Carnosine and related dipeptides as quenchers of reactive carbonyl species: From structural studies to therapeutic perspectives
Carnosine and related dipeptides as quenchers of reactive carbonyl species: From structural studies to therapeutic perspectives
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DOI：
10.1002/biof.5520240109
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发表时间：
2005-01-01
期刊：
影响因子：
6
通讯作者：
Carini, M
中科院分区：
文献类型：
--
作者：
Aldini, G;Facino, RM;Carini, M
肌肽(β-丙氨酰-L-组氨酸)及其相关多肽，如同肌肽(γ-氨基-丁酰组氨酸)、香豆碱(β-丙氨基-L-3-甲基组氨酸)和氨丝氨酸(β-丙氨酰-L-1-甲基组氨酸)是含有组氨酸的二肽，在神经系统和骨骼肌等兴奋性组织中尤为丰富。尽管它们的生化作用尚不清楚，但一些证据表明，这些内源化合物可以作为活性和细胞毒性羰基的猝灭剂。在本报告中，我们将回顾支持这一假说的结构证据和体外数据。我们首先阐明了肌肽作为α，β-不饱和醛如4-羟基-2，3-壬烯醛(HNE)和丙烯醛(ACR)的猝灭剂的反应机理，然后用LC-ESI-MS/MS(LC-ESI-MS/MS)检测粗生物基质中相应的HNE-Michael加合物，证明了肌肽及其相关多肽作为自发性氧化大鼠骨骼肌HNE的解毒剂的有效性。最后，我们建立并验证了一种灵敏、选择性和特异性的LC-ESI-MS/MS方法，用于测定HD和相应的HNE-Michael加合物，以监测它们在以羰基介导的退行性超负荷为特征的生理(衰老)和病理条件(糖尿病、动脉粥样硬化)中的分布。所得结果不仅有助于理解组氨酸-二肽的生化作用，还为设计新型的具有解毒活性的外源试剂提供了有力的依据。
Carnosine (beta-alanyl-L-histidine) and related peptides such as homocarnosine (gamma-amino-butyryl-histidine), balenine (beta-alanyl-L-3-methylhistidine) and anserine (beta-alanyl-L-1-methylhistidine) are histidine-containing dipeptides (HD) particularly abundant in excitable tissues such as nervous system and skeletal muscle. Although their biochemical role is still unknown, several evidences indicate that these endogenous compounds act as quenchers of reactive and cytotoxic carbonyl species. In this presentation we will review the structural evidences and ex vivo data supporting this hypothesis. We first elucidated the reaction mechanism of carnosine as quencher of alpha,beta-unsaturated aldehydes such as 4-hydroxy-trans-2,3-nonenal (HNE) and acrolein (ACR) and then demonstrated the efficacy of carnosine and related peptides as detoxifying agents of HNE in spontaneously oxidized rat skeletal muscle, by detecting the corresponding HNE-Michael adducts in the crude biological matrix by liquid chromatography/ electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). Finally, we set-up and validated a sensitive, selective and specific LC-ESI-MS/MS method for the determination of HD and of the corresponding HNE-Michael adducts to monitor their profile in physiological ( aging) and pathological conditions ( diabetes, atherosclerosis) characterized by a carbonyl-mediated degenerative overload. The results obtained, beside to give a contribution to the understanding of the biochemical role of histidine-dipeptides, provide a strong rational to the design of novel derivatives, active as exogenous agents able to detoxify carbonyl compounds.