Editing mechanism of aminoacyl-tRNA synthetases operates by a hybrid ribozyme/protein catalyst.
Aminoacyl-tRNA synthetases (aaRSs) are critical for the translational process, catalyzing the attachment of specific amino acids to their cognate tRNAs. To ensure formation of the correct aminoacyl-tRNA, and thereby enhance the reliability of translation, several aaRSs have an editing capability that hinders formation of misaminoacylated tRNAs. We investigated theoretically the mechanism of the editing reaction for a class I enzyme, leucyl-tRNA synthetase (LeuRS), complexed with a misaminoacylated tRNA(Leu), employing ab initio hybrid quantum mechanical/molecular mechanical potentials in conjunction with molecular dynamics simulations. It is shown that the water molecule that acts as the nucleophile in the editing reaction is activated by a 3'-hydroxyl group at the 3'-end of tRNA(Leu) and that the O2' atom of the leaving group of the substrate is capped by one of the water's hydrogen atoms. Thus, it is shown that editing is a self-cleavage reaction of the tRNA and so it is the tRNA, and not the protein, that drives the reaction. The protein does, however, have an important stabilizing effect on some high-energy intermediates along the reaction path, which is more efficient than the ribozyme would be alone. This indicates that editing is achieved by a novel "hybrid ribozyme/protein catalyst". Analysis of existing experimental data and additional modeling shows that this ribozymal mechanism appears to be widespread, occurring in the ribosome as well as in other aaRSs. It also suggests transitional forms that could have played an important role in the RNA world hypothesis for the origin of life.
Center for Computational Sciences, University of Tsukuba, Tennodai 1-1-1, Tsukuba Science City, Ibaraki 305-8577, Japan.
Yohsuke
Y
Hagiwara
Martin J
MJ
Field
Osamu
O
Nureki
Masaru
M
Tateno
D007935:Leucine-tRNA Ligase / Q000737:chemistry* / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D011789:Quantum Theory; D016337:RNA, Catalytic / Q000378:metabolism; D012346:RNA, Transfer, Amino Acyl / Q000737:chemistry* / Q000378:metabolism*; D016963:Thermus thermophilus / Q000201:enzymology*
D016337:RNA, Catalytic; D012346:RNA, Transfer, Amino Acyl; D007935:Leucine-tRNA Ligase