceptive activity and other biological functionalities. As one of the richest sources of natural flavonoids, plants in the grass family provide a wide array of chemically diverse CGFs in their edible and inedible parts. The C-glucosylated intermediates are unstable and undergo spontaneous dehydration in acidic solvent (Fig. 1), leading to a mixture of Vit (apigenin 8-Cβ-D-glucoside)/isovitexin (Isovit, apigenin 6-C-β-D-glucoside) and Ori (luteolin 8-C-β-D-glucoside)/isoorientin (Isoori, luteolin 6-Cβ-D-glucoside)

Methods

Results

Conclusion