Many bioactive plant cyclic peptides form side-chain-derived macrocycles. Lyciumins, cyclic plant peptides with tryptophan macrocyclizations, are ribosomal peptides (RiPPs) originating from repetitive core peptide motifs in precursor peptides with plant-specific BURP (BNM2, USP, RD22 and PG1beta) domains, but the biosynthetic mechanism for their formation has remained unknown. Here, we characterize precursor-peptide BURP domains as copper-dependent autocatalytic peptide cyclases and use a combination of tandem mass spectrometry-based metabolomics and plant genomics to systematically discover five BURP-domain-derived plant RiPP classes, with mono- and bicyclic structures formed via tryptophans and tyrosines, from botanical collections. As BURP-domain cyclases are scaffold-generating enzymes in plant specialized metabolism that are physically connected to their substrates in the same polypeptide, we introduce a bioinformatic method to mine plant genomes for precursor-peptide-encoding genes by detection of repetitive substrate domains and known core peptide features. Our study sets the stage for chemical, biosynthetic and biological exploration of plant RiPP natural products from BURP-domain cyclases.

许多具有生物活性的植物环肽形成侧链衍生的大环化合物。Lyciumins，具有色氨酸大环化的环状植物肽，是核糖体肽 (RiPP)，源自具有植物特异性 BURP（BNM2、USP、RD22 和 PG1beta）结构域的前体肽中的重复核心肽基序，但其形成的生物合成机制仍然未知. 在这里，我们将前体肽 BURP 结构域表征为铜依赖性自催化肽环化酶，并结合基于串联质谱的代谢组学和植物基因组学，系统地发现五个 BURP 结构域衍生的植物 RiPP 类，形成单环和双环结构通过来自植物收藏的色氨酸和酪氨酸。由于 BURP 域环化酶是植物专门代谢中的支架生成酶，它们在同一多肽中与它们的底物物理连接，我们引入了一种生物信息学方法，通过检测重复底物域和已知的前体肽编码基因来挖掘植物基因组核心肽特征。我们的研究为化学、生物合成和生物学探索来自 BURP 域环化酶的植物 RiPP 天然产物奠定了基础。