Formation mechanism of glyoxal-DNA adduct, a DNA cross-link precursor

Abstract

[eng] DNA nucleobases suffer non-enzymatic glycation, generating nucleobase adducts that can play an important role in vivo. In this work, we have carried out a completed experimental and theoretical kinetic study of the mechanisms of formation of glyoxal-guanine adducts in a wide pH region in order to understand the molecular basis of the glycation process. On the other hand, molecular dynamics simulations have been performed to elucidate how open or cyclic glyoxal-guanine adducts might cause structural changes in an oligonucleotide model. A thermodynamic study with other glycating agents (methylglyoxal, acrolein, crotonaldehyde, 4-hydroxynonenal and 3-deoxyglucosone) has been done and we show that, at neutral pH, the cyclic adducts were more stable than the open ones; whereas at basic pH, the open adduct structures of 3-deoxyglucosone, methylglyoxal, and glyoxal were most stable than the cyclic ones. This fact is related to the propensity of these adducts to cross-link DNA. Our new insights contribute toward a better understanding of the link between glycation and DNA cross-link.