Sulfomycins are sulfur-rich, ribosomally synthesized, and post-translationally modified peptides (RiPPs) that are characterized by a 35-membered macrocyclic ring system with a pyridine domain central to five azoles and additional dehydroamino acids. The pathway through which these large thiopeptide antibiotics are formed in Streptomyces viridochromogene remains elusive. Starting with the cloning of the biosynthetic gene cluster of sulfomycins, we here dissect a two-stage process in which an unusual dehydrogenase heterotrimer functions with two distinct YcaO proteins to install five azole heterocycles into the core peptide sequence of the precursor peptide. The first stage involves the activity of a typical cyclodehydratase complex composed of a didomain E1-YcaO protein and an F-protein partner to heterocyclize distant residues l-Cys2 and l-Thr9 and then the activity of the heterotrimeric dehydrogenase complex that converts the resulting azolines to azoles. In the second stage, this dehydrogenase complex associates with a discrete YcaO protein to form an atypical, four-component azole synthase complex, which is capable of sequentially converting residues l-Cys7, l-Thr5, and l-Ser12 to azoles in a distinct manner. During this process, an E1-like partner protein plays a critical role and functions through the two stages to mediate a variety of specific protein-protein interactions. This partner protein participates in the formation of the active dehydrogenase heterotrimer and the engagement of discrete YcaO activity to form the azole synthase heterotetramer. The findings in this study advance the understanding in the biosynthesis of different azole-containing RiPPs and set the stage for the discovery, engineering, and creation of new thiopeptides using genome mining and synthetic biology approaches.

中文翻译：

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对“具有 2 个不同 YcaO 蛋白的异三聚体脱氢酶复合物功能以在 35 分子硫霉素硫肽中安装 5 个唑杂环”的更正

磺霉素是富含硫的、核糖体合成的、翻译后修饰的肽 (RiPPs)，其特征是一个 35 元大环系统，吡啶结构域位于五个唑和额外的脱氢氨基酸的中心。在绿色产色链霉菌中形成这些大硫肽抗生素的途径仍然难以捉摸。从磺霉素生物合成基因簇的克隆开始，我们在这里剖析了一个两阶段过程，在该过程中，一种不寻常的脱氢酶异源三聚体与两种不同的 YcaO 蛋白一起发挥作用，将五个唑杂环安装到前体肽的核心肽序列中。第一阶段涉及由双结构域 E1-YcaO 蛋白和 F 蛋白伴侣组成的典型环化脱水酶复合物的活性，以杂环化远处的残基 l-Cys2 和 l-Thr9，然后是异三聚体脱氢酶复合物的活性，将所得的唑啉转化唑类。在第二阶段，该脱氢酶复合物与离散的 YcaO 蛋白结合形成非典型的四组分唑类合酶复合物，能够依次将 l-Cys7、l-Thr5 和 l-Ser12 残基转化为不同的唑类。方式。在此过程中，E1 样伙伴蛋白在介导各种特定蛋白质 - 蛋白质相互作用的两个阶段中发挥关键作用和功能。该伙伴蛋白参与活性脱氢酶异源三聚体的形成和离散 YcaO 活性的参与以形成唑合酶异源四聚体。本研究的发现促进了对不同含唑类 RiPP 生物合成的理解，并为使用基因组挖掘和合成生物学方法发现、改造和创造新的硫肽奠定了基础。