Fig. 2

Formation, glycation and detoxification of methylglyoxal (MGO). MGO can be formed endogenously from glucose through auto-oxidation [26], or spontaneous degradation of dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (G3P) during glycolysis [25]. Additionally, MGO can be formed through lipid peroxidation [27], threonine catabolism [28], ketone body oxidation [29], and the degradation of advanced glycation end-products (AGEs) [26]. Moreover, MGO can be increased in a system through exogenous sources in the form of dietary intake [22] and local formation by the gut microbiome [31,32,33]. MGO can glycate to form AGEs. These include glycation with arginine forming hydroimidazolones (MG-H1, MG-H2 and MG-H3), Nδ-(5-hydroxy-4,6-dimethylpyrimidine-2-yl)-L-ornithine argpyrimidine (Arg-Pyr) or Nδ-(4-carboxy-4,6-dimethyl-5,6-dihydroxyt-1,4,5,6-tetrahydropyrimine-2-yl)-L-ornithine (THP) [22, 38, 40]. MGO glycation with lysine forms N^ε-(1-carboxyethyl)lysine (CEL) or the lysine dimer 1,3-di(N^ε-lysino)-4-methyl-imidazolium (MOLD) [41]. Crosslinking between arginine and cysteine leads to the formation of mercaptomethylimidazole crosslinks between arginine and cysteine (MICA) [43]. Crosslinking between arginine and lysine results in 2-ammonio-6-((2-[(4-ammonio-5-oxido-5-oxopentyl)amino]-4-methyl-4,5-dihydro-1H-imidazol-5-ylidene)amino)hexanoate (MODIC) [42]. DNA glycation can occur between MGO and deoxyguanosine resulting in products N2-carboxyethyl-2’-deoxyguanosine (CEdG) and 3-(2’-deoxyribosyl-6,7-dihydro-6,7-dihydroxy-6/7-methylimidazo-[2,3-b]purin-9(8)one (MGdG) [45]. MGO can be detoxified into D-lactate through the glyoxalase system entailing glyoxalase 1 (Glo1) and glyoxalase 2 (Glo2), with glutathione (GSH) as a co-factor [37, 38]. Additionally, minor detoxification pathways exist, such as aldehyde dehydrogenase and aldo-keto reductase [22]. Lastly, MGO can be cleared through the kidneys without any detoxification or glycation [22]