Diversity in mechanism and function of tRNA methyltransferases

Abstract

tRNA molecules undergo extensive post-transcriptional processing to generate the mature functional tRNA species that are essential for translation in all organisms. These processing steps include the introduction of numerous specific chemical modifications to nucleotide bases and sugars; among these modifications, methylation reactions are by far the most abundant. The tRNA methyltransferases comprise a diverse enzyme superfamily, including members of multiple structural classes that appear to have arisen independently during evolution. Even among closely related family members, examples of unusual substrate specificity and chemistry have been observed. Here we review recent advances in tRNA methyltransferase mechanism and function with a particular emphasis on discoveries of alternative substrate specificities and chemistry associated with some methyltransferases. Although the molecular function for a specific tRNA methylation may not always be clear, mutations in tRNA methyltransferases have been increasingly associated with human disease. The impact of tRNA methylation on human biology is also discussed.

Transfer RNA methyltransferases with a SpoU‐TrmD (SPOUT) fold and their modified nucleosides in tRNA

“…The reaction mechanisms of base methylations by tRNA methyltransferases have been recently reviewed [50,51]. To avoid duplication, therefore, I describe only the 2’- O -methylation of ribose by tRNA methyltransferases with a SPOUT fold.…”

Factors That Shape Eukaryotic tRNAomes: Processing, Modification and Anticodon–Codon Use

“…Methylation is a most pervasive and ancient modification to tRNA, occurring on all of the bases in all domains of life, in some cases at multiple positions on the base, and/or in conjunction with or added to other modifications, as well as to the ribose moiety of the nucleotide [149]. The tRNA methyltransferases (TRMs) encompass a diverse family of enzymes, that includes several different structural classes and mechanisms of catalysis, that appear to have evolved independently [149].…”

“…The tRNA methyltransferases (TRMs) encompass a diverse family of enzymes, that includes several different structural classes and mechanisms of catalysis, that appear to have evolved independently [149]. A compilation of mammalian homologs of the known S. cerevisiae TRMs revealed multiple for several [150].…”

The m1A58 modification in eubacterial tRNA: An overview of tRNA recognition and mechanism of catalysis by TrmI

“…The mechanism is therefore quite different when a proton is present, since it must be removed before or during the methyl transfer step. This proton removal, if present, is absolutely required and increases the nucleophilicity of the nitrogen for a proper methyl transfer following an S N 2-like mechanism [51,52,57,58]. In the case of the N 1 position in adenines, there is no proton attached to the endocyclic nitrogen, meaning the methyl transfer could occur without a preliminary deprotonation.…”

“…However, in the field of RNA N-methylation, the beststudied mechanisms are for the N 1 of guanines [59][60][61] and the N 6 of adenines [62,63], two cases where a preliminary deprotonation is needed to reveal the nucleophilicity of the corresponding centers. Similarly, but without experimental and/or computational arguments, it was proposed that the N 1 -methylation of adenines would proceed via the deprotonation of the N 6 exocyclic nitrogen [58]. Although the need for a deprotonation is still in question, we had previously proposed that, if present at all, the deprotonation could be performed by D170 [28].…”