Ristoff E, Larsson A
Department of Pediatrics, Karolinska Institute, Huddinge University Hospital, Sweden.
Chem Biol Interact. 1998 Apr 24;111-112:113-21. doi: 10.1016/s0009-2797(97)00155-5.
In the gamma-glutamyl cycle, hereditary defects have been described in four of the six enzymes namely: gamma-GC synthetase; GSH synthetase; gamma-glutamyl transpeptidase and 5-oxoprolinase. Mutants are still to be found in gamma-glutamyl cyclotransferase and in the dipeptidase. Deficiency of GSH synthatase or gamma-GC synthetases results in low levels of GSH. In gamma-GC synthetase deficiency hemolytic anemia is the most prominent symptom, with or without hepatosplenomegaly. In generalized GSH synthetase deficiency 5-oxoproline is overproduced due to lack of feedback inhibition of gamma-GC synthetase. These patients have metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and about 50% of them also have progressive neurological symptoms. Treatment includes acidosis correction, high doses of vitamin E and C and avoidance of drugs precipitating hemolytic crises in G6PD deficiency. Therapeutic trials with GSH analogues, N-acetylcysteine and GSH esters have been carried out. Glutathione synthetase deficiency restricted to erythrocytes results in hemolytic anemia but no 5-oxoprolinuria. gamma-Glutamyl transpeptidase deficiency is associated with GSH-emia and GSH-uria whereas 5-oxoprolinase deficiency is associated with 5-oxoprolinuria. In diagnostic work it must be emphasized that erythrocytes contain an incomplete gamma-glutamyl cycle; they lack both gamma-glutamyl transpeptidase and 5-oxoprolinase and these enzyme activities must therefore be analyzed in other types of cells such as leukocytes and fibroblasts. It is also important to investigate other patients with inherited defects in the gamma-glutamyl cycle to learn more about the biological role of GSH in man.
在γ-谷氨酰循环中，已发现六种酶中的四种存在遗传性缺陷，即：γ-谷氨酰半胱氨酸合成酶、谷胱甘肽合成酶、γ-谷氨酰转肽酶和5-氧脯氨酸酶。γ-谷氨酰环化转移酶和二肽酶的突变体尚未被发现。谷胱甘肽合成酶或γ-谷氨酰半胱氨酸合成酶缺乏会导致谷胱甘肽水平降低。γ-谷氨酰半胱氨酸合成酶缺乏时，溶血性贫血是最突出的症状，可伴有或不伴有肝脾肿大。在全身性谷胱甘肽合成酶缺乏时，由于缺乏对γ-谷氨酰半胱氨酸合成酶的反馈抑制，5-氧脯氨酸会过度产生。这些患者有代谢性酸中毒、5-氧脯氨酸尿症、溶血性贫血，其中约50%还伴有进行性神经症状。治疗包括纠正酸中毒、大剂量使用维生素E和C，以及避免使用可引发G6PD缺乏症患者溶血性危机的药物。已进行了谷胱甘肽类似物、N-乙酰半胱氨酸和谷胱甘肽酯的治疗试验。仅限于红细胞的谷胱甘肽合成酶缺乏会导致溶血性贫血，但无5-氧脯氨酸尿症。γ-谷氨酰转肽酶缺乏与谷胱甘肽血症和谷胱甘肽尿症有关，而5-氧脯氨酸酶缺乏与5-氧脯氨酸尿症有关。在诊断工作中必须强调，红细胞中的γ-谷氨酰循环不完整；它们缺乏γ-谷氨酰转肽酶和5-氧脯氨酸酶，因此必须在其他类型的细胞如白细胞和成纤维细胞中分析这些酶的活性。研究γ-谷氨酰循环存在遗传性缺陷的其他患者，以更多了解谷胱甘肽在人体中的生物学作用也很重要。
