针对域的代谢学描述了可利巴克生物合成的异环组合步骤
Eric P Trautman1,2, Alan R Healy1,2, Emilee E Shine2,3
1Department of Chemistry, Yale University , New Haven, Connecticut 06520, United States.
Journal of the American Chemical Society
|February 28, 2017
概括
我们开发了针对域的代谢学来研究多基合成酶 (PKS) 和非核糖体合成酶 (NRPS). 这种方法揭示了小分子生物合成中的个体域功能,比如大肠杆菌中的菌素生产.
科学领域:
- 生物化学
- 分子生物学
- 代谢学
背景情况:
- 模块化多基合成酶 (PKS) 和非核糖体合成酶 (NRPS) 是合成各种小分子至关重要的大型酶.
- 目前研究这些酶的方法通常涉及基因删除或过度表达,限制单个领域的细胞水平功能分析.
- 在细胞层面上理解这些催化域的确切作用仍然是一个挑战.
研究的目的:
- 介绍和验证一个小说
- 针对域名的
- 在 PKS 和 NRPS 途径中剖析单个催化域的代谢学策略.
- 将这种策略应用于细菌大肠杆菌的混合NRPS-PKS系统,以了解其代谢贡献.
- 描述细胞代谢组内的NRPS-PKS域的功能读数 (多域签名).
主要方法:
- 基因组编辑与途径分析相结合,在PKS和NRPS基因中产生向突变.
- 应用代谢学分析来分析这些向突变对小分子产生的影响.
- 关键途径中间体和代谢物的结构特征.
主要成果:
- 以域为目标的代谢学方法成功生成了反映单个PKS和NRPS域贡献的"多域签名".
- 实验证据证明了该域在胆固醇生物合成中的特定作用以及异环形成的时间.
- 两种反应性前科利巴克代谢物的结构特征,其代谢命运在酶ClbP的存在和缺失中得到阐明.
- 这项研究提供了一种因 colibactin 引起的基因毒性机制模型的代谢支持.
结论:
- 域向代谢学提供了一个精确的方法来研究复杂的NRPS-PKS通路中的单个催化域的体内功能.
- 这种方法为表征这些生物合成组装线提供了前所未有的遗传和代谢分辨率.
- 这些发现有助于我们更好地了解胆固醇生物合成和基因毒性,并有助于研究其他NRPS-PKS系统.
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