Activation and inhibition of DNA methyltransferases by S-adenosyl-l-homocysteine analogues

Abstract

The inhibition of methyltransferases is currently of high interest, particularly in the areas of microbial infection and cell proliferation, as there have been serious attempts to develop novel anti-microbial agents. In the present investigation, a series of 11 S-adenosyl-l-homocysteine analogues have been synthesized and effect of these analogues on DNA methylation catalyzed by DNA methyltransferases was studied. It was found that, while 5'-S-(propionic acid)5'-deoxy-9-(1'-˪-d-ribofuranosyl)1,3-dideazaadenine was an activator of EcoP15I and HhaI DNA methyltransferases, 5'-S-(propionic acid)5'-deoxy-9-(1'-˪-dribofuranosyl)adenine inhibited the methyltransferases in a non-competitive manner. An understanding of the binding of analogues to DNA methyltransferases will greatly assist the design of novel anti-microbial compounds.