Theoretical studies on models of lysine-arginine cross-links derived from α-oxoaldehydes: a new mechanism for glucosepane formation.

Availability and high reactivity of α-oxoaldehydes have been approved by experimental techniques not only in vivo systems but also in foodstuffs. In this article we re-examine the mechanism of glucosepane formation by using computational model chemistry. Density functional theory has been applied to propose a new mechanism for glucosepane formation through reaction of α-oxoaldehydes with methyl amine (MA) and methyl guanidine (MGU) models of lysine and arginine residues respectively. This non enzymatic process can be described in three main steps: (1) Schiff base formation from methyl amine, methyl glyoxal (MGO) (2) addition of methyl guanidine and (3) addition of glyceraldehyde. We show that this process is thermodynamically possible and presents a rate-determining step with a reasonable free energy barrier equal to 37.8 kcal mol(-1) in water solvent. Comparisons were done with the mechanism formation of GODIC (glyoxal-derived imidazolium cross-link) and MODIC (methyl glyoxal-derived imidazolium cross-link), two other important cross-links in vivo.