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Characterization of Histidine Functionalization and Its Timing in the Biosynthesis of Ribosomally Synthesized and Posttranslationally Modified Thioamitides
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2022-03-01 , DOI: 10.1021/jacs.1c11669
Ling Hu 1 , Yi Qiao 1 , Jingyu Liu 1 , Chao Zheng 2 , Xiaofeng Wang 1 , Peng Sun 3 , Yucheng Gu 4 , Wen Liu 1
Affiliation  

Thioamitides are ribosomally synthesized and posttranslationally modified peptide (RiPP) natural products that hold great potential in anticancer drug development. Members in this RiPP family feature a thioamidated peptidyl chain conjugated with a macrocyclic ring system that contains two nonproteinogenic residues, 2-aminovinyl-cysteine (AviCys) and β-hydroxy-N,N-dimethyl-l-histidine (hdmHis). Focusing on the hdmHis residue that is unique to thioamitides, we report the enzymatic process for His functionalization and, more importantly, the timing of its related reactions with the other posttranslational modifications (PTMs) involved in thioamitide biosynthesis. His functionalization involves the activities of an S-adenosyl-l-methionine-dependent protein and a 2-oxoglutarate-Fe(II) monooxygenase for His bis-N-dimethylation and subsequent β-hydroxylation in a highly ordered manner. This process relies on the leader peptide sequence of the precursor peptide and on the establishment of the AviCys-containing, C-terminal macrocyclic ring system in particular. In contrast, prior peptide thioamidation is not required. Knowledge gained from the catalytic logic, specificity, and compatibility of His functionalization greatly furthers our understanding of the process through which nature develops thioamitides from a ribosomally synthesized peptide precursor.

中文翻译:

组氨酸功能化的表征及其在核糖体合成和翻译后修饰的硫代酰胺生物合成中的时机

硫酰胺是核糖体合成的翻译后修饰肽 (RiPP) 天然产物,在抗癌药物开发中具有巨大潜力。该RiPP家族的成员具有与包含两个非蛋白质残基大环系统共轭的硫代酰胺化肽链,即 2- 氨基乙烯基半胱氨酸( AviCys ) 和 β-羟基- N,N - d i m ethyl- l -他的tidine (hdmHis)。着眼于硫代酰胺特有的 hdmHis 残基,我们报告了 His 功能化的酶促过程,更重要的是,报告了其与硫代酰胺生物合成中涉及的其他翻译后修饰 (PTM) 相关反应的时间。His 功能化涉及S-腺苷-L-蛋氨酸依赖性蛋白和His bis- N的 2-氧代戊二酸-Fe(II) 单加氧酶的活性。-二甲基化和随后的高度有序的β-羟基化。该过程依赖于前体肽的前导肽序列,特别是依赖于含 AviCys 的 C 端大环系统的建立。相反,不需要预先进行肽硫代酰胺化。从 His 功能化的催化逻辑、特异性和相容性中获得的知识极大地加深了我们对自然界从核糖体合成的肽前体中产生硫代酰胺的过程的理解。
更新日期:2022-03-01
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