The ammosamides (AMMs) are a family of pyrroloquinoline alkaloids that exhibits a wide variety of bioactivities. A biosynthetic gene cluster (BGC) that is highly homologous in both gene content and genetic organization to the amm BGC was identified by mining the Streptomyces uncialis DCA2648 genome, leading to the discovery of a sub-family of new AMM congeners, named ammosesters (AMEs). The AMEs feature a C-4a methyl ester, differing from the C-4a amide functional group characteristic to AMMs, and exhibit modest cytotoxicity against a broad spectrum of human cancer cell lines, expanding the structure-activity relationship for the pyrroloquinoline family of natural products. Comparative analysis of the ame and amm BGCs supports the use of a scaffold peptide as an emerging paradigm for the biosynthesis of the pyrroloquinoline family of natural products. AME and AMM biosynthesis diverges from a common intermediate by evolving the pathway-specific Ame24 O-methyltransferase and Amm20 amide synthetase, respectively. These findings will surely inspire future efforts to mimic Nature's combinatorial biosynthetic strategies for natural product structural diversity.

中文翻译：

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通过挖掘 Streptomyces uncialis DCA2648 基因组发现氨酯，揭示了对氨酰胺生物合成的新见解。

氨酰胺 (AMM) 是一类具有多种生物活性的吡咯并喹啉生物碱。通过挖掘 Streptomyces uncialis DCA2648 基因组，发现了一个在基因含量和遗传组织上与 amm BGC 高度同源的生物合成基因簇 (BGC)，从而发现了一个新的 AMM 同源物亚科，命名为氨酯酶 (AMEs) ). AME 具有 C-4a 甲酯，不同于 AMM 特有的 C-4a 酰胺官能团，并且对广谱人类癌细胞系表现出适度的细胞毒性，扩展了吡咯并喹啉家族天然产物的结构-活性关系. ame 和 amm BGC 的比较分析支持使用支架肽作为吡咯并喹啉家族天然产物生物合成的新兴范例。AME 和 AMM 生物合成从一个共同的中间体中分离出来，分别通过进化途径特异性 Ame24 O-甲基转移酶和 Amm20 酰胺合成酶。这些发现肯定会激发未来的努力，以模仿自然界针对天然产物结构多样性的组合生物合成策略。