Developing novel biocatalysts for industrial biocatalysis.

许多制药公司，如默克公司，美国已经使用工程酶，使昂贵的药物分子（如糖尿病药物西格列汀）在一个有效的，毒性较低的方式相比，目前的合成方法。我的项目集中于设计一系列被称为腺苷酸化酶的生物催化剂，用于天然产物的合成。具体来说，酶TamA，从tambjamine天然产物途径，和BioW，这是参与生产的维生素生物素。腺苷酸化酶是通过形成高反应性中间体来活化羧酸以与其它化合物反应的多种酶家族。通过定点诱变和易错PCR等方法对这些酶进行工程改造，我们能够使这些酶的特异性降低。我已经研究了TamA的截短形式的使用，并表明它可以用于制备一系列酰胺分子。这项工作发表在皇家化学学会期刊Med. Chem. Comm.上（Marchetti，Richardson等，10，1192-1196）。我们的长期目标是利用大自然的力量，设计这些强大的催化剂，以比传统化学工业更环保，更有效的方式制造治疗有用的化合物。这是一个令人兴奋的领域，与2018年诺贝尔化学奖一起授予弗朗西斯·阿诺德（加州理工学院），以表彰她利用进化和自然选择方法对酶进行工程改造的工作。

Many pharma companies such as Merck, USA are already using engineered enzymes to make expensive drug molecules (e.g. the diabetic drug sitagliptin) in an efficient, less toxic way compared with synthetic current methods. My project focuses on engineering a series of biocatalysts known as the adenylating enzymes for natural product synthesis. Specifically, the enzymes TamA, from the tambjamine natural product pathway, and BioW, which is involved in the production of the vitamin biotin. Adenylating enzymes are a diverse family of enzymes that activate carboxylic acids for reaction with other compounds by forming a highly reactive intermediate. By engineering these enzymes through methods such as site-directed mutagenesis and error prone PCR, we are able to make these enzymes less specific. Already, I have investigated the use of a truncated form of TamA and shown that it can be used to prepare a range of amide molecules. This work was published by the Royal Society of Chemistry journal Med. Chem. Comm. (Marchetti, Richardson et al, 10, 1192-1196). Our long term goal is to harness the power of nature and engineer these powerful catalysts to make therapeutically useful compounds in a greener, more efficient way than the traditional chemical industry. It is an exciting field to have joined with the 2018 Nobel Prize in Chemistry being awarded to Frances Arnold (Caltech) for her work on the engineering of enzymes using evolution and natural selection methods.