Departments of Chemical and Biomolecular Engineering, University of California, Los Angeles, California 90095, United States.
Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States.
J Am Chem Soc. 2024 Aug 28;146(34):23933-23942. doi: 10.1021/jacs.4c06734. Epub 2024 Aug 14.
Nature uses compact but functionalized biosynthetic fragments as building blocks to generate complex natural products. To leverage this strategy for the discovery of natural products with new scaffolds, we performed genome mining to identify biosynthetic gene clusters (BGCs) in fungi that embed genes that can synthesize targeted fragments. The three-enzyme pathway that biosynthesizes the strained dityrosine cyclophane in the herquline A pathway was used to identify a large number of potential BGCs that may use the cyclophane as a fragment. Characterization of a conserved BGC from fungal strains led to the isolation of octacyclin A, an octacyclic natural product with an unprecedented structure, including two hetero-[3.3.1]bicycles and a combination of fused, bridged, and macrocyclic rings. Biosynthetic steps leading to octacyclin A were fully elucidated using pathway reconstitution and enzymatic assays, unveiling intriguing chemical logic and new enzymatic reactions in building the octacyclic core. Our work demonstrates the potential utility of fragment-guided genome mining in expanding natural product chemical space.
大自然利用紧凑但功能化的生物合成片段作为构建块来生成复杂的天然产物。为了利用这种策略来发现具有新骨架的天然产物，我们进行了基因组挖掘，以鉴定真菌中的生物合成基因簇 (BGCs)，其中嵌入了能够合成目标片段的基因。用于合成 herquline A 途径中应变二酪氨酸环肽的三酶途径被用于鉴定大量可能将环肽用作片段的潜在 BGCs。从真菌菌株中对保守 BGC 的表征导致了 octacyclin A 的分离，这是一种具有前所未有的结构的八环天然产物，包括两个杂 [3.3.1] 双环和融合、桥接和大环环的组合。使用途径重建和酶测定法充分阐明了导致 octacyclin A 的生物合成步骤，揭示了构建八环核心的有趣化学逻辑和新的酶反应。我们的工作证明了片段导向的基因组挖掘在扩展天然产物化学空间方面的潜在用途。
