Exploring the potential of engineered enzyme families for selective N-alkylation of heteroarenes: A convergent synthesis approach with SAM analogs as intermediates

探索工程化酶家族选择性 N-烷基化杂芳烃的潜力：以 SAM 类似物为中间体的聚合合成方法

• 批准号: 530620252
• 负责人: Professor Dr. Stephan C. Hammer
• 金额: --
• 依托单位: Lehrstuhl für Organischen Chemie und Biokatalyse
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/530620252?language=en
• 关键词: Exploring; potential; engineered; enzyme; families

The selective N-alkylation of heteroarenes could drastically shortcut synthesis of complex molecules, especially if two larger fragments could be coupled by selective C-N bond formation in a convergent approach. Here we propose to engineer, understand and apply enzyme families that synthesize and use S-adenosyl-L-methionine (SAM) analogs as intermediates for selective N-alkylation of heteroarenes. Our goal is to generate two enzyme families, namely sulfonium ion synthases that generate SAM analogs from S-adenosyl-L-homocysteine and "off the shelf" haloalkanes, and N-alkyltransferases that use these SAM analogs as co-substrates in selective C–N bond formations with heteroarene building blocks. This research i) aims to develop a catalytic method for a sought-after chemical transformation, ii) uses in silico mutagenesis for computational design of mutant libraries to systematically explore large regions of the amino acid sequence space, and iii) explores the potential of SAM analogs in convergent synthesis by coupling readily available fragments to complex molecules.

杂芳烃的选择性N-烷基化可以极大地缩短复杂分子的合成，特别是如果两个较大的片段可以通过选择性C-N键形成以会聚方法偶联。在这里，我们建议工程师，理解和应用酶家族，合成和使用S-腺苷-L-甲硫氨酸（SAM）类似物作为中间体的选择性N-烷基化杂芳烃。我们的目标是产生两个酶家族，即从S-腺苷-L-高半胱氨酸和“现成的”卤代烷产生SAM类似物的锍离子转移酶，和使用这些SAM类似物作为与杂芳烃结构单元的选择性C-N键形成中的共底物的N-烷基转移酶。本研究i）旨在开发一种催化方法，用于寻求化学转化，ii）使用计算机诱变进行突变体库的计算设计，以系统地探索氨基酸序列空间的大区域，iii）通过将容易获得的片段偶联到复杂分子，探索SAM类似物在收敛合成中的潜力。