Heterologous Expression of the Fellutanine Biosynthetic Gene Cluster and Characterization of the Dual Prenylation of cyclo( l -Trp- l -Trp) by a Single DMATS Enzyme

作者：Weipeng Chen, Lin Wei, Wei Chen, Shuzhen Chen, Jianbin Xiao, Xing-Tong Chen, Chao Chen, Fan Cai, Mingliang Zhang, Qin Li, Huaidong Zhang, Li Li, Hui Zhang · 发表于：Journal of Natural Products · 年份：2025 · DOI：10.1021/acs.jnatprod.4c01116 · 被引用次数：4 · 研究领域：Microbial Natural Products and Biosynthesis、Plant biochemistry and biosynthesis、Natural product bioactivities and synthesis

2,5-Diketopiperazines (2,5-DKPs) are recognized for their structural rigidity and diverse bioactivities, making them significant in drug discovery. However, the stereochemical complexity of 2,5-DKPs presents challenges in chemical synthesis, particularly concerning indole derivatives such as indole diketopiperazines (IDKPs). Prenylation and oxidation further diversify these structures, enhancing their bioactivity and membrane affinity. Despite recent advances, the biosynthetic pathways of IDKPs, especially those involving dual prenylation, remain inadequately understood. In this study, the fellutanine biosynthetic gene cluster from Nannizzia fulva was cloned and heterologously expressed in Aspergillus nidulans . A partially oxidized intermediate in the fellutanine biosynthetic pathway was characterized. The dimethylallyl tryptophan synthase (DMATS) enzyme FelB was shown to catalyze consecutive prenylations at two C-2 positions of cyclo( l -Trp- l -Trp) in both in vivo and in vitro assays. Additionally, comparative studies with the known DMATS enzyme OkaC revealed differences in the regioselectivity. Furthermore, the biprenylation mechanism of FelB and OkaC was elucidated through molecular docking and active site analysis.