Discovery of Venturicidin Congeners and Identification of the Biosynthetic Gene Cluster from Streptomyces sp. NRRL S-4,Journal of Natural Products

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Discovery of Venturicidin Congeners and Identification of the Biosynthetic Gene Cluster from Streptomyces sp. NRRL S-4
Journal of Natural Products ( IF 3.3 ) Pub Date : 2020-12-23 , DOI: 10.1021/acs.jnatprod.0c01177
Huanhuan Li _{1,

2} , Mengxue Zhang _{1,

2} , Hongji Li ₁ , Hai Yu ₁ , Shuo Chen _{1,

2} , Wenhui Wu ₂ , Peng Sun ₁

Affiliation

Chemical screening of Streptomyces sp. NRRL S-4 with liquid chromatography–mass spectrometry (LC–MS) and the following chromatographic isolation led to the discovery of four 20-membered macrolides, venturicidin A (4) and three new congeners venturicidins D–F (1–3). Genome sequencing of strain S-4 revealed the presence of a biosynthetic gene cluster (BGC) encoding glycosylated type I polyketides (PKS). The BGC designated to venturicidin biosynthesis (ven) was supported by the proposed biosynthetic pathway and confirmed by inactivation of the core PKS gene of venK. Bioinformatic analyses on the conserved motifs and known stereospecificities in PKS modules are consistent with the structure and absolute configuration. This is the first report of venturicidin BGC since the discovery of the macrolide in 1961. In the biological assays, venturicidin A (4) and E (2) displayed a high selective cytotoxicity against acute monocytic leukemia MV-4-11 cells with IC₅₀ values of 0.09 and 0.94 μM, respectively. Venturicidin A (4) also showed a weak inhibitory activity on FMS-like-tyrosine kinase.

中文翻译：

Venturicidin 同源物的发现和链霉菌属生物合成基因簇的鉴定。NRRL S-4

链霉菌属的化学筛选。NRRL S-4 与液相色谱-质谱联用 (LC-MS) 和以下色谱分离导致发现了四种 20 元大环内酯、文氏菌素 A ( 4 ) 和三种新的同源物文氏菌素 D-F ( 1 - 3 )。菌株 S-4 的基因组测序揭示存在编码糖基化 I 型聚酮化合物 (PKS) 的生物合成基因簇 (BGC)。指定用于文氏菌素生物合成 ( ven )的 BGC得到了所提出的生物合成途径的支持，并通过venK的核心 PKS 基因的失活得到了证实。. PKS 模块中保守基序和已知立体特异性的生物信息学分析与结构和绝对构型一致。这是自 1961 年发现大环内酯后首次报道文氏菌素 BGC。在生物测定中，文氏菌素 A ( 4 ) 和 E ( 2 ) 显示出对急性单核细胞白血病 MV-4-11 细胞的高选择性细胞毒性，IC ₅₀值分别为 0.09 和 0.94 μM。Venturicidin A ( 4 ) 也对 FMS 样酪氨酸激酶显示出微弱的抑制活性。

更新日期：2021-01-22

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