The 1-azabicyclo[3.1.0]hexane ring is a key moiety in natural products for biological activities against bacteria, fungi, and tumor through DNA alkylation. Ficellomycin is a dipeptide that consists of L-valine and a non-proteinogenic amino acid with the 1-azabicyclo[3.1.0]hexane ring structure. Although the biosynthetic gene cluster of ficellomycin has been identified, the biosynthetic pathway currently remains unclear. We herein report the final stage of ficellomycin biosynthesis involving ring modifications and successive dipeptide formation. After the ring is formed, the hydroxy group of the ring is converted into the guanidyl unit by three enzymes, which include an aminotransferase with a novel inter ω–ω amino-transferring activity. In the last step, the resulting 1-azabicyclo[3.1.0]hexane ring-containing amino acid is connected with L-valine by an amino acid ligase to yield ficellomycin. The present study revealed a new machinery that expands the structural and biological diversities of natural products.

中文翻译：

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ficellomycin 中 1-氮杂双环 [3.1.0] 己烷环的胍基修饰对其生物活性至关重要。

1-氮杂双环[3.1.0]己烷环是天然产物中通过DNA烷基化作用对抗细菌、真菌和肿瘤的生物活性的关键部分。Ficellomycin 是一种二肽，由L-缬氨酸和具有 1-氮杂双环 [3.1.0] 己烷环结构的非蛋白氨基酸。尽管已经确定了ficellomycin 的生物合成基因簇，但其生物合成途径目前仍不清楚。我们在此报告了涉及环修饰和连续二肽形成的 ficellomycin 生物合成的最后阶段。环形成后，环的羟基被三种酶转化为胍基单元，其中包括一种具有新的 ω-ω 间氨基转移活性的氨基转移酶。最后一步，得到的含1-氮杂双环[3.1.0]己烷环的氨基酸与L连接-缬氨酸通过氨基酸连接酶产生ficellomycin。本研究揭示了一种扩展天然产物结构和生物多样性的新机制。