Mechanism for the inhibition of transglutaminase 2 by cystamine
Mechanism for the inhibition of transglutaminase 2 by cystamine
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DOI：
10.1016/j.bcp.2004.12.011
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发表时间：
2005-03-15
影响因子：
5.8
通讯作者：
Cooper, AJL
中科院分区：
文献类型：
--
作者：
Jeitner, TM;Delikatny, EJ;Cooper, AJL
胱胺在许多神经变性模型中具有神经保护作用。胱胺的治疗益处已被归因于，部分与其对转氨酶活性抑制有关。胱胺[β-巯基乙醇胺（MEA）二硫化物]在细胞内被还原为MEA，这在很大程度上是其二硫化物前体体内效应的原因。在当前的研究中，MEA的胺基被证明作为转氨酶（TG）底物，导致N-β-（γ-L-谷氨酰基）-MEA键的形成。这种键的形成将与其他TG催化的反应的产生竞争，这些反应可能导致神经变性，如多胺化、蛋白质交联、脱氨基和神经酰胺与蛋白质的共价连接。证明胱胺衍生的MEA可以形成N-β-（-γ-L-谷氨酰基）-MEA键提供了用于鉴定体内患病脑中发生的TG底物的独特工具。结构-功能研究还表明，MEA的巯基基团显着影响该化合物的底物行为。这些结构-功能研究还确定了以下层次的物理化学特征：疏水性> S作为第VIII族原子>距离分离，N和基团。VIII原子，作为主要的决定因素，有助于为低分子量胺底物TG 2的基板行为。(c)2005年爱思唯尔公司All rights reserved.
Cystamine is neuroprotective in a number of models of neurodegeneration. The therapeutic benefit of cystamine has been attributed., in part, to its inhibition of transglutaminase activity. Cystamine [beta-mercaptoethanolamine (MEA) disulfide] is reduced within cells to MEA which is largely responsible for the in vivo effects of its disulfide precursor. In the current study, the amine group of MEA was shown to act as a transglutaminase (TG) substrate resulting in the formation of N-beta-(gamma-L-glutamyl)-MEA bonds. The formation of such bonds would compete with the generation of other TG-catalyzed reactions that may contribute to neurodegeneration such as polyamination, protein cross-linking, deamination and the covalent attachment of ceramide to proteins. The demonstration that cystamine-derived MEA can form N-beta-(-gamma-L-glutamyl)-MEA bonds offers a unique tool for identifying the TG substrates that occur in diseased brains in vivo. Structure-function studies also indicated that the mercapto group of MEA significantly influences the substrate behavior of this compound. These structure-function studies also identified the following hierarchy of physico-chemical characteristics: hydrophobicity > S as the group VIII atom > distance separating, the N and group. VIII atom, as the major determinants contributing to the substrate behavior for low-molecular weight amine substrates of TG 2. (c) 2005 Elsevier Inc. All rights reserved.