Biomade Technology Foundation, Nijenborgh 4, 9747 AG Groningen, the Netherlands.
Curr Protein Pept Sci. 2013 Mar;14(2):85-96. doi: 10.2174/1389203711314020001.
Lanthipeptides are ribosomally synthesized and posttranslationally modified peptides produced by microorganisms. The name lanthipeptide is derived from lanthionine, a thioether-bridged amino acid installed by dedicated modification enzymes. Serines and threonines are dehydrated and subsequently coupled to cysteines, thus forming intramolecular lanthionine rings. A well-known subclass of lanthipeptides are lantibiotics: lanthipeptides with antimicrobial activity. The lantibiotic nisin is applied worldwide in the food industry to prevent food spoilage. This review focuses on lanthipeptide leader peptides, which have a crucial and central role in lanthipeptide biosynthesis. Lanthipeptide leader peptides are present at the N-terminus within precursor lanthipeptides. Intriguingly, a single leader peptide can interact with highly different modifying enzyme(s) (domains) and furthermore induce export out of the cell via a dedicated export protein. Eventually the leader peptide is cleaved off by a leader peptidase, either extracellularly or intracellularly as part of the transporter. Recent exciting mechanistic and engineering studies ignited the unraveling of the fascinating interactions of lanthipeptide leader peptides with the lanthipeptide modification enzymes and transporters. The biosynthesis of at least some lanthipeptides is performed by a highly flexible enzyme system. Novel lantibiotics can be synthesized by fusing lanthipeptide leader peptides to completely different silent lantibiotics obtained by genome mining. Moreover, the fusion of leader peptides to the N-terminus of medically and economically important therapeutic peptides has resulted in lanthioninestabilized therapeutics with enhanced bioavailability and optimized receptor interaction.
类硫酯肽是由微生物产生的核糖体合成和翻译后修饰的肽。类硫酯肽这个名称来源于硫醚桥连氨基酸——通过专用修饰酶形成的结构。丝氨酸和苏氨酸发生脱水反应，然后与半胱氨酸偶联，从而形成分子内硫醚环。一类著名的类硫酯肽是类抗生素：具有抗菌活性的类硫酯肽。类抗生素乳链菌肽在全球食品工业中被广泛应用于防止食品腐败。本文重点介绍了类硫酯肽的前导肽，它在类硫酯肽生物合成中起着至关重要的核心作用。类硫酯肽的前导肽位于前体类硫酯肽的 N 端。有趣的是，单个前导肽可以与高度不同的修饰酶（结构域）相互作用，并通过专用的输出蛋白诱导细胞外输出。最终，前导肽被前导肽酶切割，无论是在细胞外还是细胞内，作为转运体的一部分。最近令人兴奋的机制和工程研究揭示了类硫酯肽前导肽与类硫酯肽修饰酶和转运体之间迷人的相互作用。至少一些类硫酯肽的生物合成是由一个高度灵活的酶系统完成的。通过将类硫酯肽前导肽融合到通过基因组挖掘获得的完全不同的沉默类抗生素中，可以合成新型的类抗生素。此外，将前导肽融合到医学和经济上重要的治疗性肽的 N 端，产生了硫醚稳定的治疗剂，提高了生物利用度和优化了受体相互作用。
