Towards the control and inhibition of glycation-the role of the guanidine reaction center with aldehydic and diketonic dicarbonyls. A mass spectrometry study.
Glycation of proteins by glucose and formation of end-stage adducts (AGEs, advanced glycation end products) has been implicated in pathological mechanisms associated with diabetic complications, macrovascular disease, chronic and renal insufficiency, Alzheimer's disease, and aging. Of the carbonyl containing compounds involved in this process, alpha-dicarbonyls have particular importance, being established as direct intermediates in the formation of well-known AGEs. The guanidino group, present in arginine residues, suffers direct modifications by sugars and its derivatives, and is considered to be an important chemical basis, targeting the control and inhibition of glycation. Seven dicarbonyl compounds, aldehydic and diketonic, were reacted with guanidine, in an attempt to establish structure/activity relationships. Electrospray mass spectrometry, together with tandem mass spectrometry, was used to identify and characterize the reaction products. The reactivity of guanidine was found to vary with the dicarbonyls used. For glyoxal, a high amount of dihydroxyimidazolidine was formed, whereas for methylglyoxal, dihydroxyimidazolidine was slowly converted into hydroimidazolone. Interestingly, aqueous guanidine was found to prevent argpyrimidine formation. The formation of several amine-dicarbonyl moieties was observed for the larger alkyl-diketonic dicarbonyls reaction systems, in particular. Molecular structures, bearing a polar chain, of an imidazole ring, and a nonpolar one, of alkyl groups, located at both sides of the imidazole rings, were attributed to these moieties. Gas-phase experiments suggested that the larger alkyl groups have a preference for being located at one of the sides of the imidazole rings. Moreover, the referred amine-dicarbonyl moieties are formed via (dihydroxyimidazolidine - 2H2O) moieties. The latter (dihydroxyimidazolidine - 2H2O) moieties are formed in high amounts in the larger alkyl-diketonic dicarbonyl reactions. Since these moieties react with dicarbonyl molecules, and react even faster with already modified amine functions, we can foresee that these species may be useful for controlling and inhibiting glycation of larger biomolecules, such as proteins.
Saraiva
Marco A
MA
Department of Chemistry and Biochemistry, Faculty of Sciences of the University of Lisbon, Campo Grande, C8, 1749-016 Lisbon, Portugal.
Borges
Carlos M
CM
Florêncio
M Helena
MH
D000447:Aldehydes / Q000737:chemistry*; D017127:Glycation End Products, Advanced / Q000737:chemistry*; D006146:Guanidines / Q000737:chemistry*; D007093:Imidazoles / Q000737:chemistry; D007202:Indicators and Reagents; D007659:Ketones / Q000737:chemistry*; D013058:Mass Spectrometry; D011765:Pyruvaldehyde / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization
D000447:Aldehydes; D017127:Glycation End Products, Advanced; D006146:Guanidines; D007093:Imidazoles; D007202:Indicators and Reagents; D007659:Ketones; D011765:Pyruvaldehyde