New catalytic reaction development by laboratory evolution of protein-based catalysts

通过蛋白质催化剂的实验室进化开发新的催化反应

• 批准号: 420112577
• 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: Independent Junior Research Groups
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/420112577?language=en
• 关键词: New; catalytic; reaction; development; laboratory

Generating molecules of interest by developing new catalytic reactions is a defining feature in current organic chemistry. Despite tremendous advances using classical approaches, such as small molecule and heterogenous catalysis, many very important reactions do not have a catalytic solution. Classical catalyst types often fail due to limited catalyst control.Proteins are superior catalysts as their macromolecular structure offers precise molecular recognition. The multitude of active site amino acid interactions provide unique control over substrate conformations, transition states and reactivities of intermediates. Capitalizing on this multitude of interactions in protein active sites, we should be able to overcome energy barriers that are unattainable by classical methods. New catalytic reactions can be envisioned that are enabled by proteins macromolecular structure and that have so far not been conquered, neither in biology nor synthetic chemistry.The proposed Emmy Noether group aims for an highly interdisciplinary approach by exploiting proteins to develop catalysts for desired C-C and C-X bond forming reactions. This will be achieved by taking advantage of reactivity patterns known from synthetic organic chemistry, exploring catalytic promiscuity of the myriad of enzyme classes and applying state of the art laboratory evolution experiments. In our proof of concept studies, we envision to generate catalysts for various sought-after reactions including 1) the enantioselective anti-Markovnikov alkene oxidation, 2) asymmetric hydrofunctionalization of unactivated alkenes, 3) regiocontrol in arene alkylation or 4) carbonyl olefination using simple alkenes as olefination reagent. The latter two will be enabled by establishing a platform for enzymatic Lewis acid catalysis that will open the door to a huge variety of very important C-C bond forming reactions. The target reactions harness different enzyme classes and use different mechanisms such as metal-dependent oxidation chemistry, metal-dependent non-redox reactions as well as cofactor-free, cooperative acid/base catalysis. Catalytic access to these reactions has disruptive potential as multi-step reaction sequences using stoichiometric reagents will be replaced with sustainable catalytic transformations that form desired bonds selectively in one synthetic operation. The evolved enzyme variants will serve as basis for mechanistic studies to gain understanding in the molecular interactions that enable these transformations and to study scope and limitations in synthesis. Further, whole new synthetic metabolic pathways will be accessible by combining these “new-to-nature” enzyme function with established biocatalysts to access even more complex overall reactions. In short, the proposed Emmy Noether group exploits protein engineering to enable and understand new chemical transformations and aims to develop a new class of protein-based catalysts for synthetic chemistry.

通过开发新的催化反应来产生感兴趣的分子是当前有机化学中的一个定义特征。尽管使用经典的方法，如小分子和多相催化，取得了巨大的进步，许多非常重要的反应没有一个催化解决方案。传统的催化剂由于催化剂控制有限而经常失效。蛋白质是上级催化剂，因为它们的大分子结构提供精确的分子识别。大量的活性位点氨基酸相互作用提供了对底物构象、过渡态和中间体反应性的独特控制。利用蛋白质活性位点中的大量相互作用，我们应该能够克服经典方法无法达到的能量障碍。新的催化反应可以设想，是由蛋白质的大分子结构，迄今尚未征服，无论是在生物学还是合成化学。拟议的埃米诺特集团的目标是一个高度跨学科的方法，通过利用蛋白质开发催化剂所需的C-C和C-X键形成反应。这将通过利用从合成有机化学中已知的反应模式，探索无数酶类的催化混杂性和应用最先进的实验室进化实验来实现。在我们的概念验证研究中，我们设想产生用于各种受欢迎的反应的催化剂，包括1）对映选择性反马尔可夫尼科夫烯烃氧化，2）未活化烯烃的不对称加氢官能化，3）芳烃烷基化中的区域控制或4）使用简单烯烃作为烯烃化试剂的羰基烯烃化。后两者将通过建立酶促刘易斯酸催化平台来实现，这将为各种非常重要的C-C键形成反应打开大门。目标反应利用不同的酶类别，并使用不同的机制，如金属依赖性氧化化学，金属依赖性非氧化还原反应以及无辅因子，协同酸/碱催化。催化进入这些反应具有破坏性的潜力，因为使用化学计量试剂的多步反应序列将被可持续的催化转化所取代，这些催化转化在一个合成操作中选择性地形成所需的键。进化的酶变体将作为机制研究的基础，以了解使这些转化成为可能的分子相互作用，并研究合成的范围和限制。此外，通过将这些“新自然”的酶功能与已建立的生物催化剂相结合，可以获得全新的合成代谢途径，以获得更复杂的整体反应。简而言之，拟议中的Emmy Noether小组利用蛋白质工程来实现和理解新的化学转化，并旨在开发一类新的基于蛋白质的合成化学催化剂。