https://pubs.acs.org/doi/10.1021/acs.chemrestox.2c00160
Glycolysis is one way.
But some say that ketone bodies are antoher
They can crosslink DNA and proteins to each other
It is estimated that 0.1–0.4% of the glycolytic flux results in MG production (Kalapos, 2008a) and that nonenzymatic MG formation rate, from GAP and DHAP, is 0.1 mM per day in rat tissues (Richard, 1991). Cerebrospinal fluid levels of MG have been estimated to be between 10 and 20 μM (Kuhla et al., 2005), and cellular levels of free MG are typically in the low μM range (Rabbani and Thornalley, 2010). Importantly, as MG is highly reactive its half life is short in a biological environment and therefore, at the time and site of production local concentrations may be significantly higher (Kalapos, 2008b). As an example of the potency at which MG reacts with biological samples, addition of 1 μM [14C]MG to human plasma ex vivo produced complete and irreversible binding of MG to plasma protein within 24 h at 37°C (Thornalley, 2005). Consistently, up to 90–99% of cellular MG is bound to macromolecules, and assessment of total (free + bound) MG, suggested that cellular concentrations up to 300 μM can be reached (Thornalley, 1996; Chaplen et al., 1998).
High levels of MG occur when the concentrations of their precursors are elevated, such as in hyperglycemia, impaired glucose utilization and triosephosphate isomerase deficiency (Ahmed et al., 2003a).
As previously mentioned, MG is one of the most potent glycating agents present in cells making its accumulation highly deleterious. For instance, MG readily reacts with lipids, nucleic acids and with lysine and arginine residues of proteins to form AGEs such as argpyrimidine, hydroimidazolone MG-H1, MG-derived lysine dimer and Nε-(1-carboxyethyl)lysine (Thornalley, 2005, 2007; Rabbani and Thornalley, 2010). Besides the direct changes in protein function by MG modifications, AGE-modified proteins also exert cellular effects via their interaction with specific AGE receptors [RAGE (receptor for AGE)] (Grillo and Colombatto, 2008; Daroux et al., 2010), which triggers an inflammatory response at the cellular level, also accounting for AGE toxicity. AGEs play an important role in various pathophysiological mechanisms, including those associated with diabetic complications, aging, and neurodegenerative disorders (Wautier and Guillausseau, 2001; Ramasamy et al., 2005; Goldin et al., 2006; Munch et al., 2012).
In order to avoid the toxic effects of MG, cells possess different detoxifying mechanisms such as the glyoxalase, aldose reductase, aldehyde dehydrogenase and carbonyl reductase pathways (Thornalley, 1993; Kalapos, 1999; Vander Jagt and Hunsaker, 2003). Undoubtedly, the glyoxalase system, an ubiquitous enzymatic pathway, is the main detoxifying system for MG and other reactive dicarbonyl compounds in eukaryotic cells, thereby playing a major role the cellular defense against glycation and oxidative stress (Thornalley, 1993; Kalapos, 2008b). It detoxifies MG through two sequential enzymatic reactions catalyzed by glyoxalase-1 (Glo-1) and glyoxalase-2 (Glo-2), using glutathione as a co-factor. Glo-1 converts the hemithioacetal formed by the non-enzymatic reaction of reduced glutathione (GSH) with MG, to S-D-lactoylglutathione. This compound is then metabolized to D-Lactate (the poorly metabolizable enantiomer of L-lactate) by Glo-2, which recycles glutathione in the process (Figure 2) (Thornalley, 1993). Since S-D-lactoylglutathione is a non-toxic compound, metabolism of the dicarbonyl compound by Glo-1 represents a crucial step for MG detoxification, implying that Glo-1 activity indirectly determines MG toxicity and the rate of AGEs formation. One should also consider that GSH recycling occurs as S-D-lactoylglutathione is metabolized to D-Lactate. This implies that large increases of MG levels or low Glo-2 activity may result in S-D-lactoylglutathione accumulation, keeping GSH trapped, hence potentially leading to decreased GSH availability for other cellular processes such as defense against oxidative stress (Dringen, 2000).