Studies on the molecular mechanism of action of 5- fluororacil : interaction of amino acyl-tRNA synthetases with 5- fluororacil substituted transfer RNA from rat liver

Abstract

FUra, a potent anticancer agent, gets incorporated into tRNA and affects the efficiency of adapter functions of tRNA. Incorporation of FUra, as a first step, interferes with the initial processes of aminoacylation.

The presence of fluorine at the C-5 position of FUra in the tRNA ?? ?? ?? affects the efficiency of aminoacyl-tRNA synthetase (AARS) to carry out hydrogen exchange, which is an essential step in aminoacylation.

Further, interaction of AARS with FUra-tRNA results in the release of FUra from tRNA ?? ?? ?? by glycosidase activity. The consequence of such glycosidase activity is the generation of nicks in FUra-tRNA. These nicks are produced mostly at positions where uracil or uracil-derived modified bases are substituted by FUra. FUra-tRNAs containing such nicks fail to accept amino acids and are subsequently degraded.

Based on the results obtained in the present study, it is concluded that the incorporation of FUra into tRNA leads to degradation of the tRNA by glycosidase activity of AARS, thus providing yet another mode of FUra-mediated cytotoxicity.