Radical S-Adenosyl Methionine Peptide Splicease 在翻译后形成 α-Keto-β-Amino acid 的机理认识

IF 16.1 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Anna L. Vagstad, Edgars Lakis, Katja-Sophia Csizi, William Walls, Daniel Richter, Kang Soo Lee, Roman Stocker, Muriel Gugger, William E. Broderick, Joan B. Broderick, Markus Reiher, Jörn Piel
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引用次数: 0

摘要

Radical S-adenosyl methionine 酶催化了蛋白质和肽底物中多种多样的翻译后修饰。其中,一个特殊且在机理上不明显的例子是,通过正式切除酪氨酸衍生的酪胺单元来安装α-酮-β-氨基酸残基。负责剪接的剪接酶是一个广泛的天然产品家族(称为剪接素)中的关键成熟酶,这些天然产品包括强效蛋白酶抑制剂,其中安装的β残基是生物活性的关键。在这里,我们建立了模型剪接酶 PcpXY 的体外活性,以探究非典型蛋白质剪接的机制。对分流产物和副产物的鉴定、氘标记研究以及对假设中间产物的密度泛函理论能量计算都支持一种机制,即酪氨酸 Cα 的氢抽取是肽自由基形成的初始位点,而 4-羟基苯甲醛作为酪氨酸衍生的副产物被释放出来。这些数据阐明了这种前所未有的由自由基介导的生物转化的关键特征,这种生物转化产生的酮酰胺药性也存在于仿肽疗法中。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Mechanistic Insights Into Post-Translational α-Keto-β-Amino Acid Formation by a Radical S-Adenosyl Methionine Peptide Splicease

Mechanistic Insights Into Post-Translational α-Keto-β-Amino Acid Formation by a Radical S-Adenosyl Methionine Peptide Splicease

Radical S-adenosyl methionine enzymes catalyze a diverse repertoire of post-translational modifications in protein and peptide substrates. Among these, an exceptional and mechanistically obscure example is the installation of α-keto-β-amino acid residues by formal excision of a tyrosine-derived tyramine unit. The responsible spliceases are key maturases in a widespread family of natural products termed spliceotides that comprise potent protease inhibitors, with the installed β-residues being crucial for bioactivity. Here, we established the in vitro activity of the model splicease PcpXY to interrogate the mechanism of non-canonical protein splicing. Identification of shunt and coproducts, deuterium labeling studies, and density functional theory energy calculations of hypothesized intermediates support a mechanism involving hydrogen abstraction at tyrosine Cα as the initial site of peptide radical formation and release of 4-hydroxybenzaldehyde as the tyrosine-derived coproduct. The data illuminate key features of this unprecedented radical-mediated biotransformation yielding ketoamide pharmacophores that are also present in peptidomimetic therapeutics.

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来源期刊
CiteScore
26.60
自引率
6.60%
发文量
3549
审稿时长
1.5 months
期刊介绍: Angewandte Chemie, a journal of the German Chemical Society (GDCh), maintains a leading position among scholarly journals in general chemistry with an impressive Impact Factor of 16.6 (2022 Journal Citation Reports, Clarivate, 2023). Published weekly in a reader-friendly format, it features new articles almost every day. Established in 1887, Angewandte Chemie is a prominent chemistry journal, offering a dynamic blend of Review-type articles, Highlights, Communications, and Research Articles on a weekly basis, making it unique in the field.
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