美国伊利诺伊大学教授Zhao, Huimin团队报道了非模块化脂肪酸合成酶在核糖体肽中产生不同的N-末端酰化。相关研究成果发表在2024年3月25日出版的《自然—化学》。

最近在核糖体合成和翻译后修饰肽（RiPP）的基因组挖掘方面的努力，扩大了翻译后修饰化学的多样性。然而，RiPP很少被报道为与其他天然产物家族的生物合成机制结合的杂交分子。

该文中，研究人员报道了脂肽，一类RiPP/脂肪酸杂化脂肽，显示出一种独特的、假定的靶向4-羟基-2,4-二甲基戊酰基（HMP）修饰的N末端的膜。HMP是通过异丁酰辅酶A（异丁酰CoA）和甲基丙二酰CoA的缩合形成的，由3-酮酰基-（酰基载体蛋白）合酶III催化，然后在脂肪酸生物合成途径中进行连续的剪裁反应。

HMP和RiPP亚结构通过酰基转移酶连接，酰基转移酶对脂肪酰基和RiPP底物表现出混合活性。总的来说，脂肽的发现为RiPP/脂肪酸杂化物提供了原型，并为脂肽生物工程提供了可能的酶促工具。

附：英文原文

Title: Non-modular fatty acid synthases yield distinct N-terminal acylation in ribosomal peptides

Author: Ren, Hengqian, Huang, Chunshuai, Pan, Yuwei, Dommaraju, Shravan R., Cui, Haiyang, Li, Maolin, Gadgil, Mayuresh G., Mitchell, Douglas A., Zhao, Huimin

Issue&Volume: 2024-03-25

Abstract: Recent efforts in genome mining of ribosomally synthesized and post-translationally modified peptides (RiPPs) have expanded the diversity of post-translational modification chemistries. However, RiPPs are rarely reported as hybrid molecules incorporating biosynthetic machinery from other natural product families. Here we report lipoavitides, a class of RiPP/fatty-acid hybrid lipopeptides that display a unique, putatively membrane-targeting 4-hydroxy-2,4-dimethylpentanoyl (HMP)-modified N terminus. The HMP is formed via condensation of isobutyryl-coenzyme A (isobutyryl-CoA) and methylmalonyl-CoA catalysed by a 3-ketoacyl-(acyl carrier protein) synthase III enzyme, followed by successive tailoring reactions in the fatty acid biosynthetic pathway. The HMP and RiPP substructures are then connected by an acyltransferase exhibiting promiscuous activity towards the fatty acyl and RiPP substrates. Overall, the discovery of lipoavitides contributes a prototype of RiPP/fatty-acid hybrids and provides possible enzymatic tools for lipopeptide bioengineering.

DOI: 10.1038/s41557-024-01491-3

Source: https://www.nature.com/articles/s41557-024-01491-3