DNA methyltransferase 2 (Dnmt2)
Schirmeister group: Marvin Schwickert, Robert Zimmermann, Laurenz Meidner
Helm group:Tim Fischer, Marlies Weber
Despite its high structural similarity to the DNA-methyltransferases (Dnmt) 1 and 3, the primary substrate of Dnmt2 is not DNA but RNA. The main target of Dnmt2 is tRNAAsp, but also further substrates were identified like the tRNAs of Glycin and Valin. Dnmt2 methylates its substrates at position C38 in the anticodon region, which leads to a m5C modification. Therefore, the cofactor S-Adenosylmethionine (SAM) is converted to S-Adenosylhomocysteine (SAH). The modification was shown to play a crucial role in epigenetic inheritance. Furthermore, the upregulation of Dnmt2 occurs in various cancer cell lines. This makes Dnmt2 not only important for the understanding of epigenetic regulation but also a potential anti-cancer target.
Our goal is to design novel Dnmt2 inhibitors. One key point in the drug development process is a functional activity assay. A Tritium Incorportion Assay is used to monitor the conversion of tritium-labeled SAM to SAH during the enzymatic reaction.
For the design of potential inhibitors, different approaches were elaborated. As a starting point, various derivatives of SAH were designed by molecular docking and subsequently synthesised and tested. Additionally structures, which are already described as inhibitors for other methyltransferases (Dnmt1/3 or Catechol–O-Methyltransferase (COMT)), were evaluated. Furthermore, a virtual screening was conducted to identify novel, non-substrate homologue scaffolds as potential Dnmt2 inhibitors.