Structure and Functional Analysis of ClbQ, an Unusual Intermediate-Releasing Thioesterase from the Colibactin Biosynthetic Pathway,ACS Chemical Biology

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Structure and Functional Analysis of ClbQ, an Unusual Intermediate-Releasing Thioesterase from the Colibactin Biosynthetic Pathway
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-09-08 00:00:00 , DOI: 10.1021/acschembio.7b00479
Naga Sandhya Guntaka ₁ , Alan R. Healy _{2,

3} , Jason M. Crawford _{2,

3,

4} , Seth B. Herzon _{2,

5} , Steven D. Bruner ₁

Affiliation

Colibactin is a genotoxic hybrid nonribosomal peptide/polyketide secondary metabolite produced by various pathogenic and probiotic bacteria residing in the human gut. The presence of colibactin metabolites has been correlated to colorectal cancer formation in several studies. The specific function of many gene products in the colibactin gene cluster can be predicted. However, the role of ClbQ, a type II editing thioesterase, has not been established. The importance of ClbQ has been demonstrated by genetic deletions that abolish colibactin cytotoxic activity, and recent studies suggest an atypical role in releasing pathway intermediates from the assembly line. Here we report the 2.0 Å crystal structure and biochemical characterization of ClbQ. Our data reveal that ClbQ exhibits greater catalytic efficiency toward acyl-thioester substrates as compared to precolibactin intermediates and does not discriminate among carrier proteins. Cyclized pyridone-containing colibactins, which are off-pathway derivatives, are not viable substrates for ClbQ, while linear precursors are, supporting a role of ClbQ in facilitating the promiscuous off-loading of premature precolibactin metabolites and novel insights into colibactin biosynthesis.

中文翻译：

从Colibactin生物合成途径中异常释放的硫酯酶ClbQ的结构和功能分析

Colibactin是一种遗传毒性杂合非核糖体肽/聚酮化合物次生代谢产物，由人类肠道中的各种致病菌和益生菌产生。在一些研究中，大肠菌素代谢产物的存在与大肠癌的形成有关。可以预测大肠菌素基因簇中许多基因产物的特异性功能。但是，尚未确定II型编辑硫酯酶ClbQ的作用。通过消除大肠菌素细胞毒活性的基因缺失已证明了ClbQ的重要性，最近的研究表明，在从组装生产线释放途径中间体方面，非典型作用。在这里，我们报告了ClbQ的2.0Å晶体结构和生化特征。我们的数据表明，与前辅乳脂蛋白中间体相比，ClbQ对酰基硫酯底物表现出更大的催化效率，并且在载体蛋白之间没有区别。环状的含吡啶酮的大肠菌素不是路途衍生物，不是ClbQ的可行底物，而线性前体则支持ClbQ在促进过早释放前colibactin代谢产物的杂物卸载和对大肠菌素生物合成的新见解中的作用。

更新日期：2017-09-08

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