Developing novel biocatalysts for industrial biocatalysis.

许多制药公司，如美国默克公司，已经在使用工程酶制造昂贵的药物分子（如糖尿病药物西格列汀），与目前的合成方法相比，这种方法有效，毒性更小。我的项目重点是设计一系列生物催化剂，即用于天然产物合成的腺苷化酶。具体来说，来自铃鼓胺天然产物途径的酶TamA和参与维生素生物素生产的酶BioW。腺苷化酶是一种不同的酶家族，通过形成高活性的中间体来激活羧酸与其他化合物反应。通过位点定向诱变和易出错PCR等方法来设计这些酶，我们能够使这些酶的特异性降低。我已经研究了截断形式的TamA的用途，并表明它可以用来制备一系列酰胺分子。这项研究发表在英国皇家化学学会的医学化学杂志上。（Marchetti, Richardson et al ., 10, 1192-1196）。我们的长期目标是利用自然的力量，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用的化合物。这是一个令人兴奋的领域，2018年诺贝尔化学奖被授予弗朗西丝·阿诺德（加州理工学院），她利用进化和自然选择方法在酶的工程方面做出了贡献。

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.