Ye Ying, Du Lei, Zhang Xingwang, Newmister Sean A, McCauley Morgan, Alegre-Requena Juan V, Zhang Wei, Mu Shuai, Minami Atsushi, Fraley Amy E, Adrover-Castellano Maria L, Carney Nolan A, Shende Vikram V, Qi Feifei, Oikawa Hideaki, Kato Hikaru, Tsukamoto Sachiko, Paton Robert S, Williams Robert M, Sherman David H, Li Shengying
Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, 266237, China.
Nat Catal. 2020 Jun;3(6):497-506. doi: 10.1038/s41929-020-0454-9. Epub 2020 May 18.
Fungal bicyclo[2.2.2]diazaoctane indole alkaloids represent an important family of natural products with a wide-spectrum of biological activities. Although biomimetic total syntheses of representative compounds have been reported, the details of their biogenesis, especially the mechanisms for assembly of diastereomerically distinct and enantiomerically antipodal metabolites, have remained largely uncharacterized. Brevianamide A represents a basic form of the sub-family bearing a dioxopiperazine core and a rare 3--ψ-indoxyl skeleton. Here, we identified the Brevianamide A biosynthetic gene cluster from NRRL 864 and elucidated the metabolic pathway. BvnE was revealed to be an essential isomerase/semi-pinacolase that specifies selective production of the natural product. Structural elucidation, molecular modeling, and mutational analysis of BvnE, and quantum chemical calculations provided mechanistic insights into the diastereoselective formation of the 3--ψ-indoxyl moiety in Brevianamide A. This occurs through a BvnE-controlled semi-pinacol rearrangement and a subsequent spontaneous intramolecular [4+2] -Diels-Alder cycloaddition.
真菌双环[2.2.2]二氮杂辛烷吲哚生物碱是一类重要的天然产物，具有广泛的生物活性。尽管已有报道对代表性化合物进行仿生全合成，但其生物合成细节，尤其是非对映异构体不同和对映体相反的代谢产物的组装机制，在很大程度上仍未得到表征。短杆菌酰胺A代表了该亚家族的一种基本形式，具有二氧哌嗪核心和罕见的3-ψ-吲哚骨架。在此，我们从NRRL 864中鉴定出短杆菌酰胺A生物合成基因簇，并阐明了代谢途径。结果表明，BvnE是一种必需的异构酶/半频哪醇酶，它决定了天然产物的选择性生产。对BvnE的结构解析、分子建模和突变分析以及量子化学计算，为短杆菌酰胺A中3-ψ-吲哚部分的非对映选择性形成提供了机理见解。这是通过BvnE控制的半频哪醇重排和随后的自发分子内[4+2]-狄尔斯-阿尔德环加成反应实现的。
