Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Nat Chem. 2024 Aug;16(8):1320-1329. doi: 10.1038/s41557-024-01491-3. Epub 2024 Mar 25.
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.
最近在核糖体合成和翻译后修饰肽（RiPPs）的基因组挖掘方面的努力扩展了翻译后修饰化学的多样性。然而，很少有报道称 RiPP 是包含其他天然产物家族生物合成机制的混合分子。在这里，我们报告了脂磷肽，这是一类 RiPP/脂肪酸混合脂肽，具有独特的、推测的靶向膜的 4-羟基-2,4-二甲基戊酰基（HMP）修饰的 N 端。HMP 通过异丁酰辅酶 A（isobutyryl-CoA）和甲基丙二酰辅酶 A的缩合形成，由 3-酮酰基（酰基载体蛋白）合酶 III 酶催化，然后在脂肪酸生物合成途径中进行连续的修饰反应。然后，HMP 和 RiPP 亚结构通过具有酰基转移酶的连接，该酶对脂肪酸酰基和 RiPP 底物表现出混杂活性。总的来说，脂磷肽的发现提供了 RiPP/脂肪酸混合体的原型，并为脂肽的生物工程提供了可能的酶工具。
