Structure, function, and post-translational regulation of the catalytic and modifier subunits of glutamate cysteine ligase.
Structure, function, and post-translational regulation of the catalytic and modifier subunits of glutamate cysteine ligase.
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DOI：
10.1016/j.mam.2008.08.009
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发表时间：
2009-02
影响因子：
10.6
通讯作者：
Kavanagh, Terrance J.
中科院分区：
文献类型：
--
作者：
Franklin, Christopher C.;Backos, Donald S.;Mohar, Isaac;White, Collin C.;Forman, Henry J.;Kavanagh, Terrance J.
谷氨酰胺（GSH）是由谷氨酸、半胱氨酸和甘氨酸组成的三肽。谷胱甘肽合成的第一步和限速步骤由谷氨酸半胱氨酸连接酶（GCL，以前称为γ-谷氨酰半胱氨酸合成酶）催化。GCL是由不同基因表达的催化亚基（GCLC）和修饰亚基（GCLM）组成的异二聚体蛋白。GCLC催化从谷氨酸到半胱氨酸的独特的γ-羧基键，并且在该反应中需要ATP和Mg++作为辅因子。GCLM增加GCLC的Vmax和Kcat，降低谷氨酸和ATP的Km，增加GSH介导的GCL反馈抑制的Ki。虽然GCLC的翻译后修饰（例如磷酸化、豆蔻酰化、半胱天冬酶介导的切割）对GCL活性具有适度的影响，但氧化应激显著影响GCL全酶的形成和活性。吡啶核苷酸也可以调节某些物种的GCL活性。GCL表达的变异性与几种疾病表型相关，转基因小鼠和大鼠模型有望用于研究GCL活性、GSH合成和人类疾病之间的关系。
Glutathione (GSH) is a tripeptide composed of glutamate, cysteine, and glycine. The first and rate-limiting step in GSH synthesis is catalyzed by glutamate cysteine ligase (GCL, previously known as γ-glutamylcysteine synthetase). GCL is a heterodimeric protein composed of catalytic (GCLC) and modifier (GCLM) subunits that are expressed from different genes. GCLC catalyzes a unique γ-carboxyl linkage from glutamate to cysteine and requires ATP and Mg++ as cofactors in this reaction. GCLM increases the Vmax and Kcat of GCLC, decreases the Km for glutamate and ATP, and increases the Ki for GSH-mediated feedback inhibition of GCL. While post-translational modifications of GCLC (e.g. phosphorylation, myristoylation, caspase-mediated cleavage) have modest effects on GCL activity, oxidative stress dramatically affects GCL holoenzyme formation and activity. Pyridine nucleotides can also modulate GCL activity in some species. Variability in GCL expression is associated with several disease phenotypes and transgenic mouse and rat models promise to be highly useful for investigating the relationships between GCL activity, GSH synthesis, and disease in humans.
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