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

First author: Yuwei Sun; Affiliations: CAS Institute of Plant Physiology and Ecology (中科院植物生理生态研究所): Shanghai, China

Corresponding author: Yong Wang 

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.

Fig. 1 Overview of the proposed biosynthetic pathway of C-monoglucosylated flavone.

C-糖基黄酮（CGFs）是抗伤害性化合物的主要候选者。竹子以及近缘草本植物的叶片是一个含多种GCFs，但还未开发的生物资源。本文中，作者报道了谷类作物和竹类物种中包括C-糖基转移酶（CGTs）和P450羟化酶在内的通路特异酶作用于CGFs的丰富积累。通过对参与类黄酮骨架修饰的CGTs酶的挖掘和P450s酶的改造能够在大肠杆菌“细胞工厂”中生产我们所需要的CGTs，产量约为20-40mg/L。作者进一步在小鼠模型中探索了主要CGTs化合物的抗伤害感受活性（antinociceptive activity），发现异荭草素（isoorientin）是最具潜力的化合物，同时在神经镇痛（neuroanalgesic）和抗炎症（anti-inflammatory）方面的效果要优于罗通定（rotundine）和阿司匹林（aspirin）等临床药物。本文的研究发现了一种先前未曾充分利用的、具镇痛功能类黄酮化合物的天然来源，即竹子和作物的叶片，并为这些化合物的通路与药理机制提供了新的视野。

通讯：王勇 (http://www.sippe.ac.cn/sourcedb_sippe/zw/zjrc/201812/t20181219_5218242.html)

个人简介：2004年，华东理工大学，博士；2005年，美国麻省理工学院、Tufts大学，博士后。

研究方向：通过解析天然产物的生物合成途径，运用合成生物学的思想和方法，基于工程化的设计和建构，改进复杂天然产物的生物合成效率和其生产方式，开发天然的或非天然的复杂天然产物活性成分。

doi: https://doi.org/10.1038/s42003-020-0834-3

Journal: Communications Biology

Published date: March 06, 2020