Pei Zeng-Fei, Vior Natalia M, Zhu Lingyang, Truman Andrew W, Nair Satish K
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Department of Molecular Microbiology, John Innes Centre, Norwich, UK.
Nat Chem Biol. 2025 Jan;21(1):143-154. doi: 10.1038/s41589-024-01736-9. Epub 2024 Sep 16.
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.
自然界中的主要生物聚合物是寡核苷酸和多肽。然而，天然存在的肽 - 核碱基杂化物很少见。在此，我们报道了一类具有嘧啶酮基序的肽 - 核碱基杂化天然产物的首个成员的表征，该天然产物来自广泛分布的核糖体合成及翻译后修饰（RiPP）生物合成途径。该途径有两个步骤，其中异源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，并且酰基酯酶选择性识别该部分以切割C端尾随肽。机理研究表明，嘧啶酮的形成以底物辅助催化的方式发生，需要前体中的一个组氨酸残基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以及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道路，这是一种越来越受关注的形式。
