Developing novel biocatalysts for industrial biocatalysis.

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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.