Department of Biological Engineering, Utah State University, 4105 Old Main Hill, Logan, UT, 84322-4105, USA.
Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, Jiangxi, China.
Appl Microbiol Biotechnol. 2020 Aug;104(16):7131-7142. doi: 10.1007/s00253-020-10765-y. Epub 2020 Jul 7.
FR901533 (1, also known as WS79089B), WS79089A (2), and WS79089C (3) are polycyclic aromatic natural products with promising inhibitory activity to endothelin-converting enzymes. In this work, we isolated five tridecaketide products from Streptosporangium roseum No. 79089, including 1-3, benaphthamycin (4) and a novel FR901533 analogue (5). The structure of 5 was characterized based on spectroscopic data. Compared with the major product 2, the new compound 5 has an additional hydroxyl group at C-12 and an extra methyl group at the 13-OH. The configuration of C-19 of these compounds was determined to be R using Mosher's method. A putative biosynthetic gene cluster for compounds 1-5 was discovered by analyzing the genome of S. roseum No. 79089. This 38.6-kb gene cluster contains 38 open reading frames, including a minimal polyketide synthase (wsaA-C), an aromatase (wsaD), three cyclases (wsaE, F, and W), and a series of tailoring enzymes such as monooxygenases (wsaO1-O7) and methyltransferases (wsaM1 and M2). Disruption of the ketosynthase gene (wsaA) in this gene cluster abolished the production of 1-5, confirming that this gene cluster is indeed responsible for the biosynthesis of 1-5. A type II polyketide biosynthetic pathway was proposed for this group of natural endothelin-converting enzyme inhibitors. KEY POINTS: • Five aromatic tridecaketides were isolated from Streptosporangium roseum No. 79089. • A novel FR901533 analogue, 12-hydroxy-13-O-methyl-WS79089A, was characterized. • The absolute configuration of C-19 of FR901533 and analogues was determined. • The biosynthetic gene cluster of FR901533 and analogues was discovered.
FR901533（1，也称为 WS79089B）、WS79089A（2）和 WS79089C（3）是具有潜在抑制内皮素转化酶活性的多环芳香天然产物。在这项工作中，我们从玫瑰色链霉菌 79089 中分离出五个十三烷酮产物，包括 1-3、苯萘霉素（4）和一种新型 FR901533 类似物（5）。5 的结构基于光谱数据进行了表征。与主要产物 2 相比，新化合物 5 在 C-12 处具有额外的羟基和 13-OH 处的额外甲基。使用 Mosher 法确定这些化合物的 C-19 构型为 R。通过分析 S. roseum No. 79089 的基因组，发现了化合物 1-5 的假定生物合成基因簇。这个 38.6kb 的基因簇包含 38 个开放阅读框，包括最小的聚酮合酶（wsaA-C）、芳香酶（wsaD）、三个环化酶（wsaE、F 和 W）以及一系列修饰酶，如单加氧酶（wsaO1-O7）和甲基转移酶（wsaM1 和 M2）。该基因簇中的酮合酶基因（wsaA）的破坏使 1-5 的产生被废除，证实该基因簇确实负责 1-5 的生物合成。提出了一组天然内皮素转化酶抑制剂的 II 型聚酮生物合成途径。关键点：• 从玫瑰色链霉菌 No. 79089 中分离出五个芳香十三烷酮。• 表征了一种新型 FR901533 类似物，12-羟基-13-O-甲基-WS79089A。• 确定了 FR901533 和类似物的 C-19 的绝对构型。• 发现了 FR901533 和类似物的生物合成基因簇。
