Institute of Microbiology, Eigenössische Technische Hochschule (ETH) Zurich, Vladimir-Prelog-Weg 1-5/10, 8093, Zurich, Switzerland.
Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore.
Angew Chem Int Ed Engl. 2018 Jan 22;57(4):977-981. doi: 10.1002/anie.201709056. Epub 2017 Dec 18.
Trans-AT polyketide synthases (PKSs) are a family of biosynthetically versatile modular type I PKSs that generate bioactive polyketides of impressive structural diversity. In this study, we detected, in the genome of several bacteria a cryptic, architecturally unusual trans-AT PKS gene cluster which eluded automated PKS prediction. Genomic mining of one of these strains, the model methylotroph Methylobacterium extorquens AM1, revealed unique epoxide- and cyclopropanol-containing polyketides named toblerols. Relative and absolute stereochemistry were determined by NMR experiments, chemical derivatization, and the comparison of CD data between the derivatized natural product and a synthesized model compound. Biosynthetic data suggest that the cyclopropanol moiety is generated by carbon-carbon shortening of a more extended precursor. Surprisingly, a knock-out strain impaired in polyketide production showed strong inhibitory activity against other methylobacteria in contrast to the wild-type producer. The activity was inhibited by complementation with toblerols, thus suggesting that these compounds modulate an as-yet unknown methylobacterial antibiotic.
反式酰基转移酶聚酮合酶（PKSs）是一类生物合成多功能的结构Ⅰ型 PKSs，能够生成具有令人印象深刻结构多样性的生物活性聚酮化合物。在本研究中，我们在几种细菌的基因组中检测到一个隐匿的、结构异常的反式酰基转移酶 PKS 基因簇，该基因簇逃避了自动化 PKS 预测。对这些菌株之一的模式甲基营养菌 Methylobacterium extorquens AM1 的基因组挖掘揭示了独特的含环氧和环丙烷醇的聚酮化合物，命名为托伯醇。相对和绝对立体化学通过 NMR 实验、化学衍生化以及衍生化天然产物与合成模型化合物之间的 CD 数据比较来确定。生物合成数据表明，环丙烷醇部分是通过更长的前体的碳-碳缩短生成的。令人惊讶的是，与野生型生产菌相比，在聚酮产物产生方面受到破坏的敲除菌株对其他甲基杆菌具有强烈的抑制活性。该活性可通过托伯醇的互补作用来抑制，因此表明这些化合物调节一种未知的甲基杆菌抗生素。
