Huang Chunshuai, Cui Haiyang, Ren Hengqian, Zhao Huimin
Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
JACS Au. 2022 Dec 30;3(1):195-203. doi: 10.1021/jacsau.2c00594. eCollection 2023 Jan 23.
Bipentaromycins are heterodimeric aromatic polyketides featuring two distinctive 5/6/6/6/5 pentacyclic ring systems and exhibit antibacterial activities. However, their overall biosynthetic mechanism, particularly the mechanism for early-stage modifications, such as hydrogenation and methylation, and late-stage dimerization, remains unknown. Herein, by integrating heterologous expression, isotope labeling, gene knockout and complementation, and computational modeling, we determined the biosynthetic origin of the skeleton, identified the enzymes involved in stereo-/regioselective hydrogenation and methylation, and provided new mechanistic insights into the dimerization. This work not only deciphers the biosynthetic mechanism of bipentaromycins but also provides new strategies for creating biologically active dimeric pharmacophores for drug discovery and development.
双戊霉素是具有两个独特的5/6/6/6/5五环系统的异源二聚体芳香聚酮化合物，并具有抗菌活性。然而，它们的整体生物合成机制，特别是早期修饰（如氢化和甲基化）以及后期二聚化的机制仍然未知。在此，通过整合异源表达、同位素标记、基因敲除与互补以及计算建模，我们确定了骨架的生物合成起源，鉴定了参与立体/区域选择性氢化和甲基化的酶，并为二聚化提供了新的机制见解。这项工作不仅破译了双戊霉素的生物合成机制，还为创造用于药物发现和开发的具有生物活性的二聚药效基团提供了新策略。
