Methylglyoxal Affects Translation Fidelity

Abstract

The ribosome, an organelle that decodes mRNA to synthesize proteins, is a molecular machine that consists of ribosomal RNAs and ribosomal proteins. Methylglyoxal, a toxic byproduct of glycolysis, reacts with biological amines, such as exposed amino and guanidino side chains in proteins and guanine bases in nucleic acids. Based on this reasoning, one might expect ribosomes to be modified by methylglyoxal (glycated) at a rate depending on the cellular metabolic context. Here, we report our first data on studying the effect of methylglyoxal on translation fidelity. Experimental elevation of methylglyoxal production in HEK293 cells was achieved with koningic acid, a specific inhibitor of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase. As dihydroxyacetone phosphate, via the interconversion from glyceraldehyde 3-phosphate, is a methylglyoxal precursor, we observed the robust accumulation of glycated intracellular proteins, following the inhibitor treatment. Concomitantly, we detected a significant increase in translation fidelity, as evidenced by the dual-reporter luciferase assay, for near-cognate, non-cognate, but not codon read-through ribosomal misreading. Moreover, the inhibition did not affect the global translation rate, leading to us hypothesizing that glycated ribosomes might exhibit altered structural/catalytic properties that account for the improved fidelity under our experimental conditions.