Discovery of cyclohexadepsipeptides with anti-Zika virus activities and biosynthesis of the nonproteinogenic building block (3S)-methyl-l-proline.
Discovery of cyclohexadepsipeptides with anti-Zika virus activities and biosynthesis of the nonproteinogenic building block (3S)-methyl-l-proline.
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DOI：
10.1016/j.jbc.2021.100822
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Lin W
中科院分区：
文献类型：
--
作者：
Yuan B;Wu Z;Ji W;Liu D;Guo X;Yang D;Fan A;Jia H;Ma M;Lin W
真菌环己糖肽(Dtxs)、isaridins(Isds)和isariins(Isariins)是由5个氨基酸残基和1个α-或β-羟基酸残基组成的19元环结构的非核糖体多肽。这些环六肽含有不寻常的非蛋白性氨基酸构建块，并具有一系列抗病毒、抗菌和其他活性。目前还没有鉴定ISDS和ISRS的生物合成基因簇，而且在DTX、ISDS和许多其他天然产物中发现的非蛋白性(3S)-甲基-L-脯氨酸残基的生物合成也缺乏完整的特征。在正在进行的寻找能够抑制寨卡病毒(ZIKV)的化合物的工作中，我们研究了海洋来源真菌白僵菌SX-6-22的提取物，发现了30个DTX、ISDS和ISR(1-30)，其中包括7个新化合物(1-7)。抗ZIKV实验表明，9-12和16-18对感染ZIKV的A549细胞具有抑制ZIKV RNA复制和NS5(非结构蛋白5)产生的活性。我们对B.Felina SX-6-22的基因组进行了测序，并鉴定了三个生物合成基因簇DETX、ISD和ISR，它们分别负责DTX、ISDS和ISRS的生物合成。对这三个基因簇的比较分析阐明了这些环六肽之间的生物合成关系。最后，我们表征了非蛋白合成积木(3S)-甲基-L-脯氨酸的整个生物合成过程。Δ1-吡咯啉-5-羧酸还原酶(P5CR)也用于L-脯氨酸的生物合成，它催化(3S)-甲基-L-脯氨酸形成的最后还原步骤，提示初级和次级代谢之间存在潜在的串扰。这些结果为生物合成途径工程产生新的抗ZIKV环己糖肽提供了机会。
The fungal cyclohexadepsipeptides destruxins (DTXs), isaridins (ISDs), and isariins (ISRs) are nonribosomal peptides whose structures include a 19-membered ring composed of five amino acid residues and one α- or β-hydroxy acid residue. These cyclohexadepsipeptides contain unusual nonproteinogenic amino acid–building blocks and possess a range of antiviral, antibacterial, and other activities. The biosynthetic gene clusters for ISDs and ISRs have not been identified, and the biosynthesis of the nonproteinogenic (3S)-methyl-l-proline residue, which is found in DTXs, ISDs, and many other natural products, lacks full characterization. In an ongoing effort to identify compounds that can inhibit the Zika virus (ZIKV), we examined the extract of marine-derived fungus Beauveria felina SX-6-22 and discovered 30 DTXs, ISDs, and ISRs (1–30) including seven new compounds (1–7). The anti-ZIKV assays showed that 9–12 and 16–18 possess inhibitory activities against ZIKV RNA replication and NS5 (nonstructural protein 5) production in ZIKV-infected A549 cells. We sequenced the genome of B. felina SX-6-22 and identified three biosynthetic gene clusters detx, isd and isr, which are responsible for the biosynthesis of DTXs, ISDs, and ISRs, respectively. Comparative analyses of the three gene clusters clarified the biosynthetic relationships among these cyclohexadepsipeptides. Finally, we characterized the entire biosynthesis of nonproteinogenic building block (3S)-methyl-l-proline. The Δ1-pyrroline-5-carboxylate reductases (P5CRs), also used in the biosynthesis of l-proline, were demonstrated to catalyze the final reduction step in (3S)-methyl-l-proline formation, suggesting potential cross talk between primary and secondary metabolisms. These results provide opportunities for biosynthetic pathway engineering to generate new anti-ZIKV cyclohexadepsipeptides.
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影响因子：
8.4
作者：
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通讯作者：
Müller R
影响因子：
5.1
作者：
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影响因子：
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通讯作者：
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影响因子：
5.1
作者：
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通讯作者：
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