近日，南京大学梁勇团队报道了细菌细胞色素p450选择性激活五环三萜中脂肪C-H键。该研究于2026年3月30日发表在《自然-化学》杂志上。

在多环萜类化合物中选择性活化脂肪族C-H键，为拓展药物设计中的化学空间提供了有效策略，然而在实现位点选择性和非对映选择性方面仍然面临挑战，尤其是在结构复杂性增加的情况下。

研究组报道了一种生物信息学驱动的萜烯-P450发现策略，用于开发细菌细胞色素P450酶，以在结构复杂的五环三萜类化合物中选择性活化脂肪族C-H键。鉴定出的ApPT表现出优雅的非对映选择性和广泛的底物耐受性，从而构建了一个化学-酶平台，能够在先前难以触及的位点探索五环三萜类的化学空间。

蛋白质晶体学和计算分析揭示了ApPT对多种五环三萜类底物初步C-H键活化选择性的机制，特别是通过1,5-氢原子转移介导的酶促C7到C15接力氧化实例。该研究提供了ApPT作为一种有价值的生物催化剂，通过脂肪族C-H键活化来探索五环三萜类的化学空间，并展示了该生物催化剂发现策略在多环萜类后期官能团化中的优势。

附：英文原文

Title: Exploring bacterial cytochrome P450s for selective activation of aliphatic C–H bonds in pentacyclic triterpenoids

Author: Zhang, Xiaowei, Chen, Hongwei, Wang, Yaxin, Xie, Shihan, Wang, Zengyuan, Qian, Jialiang, Lin, Xiaoxu, Li, Fang-Ru, Pan, Xingming, Xu, Hui-Min, Liang, Yong, Dong, Liao-Bin

Issue&Volume: 2026-03-30

Abstract: Selective activation of aliphatic C–H bonds in polycyclic terpenoids offers a potent strategy for exploring diverse chemical space in drug design, yet challenges persist in achieving site- and diastereoselectivity, especially with increasing structural complexity. Here we report a bioinformatics-driven terpene–P450 discovery strategy to develop bacterial cytochrome P450s for selective activation of aliphatic C–H bonds in structurally intricate pentacyclic triterpenoids (PTs). The identified ApPT demonstrated elegant diastereoselectivity and broad substrate tolerance, facilitating a chemo-enzymatic platform to explore the chemical space of PTs at previously inaccessible sites. Protein crystallization and computational analysis reveal the mechanism of the preliminary C–H bond activation selectivity of ApPT towards various PTs, particularly an example of enzymatic C7-to-C15 relay oxidation mediated by 1,5-hydrogen atom transfer. This work offers ApPT as a valuable biocatalyst to explore the chemical space of PTs via aliphatic C–H bond activation, demonstrating the advantage of our biocatalyst-discovery strategy for the late-stage diversification of polycyclic terpenoids.

DOI: 10.1038/s41557-026-02106-9

Source: https://www.nature.com/articles/s41557-026-02106-9