Expanded Sequence Space of Radical S-Adenosylmethionine-Dependent Enzymes Involved in Post-translational Macrocyclization
Expanded Sequence Space of Radical S-Adenosylmethionine-Dependent Enzymes Involved in Post-translational Macrocyclization
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DOI：
10.1002/anie.202212447
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发表时间：
2022-10-26
影响因子：
16.6
通讯作者：
Li, Yong-Xin
中科院分区：
文献类型：
--
作者：
He, Bei-Bei;Cheng, Zhuo;Li, Yong-Xin
核糖体合成和后修饰的肽（RiPPs）代表了细菌中最大但主要未被探索的天然产物家族之一。RIPP的遗传编码性质简化了其生物合成基因簇（BGC）的预测和优先级排序。我们报告了一个小肽和酶共现分析工作流程（SPECO），该工作流程使我们能够从161 954个细菌基因组中识别出32 220个前瞻性rSAM催化的RiPP BGC，并优先考虑25个具有新生物合成结构或前体模式的家族。我们表征了三种新的酶，分别催化半胱氨酸-甘氨酸（BlaB），组氨酸-脂肪族侧链（ScaB）和酪氨酸/组氨酸-精氨酸（VguB）交联。环番形成酶ScaB具有广泛的底物选择性，使其能够催化多种三肽的形成。这些结果证明了SPECO工作流程在发现用于肽大环化的新酶方面的优势。
Ribosomally synthesized and post-translationally modified peptides (RiPPs) represent one of the largest but primarily underexplored natural product families in bacteria. The genetically encoded nature of RiPPs simplifies the prediction and prioritization of their biosynthetic gene clusters (BGCs). We report a small peptide and enzyme co-occurrence analysis workflow (SPECO), which allowed us to identify 32 220 prospective rSAM-catalyzed RiPP BGCs from 161 954 bacterial genomes and prioritize 25 families with new biosynthetic architectures or precursor patterns. We characterized three new enzymes that respectively catalyze cysteine-glycine (BlaB), histidine-aliphatic side chain (ScaB), and tyrosine/histidine-arginine (VguB) cross-links. The cyclophane-forming enzyme ScaB exhibits broad substrate selectivity, allowing it to catalyze diverse triceptide formation. These results demonstrate the strength of the SPECO workflow in discovering new enzymes for peptide macrocyclization.