College of Pharmaceutical Science and Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education and Key Laboratory of Pharmaceutical Engineering of Zhejiang Province, Zhejiang University of Technology, Hangzhou, China.
Appl Environ Microbiol. 2024 Nov 20;90(11):e0160324. doi: 10.1128/aem.01603-24. Epub 2024 Oct 24.
Fungi generate a diverse array of bioactive compounds with significant pharmaceutical applications. However, the chemical diversity of natural products in fungi remains largely unexplored. Here, we present a paradigm for specifically discovering diverse and bioactive compounds from fungi by integrating genome mining with building block molecular network and coculture analysis. Through pangenome and sequence similarity network analysis, we identified a rare type I polyketide enzyme from sp. ZJUT-34. Subsequent building block molecular network and coculture strategy led to the identification and isolation of a pair of novel polyketides, (±)-peniphenone E [(±)-], three known polyketides (), and three precursor compounds () from a combined culture of sp. ZJUT-34 and sp. ZJUT23. Their structures were established through extensive spectroscopic analysis, including NMR and HRESIMS. Chiral HPLC separation of compound yielded a pair of enantiomers (+)- and (-)-, with their absolute configurations determined using calculated ECD methods. Compound (±)- is notable for its unprecedented structure, featuring a unique 2-methyl-hexenyl-3-one moiety fused with a polyketide clavatol core. We proposed a hypothetical biosynthetic pathway for (±)-. Furthermore, compounds , , and exhibited strong antioxidant activity, whereas (-)-, (+)-, , and four exhibited moderate antioxidant activity compared to the positive control, ascorbic acid. Our research demonstrates a pioneering strategy for uncovering novel polyketides by merging genome mining, metabolomics, and cocultivation methods. This approach addresses the challenge of discovering natural compounds produced by rare biosynthetic enzymes that are often silent under conventional conditions due to gene regulation.IMPORTANCEPolyketides, particularly those with complex structures, are crucial in drug development and synthesis. This study introduces a novel approach to discover new polyketides by integrating genomics, metabolomics, and cocultivation strategies. By combining genome mining, building block molecular networks, and coculturing techniques, we identified and isolated a unique polyketide, (±)-peniphenone E, along with three known polyketides and three precursor compounds from sp. ZJUT-34 and sp. ZJUT23. This approach highlights the potential of using combined strategies to explore fungal chemical diversity and discover novel bioactive compounds. The successful identification of (±)-peniphenone E, with its distinctive structure, demonstrates the effectiveness of this integrated method in enhancing natural product discovery and underscores the value of innovative approaches in natural product research.
真菌产生具有显著药物应用的各种生物活性化合物。然而，真菌中天然产物的化学多样性在很大程度上尚未得到探索。在这里，我们通过整合基因组挖掘与构建块分子网络和共培养分析，提出了一种专门从真菌中发现多样和生物活性化合物的范例。通过泛基因组和序列相似性网络分析，我们从 sp. ZJUT-34 中鉴定出一种罕见的 I 型聚酮酶。随后的构建块分子网络和共培养策略导致从 sp. ZJUT-34 和 sp. ZJUT23 的组合培养中鉴定和分离出一对新型聚酮类化合物（±）-peniphenone E [(±)-]、三种已知的聚酮类化合物（）和三种前体化合物（）。通过广泛的光谱分析，包括 NMR 和 HRESIMS，确定了它们的结构。化合物 的手性 HPLC 分离得到一对对映异构体 (+)-和 (-)-，其绝对构型通过计算 ECD 方法确定。（±）-值得注意的是，它具有前所未有的结构，具有独特的 2-甲基-己烯-3-酮部分与聚酮 clavatol 核心融合。我们提出了（±）-的假设生物合成途径。此外，化合物 、 、和 表现出强烈的抗氧化活性，而 (-)-、(+)-、 、和四者与阳性对照抗坏血酸相比表现出中等抗氧化活性。我们的研究展示了一种通过合并基因组挖掘、代谢组学和共培养方法揭示新型聚酮类化合物的开创性策略。这种方法解决了由于基因调控，在常规条件下通常沉默的稀有生物合成酶产生的天然化合物的发现问题。
聚酮类化合物，特别是那些具有复杂结构的聚酮类化合物，在药物开发和合成中至关重要。本研究介绍了一种通过整合基因组学、代谢组学和共培养策略发现新的聚酮类化合物的新方法。通过组合基因组挖掘、构建块分子网络和共培养技术，我们从 sp. ZJUT-34 和 sp. ZJUT23 中鉴定并分离出一种独特的聚酮类化合物（±）-peniphenone E，以及三种已知的聚酮类化合物和三种前体化合物。这种方法强调了使用组合策略探索真菌化学多样性和发现新型生物活性化合物的潜力。（±）-peniphenone E 的成功鉴定，其独特的结构，证明了这种综合方法在增强天然产物发现方面的有效性，并强调了创新方法在天然产物研究中的价值。
