Niwa Kanji, Delgadillo David A, Yee Danielle A, Luo Chuhang, Fan Flora, Jha Kunal K, Nelson Hosea M, Tang Yi
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California 90095, United States.
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
J Nat Prod. 2025 Jun 27;88(6):1506-1513. doi: 10.1021/acs.jnatprod.5c00455. Epub 2025 Jun 9.
Arginine-containing cyclodipeptide synthases (RCDPSs) from fungi constitute a new family of tRNA-dependent enzymes that can biosynthesize cyclo-Arg-Xaa dipeptides. The incorporation of an arginine residue significantly expands the chemical space of guanidine-containing natural products. Here, we mined fungal biosynthetic gene clusters (BGCs) containing different RCDPS to discover aza-polycyclic natural products. The BGC from produced pentacyclic pyrroloindoline diketopiperazines (DKPs) of which the arginine side chain is oxidatively cyclized into a guanidino-proline. Two RCDPS-encoding BGCs, and from and , respectively, produced DKPs connected to five- and seven-membered spirocycles as a result of oxidative cyclization of the guanidino group catalyzed by α-ketoglutarate/Fe(II)-dependent oxygenases. The pathway involves a tandem cyclization and epimerization to generate the guanidino-bridged tricyclo-[3.3.2.2]-piperazinedione core. The aza-polycyclic structures characterized in this work demonstrate the potential of using RCDPS as a starting point for the discovery of new natural products.
来自真菌的含精氨酸环二肽合酶（RCDPSs）构成了一类新的依赖于tRNA的酶家族，能够生物合成环-精氨酸-Xaa二肽。精氨酸残基的掺入显著扩展了含胍天然产物的化学空间。在此，我们挖掘了包含不同RCDPS的真菌生物合成基因簇（BGCs），以发现氮杂多环天然产物。来自[具体名称未给出]的BGC产生了五环吡咯并吲哚二酮哌嗪（DKPs），其中精氨酸侧链被氧化环化形成胍基脯氨酸。分别来自[具体名称未给出1]和[具体名称未给出2]的两个编码RCDPS的BGC，由于α-酮戊二酸/铁（II）依赖性加氧酶催化的胍基氧化环化作用，产生了与五元环和七元环螺环相连的DKPs。[具体名称未给出3]途径涉及串联环化和差向异构化以生成胍基桥连的三环-[3.3.2.2]-哌嗪二酮核心。这项工作中表征的氮杂多环结构证明了将RCDPS作为发现新天然产物起点的潜力。
