The past decade has seen impressive advances in understanding the biosynthesis of ribosomally synthesized and posttranslationally modified peptides (RiPPs). One of the most common modifications found in these natural products is macrocyclization, a strategy also used by medicinal chemists to improve metabolic stability and target affinity and specificity. Another tool of the peptide chemist, modification of the amides in a peptide backbone, has also been observed in RiPPs. This review discusses the molecular mechanisms of biosynthesis of a subset of macrocyclic RiPP families, chosen because of the unusual biochemistry involved: the five classes of lanthipeptides (thioether cyclization by Michael-type addition), sactipeptides and ranthipeptides (thioether cyclization by radical chemistry), thiopeptides (cyclization by [4+2] cycloaddition), and streptide (cyclization by radical C–C bond formation). In addition, the mechanisms of backbone amide methylation, backbone epimerization, and backbone thioamide formation are discussed, as well as an unusual route to small molecules by posttranslational modification.

中文翻译：

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RiPP 生物合成中的大环化和主链修饰

过去十年，我们在了解核糖体合成肽和翻译后修饰肽 (RiPP) 的生物合成方面取得了令人瞩目的进展。这些天然产物中最常见的修饰之一是大环化，药物化学家也使用这种策略来提高代谢稳定性以及目标亲和力和特异性。肽化学家的另一个工具是对肽主链中酰胺的修饰，也在 RiPP 中观察到。本综述讨论了大环 RiPP 家族子集生物合成的分子机制，之所以选择这些家族是因为涉及不寻常的生物化学：五类羊毛硫肽（通过迈克尔型加成进行硫醚环化）、sacipeptides 和 ranthipeptides（通过自由基化学进行硫醚环化）、硫肽（通过[4+2]环加成环化）和链肽（通过自由基C-C键形成环化）。此外，还讨论了主链酰胺甲基化、主链差向异构化和主链硫代酰胺形成的机制，以及通过翻译后修饰获得小分子的不寻常途径。