Myxobacteria are a prolific source of secondary metabolites with sheer chemical complexity, intriguing biosynthetic enzymology, and diverse biological activities. In this study, we report the discovery, biosynthesis, biomimetic total synthesis, physiological function, structure–activity relationship, and self-resistance mechanism of the 5-methylated pyrazinone coralinone from a myxobacterium Corallococcus exiguus SDU70. A single NRPS/PKS gene corA was genetically and biochemically demonstrated to orchestrate coralinone, wherein the integral PKS part is responsible for installing the 5-methyl group. Intriguingly, coralinone exacerbated cellular aggregation of myxobacteria grown in liquid cultures by enhancing the secretion of extracellular matrix, and the 5-methylation is indispensable for the alleged activity. We provided an evolutionary landscape of the corA-associated biosynthetic gene clusters (BGCs) distributed in the myxobacterial realm, revealing the divergent evolution for the diversity-oriented biosynthesis of 5-alkyated pyrazinones. This phylogenetic contextualization provoked us to identify corB located in the proximity of corA as a self-resistance gene. CorB was experimentally verified to be a protease that hydrolyzes extracellular proteins to antagonize the agglutination-inducing effect of coralinone. Overall, we anticipate these findings will provide new insights into the chemical ecology of myxobacteria and lay foundations for the maximal excavation of these largely underexplored resources.

中文翻译：

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破译粘细菌产生的 5-甲基化吡嗪酮的生物合成和生理功能

粘细菌是次级代谢产物的丰富来源，具有纯粹的化学复杂性、有趣的生物合成酶学和多样化的生物活性。在本研究中，我们报道了来自粘杆菌Corallococcus exiguus SDU70 的 5-甲基化吡嗪酮 Coralinone 的发现、生物合成、仿生全合成、生理功能、构效关系和自身抵抗机制。单个 NRPS/PKS 基因corA在遗传和生物化学上被证明可以协调 Coralinone，其中完整的 PKS 部分负责安装 5-甲基。有趣的是，珊瑚酮通过增强细胞外基质的分泌，加剧了液体培养中生长的粘细菌的细胞聚集，而 5-甲基化对于所谓的活性是必不可少的。我们提供了分布在粘细菌领域的corA相关生物合成基因簇（BGC）的进化景观，揭示了5-烷基化吡嗪酮的多样性导向生物合成的趋异进化。这种系统发育背景促使我们将位于corA附近的corB识别为一种自我抵抗基因。 CorB经实验证实是一种蛋白酶，可水解细胞外蛋白质以拮抗珊瑚酮的凝集诱导作用。总的来说，我们预计这些发现将为粘细菌的化学生态学提供新的见解，并为最大限度地挖掘这些很大程度上尚未开发的资源奠定基础。