Unlocking the potential of engineered C-C bond forming enzymes for biocatalysis

全球制药和化学工业的未来成功取决于成功开发高效、选择性和可持续的方法来制造具有有用特性的新有机分子。历史上，这些方法集中于使用合成有机化学来将简单的化学结构单元融合和定制成大量复杂的分子结构，这些分子结构又可以用作新药、作物保护剂或材料等的基础。尽管合成化学取得了巨大的成功，但仍然存在问题，包括过度依赖某些类型的反应，这导致了具有主要平坦的2D结构的分子的过度表示，这些分子作为药物的价值有限。与化学催化剂相比，生物催化剂（称为酶）能够进行具有挑战性的化学反应，可以在精确的立体化学控制下快速构建具有多个键的复杂3D化学结构。此外，酶可以在环境条件下进行这样的反应，而不需要任何对环境有害的试剂。由于这些原因，人们对开发当前和未来药物和类似重要分子的生物催化途径非常感兴趣。碳-碳键形成反应被称为狄尔斯-阿尔德反应，是一种在单一步骤中构建复杂3D分子的有效方法。然而，该反应的局限性在于，为了实现高产率、立体选择性和区域选择性，反应物的电子性质需要互补，并且通常需要苛刻的反应条件。该研究项目建立在我们最近发现的一种天然进化的辅助因子独立酶的基础上，该酶在室温下催化Diels-Alder反应，并且在使用常规合成有机化学不能转化的底物上。这一发现开辟了利用这种酶产生一系列全新的复杂分子的可能性，这些分子可以形成新药或类似重要化合物的基础。在这个项目中，我们将建立这种和其他相关的狄尔斯-阿尔德酶可以催化的反应的实际和理论限制，我们还将合理地重新设计这些酶，有目的地改变它们的功能，以允许获得更多种类的产品。我们将这些工程生物催化剂与辅助酶合作，催化进一步的成环反应，以开发工业上有用的分子路线。该项目是布里斯托大学和制药公司阿斯利康之间的一个具有重要战略意义的合作伙伴关系，我们将共同开发天然和工程酶，并将其用于产生大量新的3D分子，这些分子可用作治疗各种人类疾病的新药的基础。

The future success of the global pharmaceutical and chemical industries is dependent on the successful development of efficient, selective and sustainable ways of making new organic molecules with useful properties. Historically, such methods have centered on the use of synthetic organic chemistry to fuse and tailor simple chemical building blocks into a vast array of complex molecular architectures, which may in-turn be used as the basis for amongst other things new drugs, crop protection agents, or materials. Despite the undoubted success of synthetic chemistry, problems exist, including the over-reliance on certain types of reactions that have led to an excessive representation of molecules with predominantly flat, 2D architectures, which are of limited value as drugs. In contrast to chemical catalysts, biological catalysts, termed enzymes, are able to perform challenging chemical reactions that can rapidly build complex 3D chemical structures with multiple bonds under precise stereochemical control. In addition, enzymes can perform such reactions under ambient conditions and without any requirement for environmentally damaging reagents. For these reasons there is significant interest in developing biocatalytic routes to current and future pharmaceuticals and similarly important molecules. A carbon-carbon bond forming reaction known as the Diels-Alder reaction is an effective means of building complex 3D molecules in a single step. However, a limitation of this reaction is that to achieve high yields, stereoselectivity and regioselectivity, the electronic properties of the reactants need to be complementary and often harsh reaction conditions are required. This research project builds on our exciting recent discovery of a naturally evolved co-factor independent enzyme that catalyzes the Diels-Alder reaction at room temperature and on substrates which cannot be transformed using conventional synthetic organic chemistry. This discovery opens up the possibility of using this enzyme to generate a whole new series of complex molecules that could form the basis of new drugs or similarly important chemical compounds. During this project we will establish the practical and theoretical limits of the reactions that this and other related Diels-Alderases can catalyze, we will also rationally re-engineer these enzyme to purposefully change their function to allow access to an even greater variety of products. We will partner these engineered biocatalysts with auxiliary enzymes which catalyze further ring forming reactions to develop routes to industrially useful molecules. This project is a strategically important partnership between the University of Bristol and the pharmaceutical company AstraZeneca, and we will work together to develop natural and engineered enzymes and deploy them to generate a vast array of new 3D molecules that can be used as the basis for new drugs to treat a diverse array of human diseases.