State Key Laboratory of Southwestern Chinese Medicine Resources, and, Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, P. R. China.
State Key Laboratory of Phytochemistry and Plant Resources in West China &, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of, Sciences, Kunming, 650201, P. R. China.
Angew Chem Int Ed Engl. 2021 Nov 22;60(48):25468-25476. doi: 10.1002/anie.202110842. Epub 2021 Oct 28.
A versatile terpene synthase (LcTPS2) producing unconventional macrocyclic terpenoids was characterized from Leucosceptrum canum. Engineered Escherichia coli and Nicotiana benthamiana expressing LcTPS2 produced six 18-/14-membered sesterterpenoids including five new ones and two 14-membered diterpenoids. These products represent the first macrocyclic sesterterpenoids from plants and the largest sesterterpenoid ring system identified to date. Two variants F516A and F516G producing approximately 3.3- and 2.5-fold, respectively, more sesterterpenoids than the wild-type enzyme were engineered. Both 18- and 14-membered ring sesterterpenoids displayed significant inhibitory activity on the IL-2 and IFN-γ production of T cells probably via inhibition of the MAPK pathway. The findings will contribute to the development of efficient biocatalysts to create bioactive macrocyclic sesterterpenoids, and also herald a new potential in the well-trodden territory of plant terpenoid biosynthesis.
从 Leucosceptrum canum 中鉴定出一种多功能萜烯合酶 (LcTPS2)，可产生非常规的大环萜类化合物。表达 LcTPS2 的工程大肠杆菌和烟草产生了六种 18-/14 元倍半萜，包括五种新化合物和两种 14 元二萜。这些产物代表了植物中环戊烷萜的首次出现，也是迄今为止鉴定到的最大的环戊烷萜环系统。工程改造了两种变体 F516A 和 F516G，它们分别产生约 3.3-和 2.5 倍于野生型酶的倍半萜。18 元和 14 元环倍半萜均显示出对 T 细胞中 IL-2 和 IFN-γ 产生的显著抑制活性，可能是通过抑制 MAPK 途径。这些发现将有助于开发有效的生物催化剂来产生生物活性的大环倍半萜，同时也预示着植物萜类生物合成这一成熟领域的新潜力。
