Transglutaminases - Possible Drug Targets in Human Diseases
Transglutaminases - Possible Drug Targets in Human Diseases
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DOI：
10.2174/1568007043482552
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发表时间：
2004-01-01
影响因子：
3
通讯作者：
Cooper, Arthur J. L.
中科院分区：
文献类型：
--
作者：
Gentile, Vittorio;Cooper, Arthur J. L.
转谷氨酰胺酶 (TGase) 属于密切相关的蛋白质家族，可催化蛋白质/肽底物的谷氨酰胺酰残基与蛋白质/肽共底物的赖氨酰残基交联，形成 N-ε-(γ-L-谷氨酰)-L-赖氨酸 [GGEL] 交联并同时释放氨。这种交联蛋白质通常是高度不溶的。神经退行性疾病，例如阿尔茨海默病 (AD)、帕金森病 (PD)、核上性麻痹和亨廷顿病 (HD)，其部分特征是大脑 TGase 活性异常以及受影响大脑中交联蛋白的增加。最近的一项研究表明，敲除 HD 转基因小鼠中的 TGase 2 可延长寿命，这支持了 TGase 导致神经退行性疾病的假设。此外，最近的研究表明，胱胺（一种体外 TGase 抑制剂）可以延长 HD 转基因小鼠的寿命。然而，这些发现并不是 TGase 参与 HD 神经病理学的明确证据。在神经退行性疾病中，大脑处于氧化应激之下，理论上胱胺可以在体内转化为有效的抗氧化剂半胱胺。胱胺也是一种 caspase 3 抑制剂。除了神经退行性疾病之外，TGase 活性异常还与乳糜泻有关。有趣的是，一部分乳糜泻患者会出现神经系统疾病。本综述重点关注最近在 TGase 抑制剂设计中采用的策略，以及选择性 TGase 抑制剂对神经退行性疾病患者或乳糜泻患者可能的治疗益处。
Transglutaminases (TGases) belong to a family of closely related proteins that catalyze the cross linking of a glutaminyl residue of a protein/ peptide substrate to a lysyl residue of a protein/ peptide cosubstrate with the formation of an N-epsilon-(gamma-L-glutamyl)-L-lysine [GGEL] cross link and the concomitant release of ammonia. Such cross-linked proteins are often highly insoluble. Neurodegenerative diseases, such as Alzheimer disease (AD), Parkinson disease (PD), supranuclear palsy and Huntington disease (HD), are characterized in part by aberrant cerebral TGase activity and by increased cross- linked proteins in affected brain. In support of the hypothesis that TGases contribute to neurodegenerative disease, a recent study shows that knocking out TGase 2 in HD-transgenic mice results in increased lifespan. Moreover, recent studies show that cystamine, an in vitro TGase inhibitor, prolongs the lives of HD-transgenic mice. However, these findings are not definitive proof of TGase involvement in HD neuropathology. In neurodegenerative diseases, the brain is under oxidative stress and cystamine can theoretically be converted to the potent antioxidant cysteamine in vivo. Cystamine is also a caspase 3 inhibitor. In addition to neurodegenerative diseases, aberrant TGase activity is associated with celiac disease. Interestingly, a subset of celiac patients develops neurological disorders. This review focuses on the strategies that have been recently employed in the design of TGase inhibitors, and on the possible therapeutic benefits of selective TGase inhibitors to patients with neurodegenerative disorders or to patients with celiac disease.