Characterization of the deoxyguanosine-lysine cross-link of methylglyoxal.

Petrova KV, Millsap AD, Stec DF, Rizzo CJ
Chem Res Toxicol. 2014 27 (6): 1019-29

PMID: 24801980 · PMCID: PMC4060920 · DOI:10.1021/tx500068v

Methylglyoxal is a mutagenic bis-electrophile that is produced endogenously from carbohydrate precursors. Methylglyoxal has been reported to induce DNA-protein cross-links (DPCs) in vitro and in cultured cells. Previous work suggests that these cross-links are formed between guanine and either lysine or cysteine side chains. However, the chemical nature of the methylglyoxal induced DPC have not been determined. We have examined the reaction of methylglyoxal, deoxyguanosine (dGuo), and Nα-acetyllysine (AcLys) and determined the structure of the cross-link to be the N2-ethyl-1-carboxamide with the lysine side chain amino group (1). The cross-link was identified by mass spectrometry and the structure confirmed by comparison to a synthetic sample. Further, the cross-link between methylglyoxal, dGuo, and a peptide (AcAVAGKAGAR) was also characterized. The mechanism of cross-link formation is likely to involve an Amadori rearrangement.

MeSH Terms (6)

Cross-Linking Reagents Deoxyguanosine Lysine Molecular Structure Pyruvaldehyde Stereoisomerism

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