| Project Detail |
Enzymatic addition of a methyl group (methylation) is the most prevalent natural modification in cells, serving a myriad of regulatory and structural functions. Abnormal methylation of DNA, RNA or histone proteins can lead to severe developmental defects and is associated with numerous human diseases. Selective methylation of biomolecular targets is carried out by dedicated methyltransferase enzymes, which use the cofactor S-adenosyl-L-methionine (AdoMet) as the source of methyl groups. Despite the high specificity and impressive diversity of MTases, the deposited methyl groups are poor reporters and hardly amenable to further derivatization. To unlock the biotechnological power of MTases, strategies for repurposing these enzymes into targeting vehicles for the transfer of useful extended groups from synthetic AdoMet analogs have been devised. However, despite substantial advances over the past decade, a widespread adoption of this enabling technology in scientific labs and clinical settings was grossly hindered by the poor availability of such synthetic cofactors. This proposal, footed on findings of our ERC-funded work, will seek to overcome the limitations of chemical synthesis and adapt our recently developed chemo-enzymatic protocols for low-cost industrial production of functionally competent AdoMet analogs. We will also seek the transfer of the technology to an industrial partner for its commercial exploitation and to ensure broad access of these valuable reagents to the scientific community and commercial stakeholders. |
