Biotechnology Research Center, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8567, Japan.
National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.
Org Biomol Chem. 2020 Jul 15;18(27):5137-5144. doi: 10.1039/d0ob00339e.
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.
1-氮杂双环[3.1.0]己烷环是天然产物中具有抗细菌、真菌和肿瘤生物活性的关键部分，通过 DNA 烷基化实现。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质氨基酸组成。尽管已经确定了 ficellomycin 的生物合成基因簇，但生物合成途径目前仍不清楚。本文报道了 ficellomycin 生物合成的最后阶段，涉及环修饰和连续二肽形成。形成环后，通过三种酶将环上的羟基转化为胍基单元，其中包括一种具有新型ω-ω氨基转移活性的氨基转移酶。在最后一步中，所得含 1-氮杂双环[3.1.0]己烷环的氨基酸通过氨基酸连接酶与 L-缬氨酸连接，生成 ficellomycin。本研究揭示了一种新的机制，扩展了天然产物的结构和生物学多样性。
