Xiangya International Academy of Translational Medicine at Central South University , Changsha , Hunan 410013 , People's Republic of China.
CAS Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia, RNAM Center for Marine Microbiology , South China Sea Institute of Oceanology, Chinese Academy of Sciences , Guangzhou 510301 , People's Republic of China.
J Nat Prod. 2020 Feb 28;83(2):202-209. doi: 10.1021/acs.jnatprod.9b00321. Epub 2020 Feb 12.
Dithiolopyrrolones are microbial natural products containing a disulfide or thiosulfonate bridge embedded in a unique bicyclic structure. By interfering with zinc ion homeostasis in living cells, they show strong antibacterial activity against a variety of bacterial pathogens, as well as potent cytotoxicity against human cancer cells. In the current study, two new dithiolopyrrolones, pyrroloformamide C () and pyrroloformamide D (), were isolated from sp. CB02980, together with the known pyrroloformamides and . The biosynthetic gene cluster for pyrroloformamides was identified from sp. CB02980, which shared high sequence similarity with those of dithiolopyrrolones, including holomycin and thiolutin. Gene replacement of , which encodes a nonribosomal peptide synthetase (NRPS), abolished the production of -. Overexpression of , a type II thioesterase gene, increased the production of and . Genome neighborhood network analysis of the characterized and orphan gene clusters of dithiolopyrrolones revealed a unified mechanism for their biosynthesis, involving an iterative-acting NRPS and a set of conserved tailoring enzymes for the bicyclic core formation.
二硫吡咯酮类化合物是微生物天然产物，含有一个二硫键或硫代磺酸盐桥，嵌入在独特的双环结构中。通过干扰活细胞中锌离子的动态平衡，它们对多种细菌病原体表现出强烈的抗菌活性，对人类癌细胞也具有很强的细胞毒性。在本研究中，从 sp. CB02980 中分离得到了两个新的二硫吡咯酮类化合物，吡咯烷酮 C () 和吡咯烷酮 D ()，以及已知的吡咯烷酮 和 。从 sp. CB02980 中鉴定出了吡咯烷酮的生物合成基因簇，与包括霍洛霉素和硫醇素在内的二硫吡咯酮类化合物具有高度的序列相似性。编码非核糖体肽合成酶（NRPS）的基因 的替换，导致 - 的产生被消除。 基因的过表达，一种 II 型硫酯酶基因，增加了 和 的产量。对二硫吡咯酮类化合物特征和孤儿基因簇的基因组邻域网络分析揭示了它们生物合成的统一机制，涉及一个迭代作用的 NRPS 和一组用于双环核心形成的保守修饰酶。
