Department of Chemistry, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea.
Bio-Med Program, KIST-School UST, Hwarang-ro 14 gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.
Biochemistry. 2022 Feb 1;61(3):183-194. doi: 10.1021/acs.biochem.1c00764. Epub 2022 Jan 21.
Backbone methylation is one of the prominent peptide modifications that can greatly enhance the pharmacological properties of a peptide. Naturally occurring backbone methylated peptides are produced via nonribosomal or ribosomal pathways, the latter of which was only recently identified in the borosin family of ribosomally synthesized and post-translationally modified peptides. Although previous bioinformatic analyses have revealed new putative genes for borosin biosynthesis, the natural scope of structural and biosynthetic diversity of the borosin family has not been thoroughly explored. Here, we report a comprehensive overview of the borosin family of peptide natural products. Using a genome mining approach, we identified more than 1400 new putative biosynthetic gene clusters for borosins and demonstrated that, unlike those previously reported, most of them are found in bacterial genomes and encode a precursor peptide unfused to its cognate methyltransferase enzyme. Biochemical analysis confirmed the backbone methylation of the precursor peptide in eight enzyme-precursor pairs and revealed two novel types of enzyme-recognizing sequences in the precursor peptide. This work significantly expands the biosynthetic diversity of borosins and paves the way for the enzymatic production of diverse backbone methylated peptides.
骨干甲基化是一种突出的肽修饰，可极大地增强肽的药理性质。天然存在的骨干甲基化肽是通过非核糖体或核糖体途径产生的，后者最近才在硼砂素家族的核糖体合成和翻译后修饰肽中被发现。尽管之前的生物信息学分析揭示了硼砂素生物合成的新假定基因，但硼砂素家族的结构和生物合成多样性的自然范围尚未得到彻底探索。在这里，我们报告了肽天然产物硼砂素家族的全面概述。使用基因组挖掘方法，我们鉴定了 1400 多个新的硼砂素假定生物合成基因簇，并表明与之前报道的不同，它们大多数存在于细菌基因组中，并编码与同源甲基转移酶未融合的前体肽。生化分析证实了前体肽中 8 对酶-前体的骨干甲基化，并在前体肽中揭示了两种新型的酶识别序列。这项工作极大地扩展了硼砂素的生物合成多样性，并为多样化骨干甲基化肽的酶生产铺平了道路。
