非典型安环素合成中催化C-C键断裂的alpj家族加氧酶的功能保守与分化

IF 3.5 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Shijie Shen, Changbiao Chi, Keqiang Fan, Qian Zhang, Yang Xu, Jinmin Gao, Huitao Hu, Lijun Wang, Donghui Yang, Ming Ma, Guohui Pan
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引用次数: 0

摘要

alpj家族加氧酶在非典型安环素天然产物的生物合成过程中催化独特的氧化b环裂解和重排反应,具有独特的化学结构和多样的生物活性。虽然已经报道了一些alpj家族酶的单独功能,但缺乏对该酶家族的系统探索和功能比较,阻碍了对alpj家族加氧酶的全面了解。在本研究中,我们对alpj家族加氧酶进行了系统的探索和分析,鉴定出49个具有代表性的同源物,并将其分为两个不同的进化类群。我们发现,来自不同基团的酶表现出明显的功能分化,可以催化相同的安古霉素底物脱氢贝洛霉素生成不同的产物,而同一基团内的酶则表现出更相似的催化功能,并具有不同程度的功能重叠。这强调了alpj家族加氧酶的有趣功能守恒和分化。此外,我们报道了第一个I族酶PenE的晶体结构。结构分析和定点诱变确定了alpj家族加氧酶的关键结构特征和残基,这些加氧酶在N端和c端都有疏水底物结合袋,这两者对于功能都是必不可少的。我们的发现为这个独特的加氧酶家族的进化、催化机制和功能分化提供了有价值的见解。对这些新发现的AlpJ同源物及其相关的生物合成基因簇的进一步研究将有助于发现具有独特催化机制的酶和具有新结构的生物活性非典型安古霉素。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Functional Conservation and Divergence of AlpJ-Family Oxygenases Catalyzing C-C Bond Cleavage in Atypical Angucycline Biosynthesis.

AlpJ-family oxygenases catalyze distinctive oxidative B-ring cleavage and rearrangement reactions during the biosynthesis of atypical angucycline natural products, which are characterized by unique chemical structures and diverse biological activities. While the individual functions of a few AlpJ-family enzymes have been reported, there is a lack of systematic exploration and functional comparison within this enzyme family, hindering a comprehensive understanding of the AlpJ-family oxygenases. In this study, we have systematically explored and analyzed AlpJ-family oxygenases, identifying 49 representative homologues, which can be classified into two distinct evolutionary groups. We revealed that enzymes from different groups exhibit clear functional differentiation, catalyzing the same angucycline substrate dehydrorabelomycin into distinct products, whereas enzymes within the same group display more similar catalytic functions with varying degrees of functional overlap. This underscores the intriguing functional conservation and divergence of the AlpJ-family oxygenases. In addition, we report the first crystal structure of a Group I enzyme, PenE. Structural analysis and site-directed mutagenesis identified key structural features and residues within AlpJ-family oxygenases, which harbor hydrophobic substrate-binding pockets at both the N- and C-termini, both of which are essential for function. Our findings provide valuable insights into the evolution, catalytic mechanisms, and functional divergence of this unique family of oxygenases. Further investigation of these newly identified AlpJ homologues and their associated biosynthetic gene clusters will facilitate the discovery of enzymes with unique catalytic mechanisms and bioactive atypical angucyclines with novel structures.

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来源期刊
ACS Chemical Biology
ACS Chemical Biology 生物-生化与分子生物学
CiteScore
7.50
自引率
5.00%
发文量
353
审稿时长
3.3 months
期刊介绍: ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology. The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies. We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.
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