Defective GCLC does not ligate L-Glu to L-Cys

Gamma-glutamylcysteine ligase (GCL) catalyses the first and rate-limiting step in GSH biosynthesis. GCL is a heterodimer of a catalytic heavy chain (GCLC) and a regulatory light chain (GCLM). Defects in the catalytic GCLC can cause hemolytic anemia due to gamma-glutamylcysteine synthetase deficiency (HAGGSD; MIM:230450), a disease characterised by hemolytic anemia, glutathione deficiency, myopathy, late-onset spinocerebellar degeneration, and peripheral neuropathy. Mutations causing HAGGSD are H370L, P185L and R127C (Beutler et al. 1999, Ristoff et al. 2000, Hamilton et al. 2003).

γ-谷氨酰半胱氨酸连接酶（GCL）催化谷胱甘肽（GSH）生物合成过程中的首步且限速反应。GCL是由催化重链（GCLC）和调控轻链（GCLM）组成的异源二聚体。催化链GCLC的缺陷可导致因γ-谷氨酰半胱氨酸合酶缺乏症（HAGGSD；MIM:230450）引起的溶血性贫血，该病症以溶血性贫血、谷胱甘肽缺乏、肌病、晚发性脊髓小脑变性以及周围神经病变为特征。导致HAGGSD的突变包括H370L、P185L和R127C（Beutler 等人，1999年，Ristoff 等人，2000年，Hamilton 等人，2003年）。