Abstract

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.

中文翻译：

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从玫瑰链霉菌（Streptosporangium roseum）79089中发现了FR901533的新型类似物和相应的生物合成基因簇。

摘要

FR901533（1，也称为WS79089B），WS79089A（2）和WS79089C（3）是多环芳香族天然产物，具有对内皮素转化酶的抑制活性。在这项工作中，我们分离从五个tridecaketide产品Streptosporangium霉79089号，其中包括1-3个，benaphthamycin（4）和一种新颖的FR901533类似物（5）。5的结构基于光谱数据表征。与主要产品2相比，新化合物5在C-12处具有额外的羟基，在13-OH处具有额外的甲基。使用Mosher方法将这些化合物的C-19构型确定为R。对于化合物推定的生物合成基因簇1-5通过分析的基因组中发现的S.玫瑰色79089.号这38.6-kb的基因簇包含38个开放阅读框，其中包括最小的聚酮化合物合酶（WSAA-C ），芳香（wsaD），三个环化酶（wsaE，F和W）以及一系列定制酶，例如单加氧酶（wsaO1 - O7）和甲基转移酶（wsaM1和M2）。该基因簇中酮合酶基因（wsaA）的破坏消除了1–5的产生，这证实了该基因簇确实是1–5的生物合成的原因。对于这组天然的内皮素转化酶抑制剂，有人提出了II型聚酮化合物的生物合成途径。

关键点

•从No. 79089的玫瑰链霉菌中分离出5种芳香族三蝶苷。

•表征了新型FR901533类似物12-羟基-13-O-甲基-WS79089A。

•确定了FR901533及其类似物的C-19的绝对构型。

•发现了FR901533及其类似物的生物合成基因簇。