Ren Jiajun, Mathew Anugraha, Rodríguez-García María, Kohler Tobias, Blacque Olivier, Linden Anthony, Eberl Leo, Sieber Simon, Gademann Karl
Department of Chemistry, University of Zurich, Zurich, Switzerland.
Department of Plant and Microbial Biology, University of Zurich, Zurich, Switzerland.
Commun Chem. 2024 Dec 19;7(1):301. doi: 10.1038/s42004-024-01372-3.
Chirality plays a critical role in the biochemistry of life and often only one enantiomeric series is observed (homochirality). Only a few natural products have been obtained as racemates, e.g. the signalling molecule valdiazen produced by Burkholderia cenocepacia H111. In this study, we investigated the ham biosynthetic gene cluster and discovered that both the enantiomerically pure (R)-fragin and the racemic valdiazen result from the same pathway. This stereodivergence is based on the unusual heterocyclic intermediate dihydrosydnone N-oxide, as evident from gene knockout, stable isotope feeding experiments, and mass spectrometry experiments. Both non-enzymatic racemisation via keto-enol tautomerisation and enzyme-mediated dynamic kinetic resolution were found to be crucial to this stereodivergent pathway. This novel mechanism underpins the production of configurationally and biologically distinct metabolites from a single gene cluster. Our findings highlight the intricate design of an intertwined biosynthetic pathway and provide a deeper understanding of microbial secondary metabolism related to microbial communication.
手性在生命生物化学中起着关键作用，通常只观察到一个对映体系列（同手性）。只有少数天然产物是以外消旋体形式获得的，例如洋葱伯克霍尔德菌H111产生的信号分子瓦尔地氮。在本研究中，我们研究了火腿生物合成基因簇，发现对映体纯的（R）-弗拉金和外消旋的瓦尔地氮都来自同一途径。这种立体发散基于不寻常的杂环中间体二氢 sydnone N-氧化物，基因敲除、稳定同位素喂养实验和质谱实验证明了这一点。发现通过酮-烯醇互变异构的非酶消旋和酶介导的动态动力学拆分对这种立体发散途径都至关重要。这种新机制支撑了从单个基因簇产生构型和生物学上不同的代谢物。我们的发现突出了相互交织的生物合成途径的复杂设计，并为与微生物通讯相关的微生物次级代谢提供了更深入的理解。
