Saraiva Marco A, Borges Carlos M, Florêncio M Helena
Department of Chemistry and Biochemistry, Faculty of Sciences of the University of Lisbon, Campo Grande, C8, 1749-016 Lisbon, Portugal.
J Mass Spectrom. 2006 Oct;41(10):1346-68. doi: 10.1002/jms.1109.
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.
葡萄糖使蛋白质糖基化并形成终末加合物（晚期糖基化终末产物，AGEs），这与糖尿病并发症、大血管疾病、慢性肾功能不全、阿尔茨海默病及衰老相关的病理机制有关。在此过程中涉及的含羰基化合物中，α-二羰基化合物尤为重要，它们被确定为形成知名AGEs的直接中间体。精氨酸残基中存在的胍基会受到糖及其衍生物的直接修饰，被认为是控制和抑制糖基化的重要化学基础。七种二羰基化合物（醛类和二酮类）与胍反应，试图建立结构/活性关系。采用电喷雾质谱联用串联质谱来鉴定和表征反应产物。发现胍的反应活性随所用二羰基化合物的不同而变化。对于乙二醛，会形成大量的二羟基咪唑烷，而对于甲基乙二醛，二羟基咪唑烷会缓慢转化为氢化咪唑酮。有趣的是，发现胍水溶液可防止精氨嘧啶的形成。特别是在较大的烷基二酮类二羰基化合物反应体系中，观察到了几种胺 - 二羰基部分的形成。这些部分的分子结构带有位于咪唑环两侧的极性链、一个咪唑环和一个非极性的烷基链。气相实验表明，较大的烷基更倾向于位于咪唑环的一侧。此外，上述胺 - 二羰基部分是通过（二羟基咪唑烷 - 2H₂O）部分形成的。后者（二羟基咪唑烷 - 2H₂O）部分在较大的烷基二酮类二羰基化合物反应中大量形成。由于这些部分与二羰基分子反应，并且与已经修饰的胺官能团反应更快，我们可以预见这些物质可能有助于控制和抑制较大生物分子（如蛋白质）的糖基化。
