State Key Laboratory of Chemical Resources Engineering, Beijing University of Chemical Technology, Beijing, 100029, People's Republic of China.
College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, People's Republic of China.
Appl Microbiol Biotechnol. 2019 Mar;103(6):2649-2664. doi: 10.1007/s00253-019-09645-x. Epub 2019 Feb 1.
Lasso peptides belong to a peculiar family of ribosomally synthesized and post-translationally modified peptides (RiPPs)-natural products with an unusual isopeptide-bonded slipknot structure. Except for assembling of this unusual lasso fold, several further post-translational modifications of lasso peptides, including C-terminal methylation, phosphorylation/poly-phosphorylation, citrullination, and acetylation, have been reported recently. However, most of their biosynthetic logic have not been elucidated except the phosphorylated paeninodin lasso peptide. Herein, we identified two novel lassomycin-like lasso peptide biosynthetic pathways and, for the first time, characterized a novel C-terminal peptide carboxyl methyltransferase involved in these pathways. Our investigations revealed that this new family of methyltransferase could specifically methylate the C terminus of precursor peptide substrates, eventually leading to lassomycin-like C-terminal methylated lasso peptides. Our studies offer another rare insight into the extraordinary strategies of chemical diversification adopted by lasso peptide biosynthetic machinery and predicated two valuable sources for methylated lasso peptide discovery.
套索肽属于一类特殊的核糖体合成和翻译后修饰肽（RiPPs）——具有不寻常的异肽键连接的套索结构的天然产物。除了组装这种不寻常的套索折叠外，最近还报道了套索肽的几种进一步的翻译后修饰，包括 C 端甲基化、磷酸化/多磷酸化、瓜氨酸化和乙酰化。然而，除了磷酸化的 paeninodin 套索肽外，它们的大多数生物合成逻辑尚未阐明。在此，我们鉴定了两种新型的 lassomycin 样套索肽生物合成途径，并首次对涉及这些途径的新型 C 端肽羧基甲基转移酶进行了特征描述。我们的研究表明，这种新型甲基转移酶家族可以特异性地甲基化前体肽底物的 C 端，最终导致 lassomycin 样 C 端甲基化套索肽。我们的研究为套索肽生物合成机制所采用的化学多样化的特殊策略提供了另一个罕见的视角，并预测了两种用于发现甲基化套索肽的有价值的来源。
