Development of new amine donors for biocatalysis

天然和工程生物催化剂通过催化官能团的高产量转化，已经对高价值药物的制造产生了影响。一旦克服了酶的局限性（如底物范围狭窄），酶在有机合成中的应用将更加常规(1)。由于参与天然产物生物合成的新酶的发现和基因组测序的加速，酶所显示的化学转化的范围继续扩大。一旦一种新的酶被选中，现代酶工程技术（如定向进化）就可以应用于产生具有广泛合成用途的定制生物催化剂。这项技术的影响得到了2018年诺贝尔化学奖授予弗朗西丝·阿诺德教授(2)的认可。在这些项目中，我们将利用酶大家族的成员来开发有效的路线，以制备商品化学品和高价值的活性药物成分（api，参考文献3）。该项目将从代谢途径中获取天然酶，并在必要时对其进行进化，以扩大其底物范围。我们将把这些生物催化剂与兼容的化学催化剂结合起来，以扩大优化路线的合成效用。我们将专门研究转氨酶（TA）生物催化剂，并探索新的合成胺供体(4)。该项目将提供现代生物催化剂方法和分析（重组DNA技术、酶表征和工程）方面的培训。我们的目标是与x射线晶体学专家合作，指导目标酶的工程/进化。此外，该项目将与我们的工业生物催化合作伙伴庄信万丰有具体的联系。

Natural and engineered biocatalysts are already having impact in the manufacture of high value pharmaceuticals by catalysing the conversion of functional groups in high yield. The use of enzymes for organic synthesis will be more routine once their limitations, such as narrow substrate range, are overcome (1). The range of chemical transformations displayed by enzymes continues to grow, fuelled by the discovery of new enzymes involved in natural product biosynthesis and accelerated by genome sequencing. Once a new enzyme is selected, modern enzyme engineering techniques (e.g. directed evolution) can be applied to generate a bespoke biocatalyst with broad synthetic utility. The impact of this technology was recognised by the award of the Nobel prize in Chemistry in 2018 to Prof. Frances Arnold (2). In these projects we will exploit members of large families of enzymes to develop efficient routes for the preparation of both commodity chemicals and high value active pharmaceutical ingredients (APIs, ref. 3).This project will source natural enzymes from metabolic pathways and where necessary, evolve them to expand their substrate scope. We will combine these biocatalysts with compatible chemo-catalysts to expand the synthetic utility of the optimised route. We will specifically work with transaminase (TA) biocatalysts and explore novel synthetic amine donors (4). The project will provide training in modern biocatalyst methodology and analysis (recombinant DNA technology, enzyme characterisation and engineering). We will aim to collaborate with experts in x-ray crystallography to guide engineering/evolution of target enzymes. Moreover, this project will have specific links with our industrial biocatalysis partner Johnson Matthey.