Protein and nucleotide damage by glyoxal and methylglyoxal in physiological systems--role in ageing and disease

Abstract

Glycation of proteins, nucleotides and basic phospholipids by glyoxal and methylglyoxal--physiological substrates of glyoxalase 1--is potentially damaging to the proteome, genome and lipidome. Glyoxalase 1 suppresses glycation by these alpha-oxoaldehyde metabolites and thereby represents part of the enzymatic defence against glycation. Albert Szent-Györgyi pioneered and struggled to understand the physiological function of methylglyoxal and the glyoxalase system. We now appreciate that glyoxalase 1 protects against dicarbonyl modifications of the proteome, genome and lipome. Latest research suggests there are functional modifications of this process--implying a role in cell signalling, ageing and disease.

Figure 1

The glyoxalase system and metabolism of methylglyoxal.

Figure 2

a. Advanced glycation endproducts residues formed from glyoxal and methylglyoxal with (a) proteins and (b) nucleotides. In (a), protein AGEs are shown as AGE residues with the peptide backbone –CO-CHR-NH- shown on the left. In (b), nucleotide AGEs are shown as nucleic acid base modifications with the 3-(2′-deoxyribosyl) moiety omitted for clarity and linkage indicated by the dashed link.

Figure 3

Biodistribution scheme illustrating flows of formation and removal of protein glycation free adducts.