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化学选择性控制的分子基础是通过实验室进化P450s催化内部基基的氧化

Jordi Soler¹, Sebastian Gergel², Stephan C Hammer²

¹Institut de Química Computacional i Catàlisi (IQCC) and Departament de Química, Universitat de Girona, Carrer Maria Aurèlia Capmany 69, 17003, Girona, Catalonia, Spain.

Chembiochem : a European journal of chemical biology

|April 3, 2024

概括

工程P450酶现在可以选择性地在基上进行基C-H氧化,克服以前的环氧化偏好. 这一突破有助于设计用于化学合成的特定生物催化剂.

科学领域:

生物催化剂是一种生物催化剂.
酵素工程是什么意思酵素工程
有机化学有机化学

背景情况:

细胞染色体P450酶催化选择性氧化,包括碳化合物的氧化和环氧化.
适应P450s对烯氧化对于开发新型合成生物催化剂至关重要.
了解P450s在区分烯环氧化和基C-H氧化中的化学选择性是合理生物催化剂设计的关键.

研究的目的:

为了研究实验室进化的P450酶中改变选择性的分子基础.
了解突变如何影响P450活性部位,有利于过氧化而不是过氧化.
揭示P450变异向基C-H基化转变背后的机制.

主要方法:

来自Labrenzia聚合物 (P450_LA1) 的P450酶的定向进化.
图书馆选以识别具有改变基质氧化偏好的变体.
多级计算方法,包括酶建模,用于分析活性位点相互作用.

主要成果:

一个P450_LA1变体 (KS) 之前已经演化为通过从trans-β-methylstyrene的carbocation中间体形成.
进一步的查发现了一种新的突变,导致94%的基C-H氧化选择性,抑制了环氧化和碳基形成.
计算分析表明,一个庞大的突变改变了基质构造,在固态上阻碍了环氧化,有利于终端氧化.

结论:

酶工程可以将P450选择性重定向到特定的氧化途径,如基C-H氧化.
由突变驱动的活性部位结构修饰对于控制P450生物催化剂中的化学选择性至关重要.
这项研究提供了关于P450生物催化剂用于向基功能化的合理设计的见解.

关键词:

化学选择性化学选择性计算机建模计算建模氧化过氧化过程中的氧化.氧化的方法是在P450酶中.

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