The main biopolymers in nature are oligonucleotides and polypeptides. However, naturally occurring peptide–nucleobase hybrids are rare. Here we report the characterization of the founding member of a class of peptide–nucleobase hybrid natural products with a pyrimidone motif from a widely distributed ribosomally synthesized and post-translationally modified (RiPP) biosynthetic pathway. This pathway features two steps where a heteromeric RRE–YcaO–dehydrogenase complex catalyzes the formation of a six-membered pyrimidone ring from an asparagine residue on the precursor peptide, and an acyl esterase selectively recognizes this moiety to cleave the C-terminal follower peptide. Mechanistic studies reveal that the pyrimidone formation occurs in a substrate-assisted catalysis manner, requiring a His residue in the precursor to activate asparagine for heterocyclization. Our study expands the chemotypes of RiPP natural products and the catalytic scope of YcaO enzymes. This discovery opens avenues to create artificial biohybrid molecules that resemble both peptide and nucleobase, a modality of growing interest.

自然界中主要的生物聚合物是寡核苷酸和多肽。然而，天然存在的肽-核碱基杂合体很少见。在这里，我们报告了一类肽-核碱基杂合天然产物的创始成员的表征，该天然产物具有来自广泛分布的核糖体合成和翻译后修饰（RiPP）生物合成途径的嘧啶酮基序。该途径有两个步骤，其中异聚 RRE-YcaO-脱氢酶复合物催化前体肽上的天冬酰胺残基形成六元嘧啶酮环，酰基酯酶选择性识别该部分以裂解 C 末端跟随肽。机理研究表明，嘧啶酮的形成以底物辅助催化方式发生，需要前体中的组氨酸残基来激活天冬酰胺进行杂环化。我们的研究扩展了 RiPP 天然产物的化学类型和 YcaO 酶的催化范围。这一发现为创造类似于肽和核碱基的人工生物杂交分子开辟了途径，这是一种越来越受关注的模式。