Comparative DFT Study To Determine if α-Oxoaldehydes are Precursors for Pentosidine Formation

We report a comprehensive density functionaltheory (DFT) study of the mechanism of pentosidine formation.This work is a continuation of our earlier studies in which weproposed pathways for formation of glucosepane (J. Mol. Model.2011, pp 1-15, DOI 10.1007/s00894-011-1161-x), GODIC(glyoxal-derived imidazolium cross-link), and MODIC (methylglyoxal-derived imidazolium cross-link; J. Phys. Chem. 2011,115, pp 13542-13555). Here we show that formation of pentosidinevia reaction of α-oxoaldehydes with lysine and arginine inaqueous solution is possible thermodynamically and kinetically,in good agreement with the available experimental evidence. Fivepathways, A-E, were characterized, as in our previous GODICand MODIC work. In pathways A and B, a Schiff base is firstformed from lysine and methyl glyoxal (MGO), and this is followed by addition of arginine and glyoxal (GO). By contrast, inpathways C, D, and E, addition of arginine to MGO occurs first, resulting in the formation of imidazolone, which then reacts withlysine and GO to give pentosidine. Our calculations show that the reaction process is highly exergonic and that the threepathways A, C, and E are competitive. These results serve to underline the potentially important role that α-oxoaldehydes play asprecursors in pentosidine formation in the complex field of glycation.