Isoprenoid modifications of proteins and peptides serve fundamental biological functions and are of therapeutic interest. While C₁₅ (farnesyl) and C₂₀ (geranylgeranyl) moieties are prevalent among proteins, known ribosomal peptide prenylations involve shorter-chain units not exceeding farnesyl in size. To our knowledge, cyclized terpene moieties have not been reported from either biomolecule class. Here, we used targeted genome mining and heterologous pathway reconstitution to identify ribosomally synthesized and post-translationally modified peptides (RiPPs) with elaborate, cyclized geranylgeranyl modifications. The installing maturases commonly feature fused prenyltransferase-terpene cyclase architectures. We characterized two bifunctional maturases with distinct prenyltransferase folds and identified the terminal product of a cyanobacterial proteusin as an exceptionally complex pseudosteroid-annelated polycyclic peptide. Bioassays suggest modest anti-cyanobacterial activity with the modification being crucial for activity. Genome data predict cyclic isoprenoid units for various RiPP families, including proteusin, Nif11, and lasso peptides, and thus the broader natural and biotechnological compatibility of the maturase system.

中文翻译：

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具有多环异戊二烯基团的核糖体肽


蛋白质和肽的类异戊二烯修饰具有基本的生物学功能，具有治疗意义。虽然 C₁₅（法呢基）和 C₂₀（香叶基香叶基）部分在蛋白质中普遍存在，但已知的核糖体肽异戊二烯基化涉及大小不超过法尼基的短链单元。据我们所知，尚未报道任何一类生物分子的环化萜烯部分。在这里，我们使用靶向基因组挖掘和异源途径重构来鉴定核糖体合成和翻译后修饰的肽 （RiPPs） 与精心设计的环化香叶基香叶酰修饰。安装成熟酶通常具有融合的异戊二烯基转移酶-萜烯环化酶结构。我们表征了两种具有不同异戊二烯基转移酶折叠的双功能成熟酶，并将蓝藻变形杆菌素的终末产物鉴定为异常复杂的假甾体退火多环肽。生物测定表明适度的抗蓝细菌活性，修饰对活性至关重要。基因组数据预测了各种 RiPP 家族的环异戊二烯单元，包括变形蛋白、Nif11 和套索肽，从而预测了成熟酶系统更广泛的自然和生物技术兼容性。