The enzymatic methylation of the peptide bond

点击翻译按钮获取中文摘要

Amino acids are nature's open source technology which can be linked together to build machines and it is increasingly realised, potential drug molecules. There are twenty natural amino acids and these have very different chemical properties, shapes and sizes. Yet they connect together using the common peptide or amide bond. Peptide molecules, in theory, could make very good drugs because one can vary the amino acid very easily to tune it for the particular need yet linear strings of amino acids are not good drugs. They are too easily degraded, they do not go into cells and they are too flexible to bind strongly. Nature has evolved a solution to all these problems. To make the macrocycle go into cells it modifies the amino acids within by adding a methyl group onto the amide. This modification would be enormously useful if we could harness it and use in the lab. However, the modification is very difficult to accomplish chemically. This is because the amide which links together amino acids is very stable and unreactive; it is precisely because it is so unreactive that proteins are natures machines. This is yet another example of nature finding an elegant solution to difficult problem. sWe have a strong track record in engineering enzymes to do difficult chemistry, but key to this is understanding the enzymes. In this grant, we seek to understand a 'methylator'. With this information in hand, we will engineer an enzyme to be used both in the lab and inside cells to make starting points for new medicines