Formation of highly reactive γ-ketoaldehudes (Neuroketals) as products of the neuroprostane pathway
Formation of highly reactive γ-ketoaldehudes (Neuroketals) as products of the neuroprostane pathway
复制标题
DOI：
10.1074/jbc.m103768200
复制
发表时间：
2001-08-17
影响因子：
4.8
通讯作者：
Roberts, LJ
中科院分区：
文献类型：
--
作者：
Bernoud-Hubac, N;Davies, SS;Roberts, LJ
神经前列腺素是由自由基诱导的二十二碳六烯酸过氧化产生的前列腺素类化合物，二十二碳六烯酸在大脑中高度丰富。我们以前将高活性的伽马酮醛(异酮)的形成描述为自由基诱导花生四烯酸过氧化的异前列腺素途径的产物。因此，我们探索了异酮类化合物(神经酮)是否也通过神经前列腺素途径形成。利用质谱分析发现，在体外，在二十二碳六烯酸氧化过程中有大量的神经酮生成，而在二十二碳六烯酸和花生四烯酸的共同氧化过程中，神经酮的生成比异酮类化合物更丰富。神经酮类化合物能迅速与赖氨酸加成，形成内酰胺和席夫碱加合物。神经酮醛赖氨酰内酰胺蛋白加合物在未氧化的大鼠脑突触体内被检测到，蛋白水平为0.09 ng(Mg)，在体外氧化后增加了19倍。在正常人脑组织中也检测到9.9+/-3.7 ng/g脑组织中的神经酮醛赖氨酰内酰胺蛋白加合物。这些研究发现了一类新的高活性分子，它们可能参与神经退行性疾病中蛋白质加合物和蛋白质-蛋白质交联链的形成，并有助于大脑中其他氧化病理的损害效应。
Neuroprostanes are prostaglandin-like compounds produced by free radical-induced peroxidation of docosahexaenoic acid, which is highly enriched in the brain. We previously described the formation of highly reactive gamma -ketoaldehydes (isoketals) as products of the isoprostane pathway of free radical-induced peroxidation of arachidonic acid. We therefore explored whether isoketal-like compounds (neuroketals) are also formed via the neuroprostane pathway. Utilizing mass spectrometric analyses, neuroketals were found to be formed in abundance in vitro during oxidation of docosahexaenoic acid and were formed in greater abundance than isoketals during co-oxidation of docosahexaenoic and arachidonic acid. Neuroketals were shown to rapidly adduct to lysine, forming lactam and Schiff base adducts. Neuroketal lysyl-lactam protein adducts were detected in nonoxidized rat brain synaptosomes at a level of 0.09 ng(mg of protein, which increased 19-fold following oxidation in vitro. Neuroketal lysyl-lactam protein adducts were also detected in vivo in normal human brain at a level of 9.9 +/- 3.7 ng/g of brain tissue. These studies identify a new class of highly reactive molecules that may participate in the formation of protein adducts and protein-protein cross-links in neurodegenerative diseases and contribute to the injurious effects of other oxidative pathologies in the brain.