29204-56-6Relevant academic research and scientific papers
Design of allele-specific protein methyltransferase inhibitors
Lin,Jiang,Schultz,Gray
, p. 11608 - 11613 (2001)
Protein arginine methyltransferases, which catalyze the transfer of methyl groups from S-adenosylmethionine (SAM) to arginine side chains in target proteins, regulate transcription, RNA processing, and receptor-mediated signaling. To specifically address the functional role of the individual members of this family, we took a "bump-and-hole" approach and designed a series of N6-substituted S-adenosylhomocysteine (SAH) analogues that are targeted toward a yeast protein methyltransferase RMT1. A point mutation was identified (E117G) in Rmt1 that renders the enzyme susceptible to selective inhibition by the SAH analogues. A mass spectrometry based enzymatic assay revealed that two compounds, N6-benzyl- and N6-naphthylmethyl-SAH, can inhibit the mutant enzyme over the wild-type with the selectivity greater than 20. When the E117G mutation was introduced into the Saccharomyces cerevisiae chromosome, the methylation of Np13p, a known in vivo Rmt1 substrate, could be moderately reduced by N6-naphthylmethyl-SAH in the resulting allele. In addition, an N6-benzyl-SAM analogue was found to serve as an orthogonal SAM cofactor. This analogue is preferentially utilized by the mutant methyltransferase relative to the wild-type enzyme with a selectivity greater than 67. This specific enzyme/inhibitor and enzyme/substrate design should be applicable to other members of this protein family and facilitate the characterization of protein methyltransferase function in vivo when combined with RNA expression analysis.
