Jeitner Thomas M, Delikatny E James, Ahlqvist Jenny, Capper Hugh, Cooper Arthur J L
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Biochem Pharmacol. 2005 Mar 15;69(6):961-70. doi: 10.1016/j.bcp.2004.12.011.
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.
胱胺在多种神经退行性疾病模型中具有神经保护作用。胱胺的治疗益处部分归因于其对转谷氨酰胺酶活性的抑制。胱胺（β-巯基乙醇胺（MEA）二硫化物）在细胞内被还原为MEA，MEA在很大程度上决定了其二硫化物前体的体内效应。在本研究中，MEA的胺基被证明可作为转谷氨酰胺酶（TG）的底物，导致形成N（β）-（γ-L-谷氨酰基）-MEA键。这种键的形成将与其他可能导致神经退行性变的TG催化反应竞争，如多胺化、蛋白质交联、脱氨以及神经酰胺与蛋白质的共价连接。胱胺衍生的MEA能够形成N（β）-（γ-L-谷氨酰基）-MEA键这一发现，为识别体内患病大脑中存在的TG底物提供了一个独特的工具。结构-功能研究还表明，MEA的巯基对该化合物的底物行为有显著影响。这些结构-功能研究还确定了以下物理化学特性的层级关系：疏水性＞作为第VIII族原子的S＞N与第VIII族原子之间的距离，这是决定TG 2低分子量胺底物底物行为的主要因素。
