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.

最近对核糖体合成和翻译后修饰肽（RiPP）进行基因组挖掘的努力扩大了翻译后修饰化学的多样性。然而，RiPP 很少被报道为结合了其他天然产品家族的生物合成机制的混合分子。在这里，我们报道了 lipoavitides，一类 RiPP/脂肪酸混合脂肽，其显示出独特的、推定的膜靶向 4-羟基-2,4-二甲基戊酰基 (HMP) 修饰的 N 末端。 HMP 是通过异丁酰辅酶 A（异丁酰辅酶 A）和甲基丙二酰辅酶 A 在 3-酮酰基-（酰基载体蛋白）合成酶 III 酶的催化下缩合形成，然后在脂肪酸生物合成途径中进行连续的剪裁反应。然后，HMP 和 RiPP 子结构通过酰基转移酶连接，该酰基转移酶对脂肪酰基和 RiPP 底物表现出混杂的活性。总体而言，脂蛋白肽的发现贡献了RiPP/脂肪酸杂化物的原型，并为脂肽生物工程提供了可能的酶工具。