New aspects of glutathione metabolism and translocation in mammals.
New aspects of glutathione metabolism and translocation in mammals.
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哺乳动物谷胱甘肽代谢和易位的新方面。
DOI：
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发表时间：
1979
期刊：
影响因子：
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通讯作者：
S. Tate
中科院分区：
文献类型：
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作者：
A. Meister;O. Griffith;A. Novogrodsky;S. Tate
哺乳动物体内相当一部分硫以谷胱甘肽的形式存在，其在各种组织中的浓度从约0.8到约8 mM不等；谷胱甘肽(主要以二硫化物的形式存在)的胞外浓度在小分子范围内。谷胱甘肽的合成和利用是由γ-谷氨酰半胱氨酸和谷胱甘肽合成酶、γ-谷氨酰转肽酶、半胱氨基甘氨酸酶、γ-谷氨酰环转移酶和5-羟脯氨酸酶催化的。γ-谷氨酰转肽酶催化转肽(与氨基酸和二肽)和与蓝硫酮及其二硫化物的水解反应。转肽酶是一种膜结缔组织，明显位于细胞外表面，存在于某些参与运输和分泌活动的解剖部位(如肾小管、空肠绒毛、脉络丛、睫状体)的上皮细胞中。伽马-谷氨酰循环在体内发生反应的证据来自对标记代谢物和选择性酶抑制剂的研究，以及与特定酶缺乏症相关的先天代谢错误的研究。体内抑制γ-谷氨酰环转移酶和5-羟基脯氨酸酶分别导致肾脏5-羟基脯氨酸水平降低和升高。给予特定的谷氨酰半胱氨酸合成酶抑制剂，如丁硫氨酸亚硫胺，会导致谷氨酰半胱氨酸合成酶的迅速下降，如丁硫氨酸亚硫胺，导致肾脏和其他组织的谷胱甘肽水平迅速下降，反映出谷胱甘肽的利用率相当高。当体内注射L或D-谷氨酰基(邻羧基)苯肼抑制γ-谷氨酰转肽酶时，可出现广泛的谷胱甘肽尿症，血浆谷胱甘肽水平升高。对小鼠给予谷胱甘肽合成和转肽抑制剂的研究表明，细胞内谷胱甘肽到膜结合的转肽酶的运输是伽马-谷氨酰循环中的一个离散步骤，血浆谷胱甘肽水平反映了(A)谷胱甘肽的合成及其在肝脏、肌肉和其他组织中的输出，以及(B)肾脏和其他组织对谷胱甘肽的利用。对几个淋巴样细胞系的研究表明，这些细胞还主动地将谷胱甘肽转移到细胞外。给出了谷胱甘肽代谢的一个概要方案，其中谷胱甘肽被转移到细胞膜上，在那里它可以作为这样的利用或被氧化成谷胱甘肽二硫化物。转肽酶的底物氨基酸的存在抑制了氧化，促进了转肽化。从含有膜结合转肽酶的细胞输出的谷胱甘肽可能通过细胞转运γ-谷氨酰氨基酸和游离氨基酸来恢复.
An appreciable fraction of the sulphur present in the mammal occurs in the form of glutathione, whose concentration in various tissues ranges from about 0.8 to about 8 mM; the extracellular concentration of glutatione (largely present as the disulphide) is in the micromolecular range. The synthesis of glutathione and its utilization take place by the reactions of the gamma-glutamyl cycle, which include those catalysed by gamma-glutamylcysteine and glutathione synthetases, gamma-glutamyl transpeptidase, cysteinylglycinase, gamma-glutamyl cyclotransferease, and 5-oxoprolinase. gamma-Glutamyl transpeptidase catalyses transpeptidation (with amino acids and dipeptides) and hydrolysis reactions with both blutathione and its disulphide. The transpeptidase is membrane-boudn, apparently to the outer surface of the cell, and is found in certain epithelial cells in anatomical sites that are involved in transport and secretory activities (e.g., renal tubule, jejunal villi, choroid plexus, ciliary body). Evidence that the reactions of the gamma-glutamyl cycle take place in vivo has come from studies with labelled metabolites and selective enzyme inhibitors, and on inborn errors of metabolism associated with specific enzyme deficiencies. Inhibition in vivo of gamma-glutamyl cyclotransferase and 5-oxoprolinase leads, respectively, to decreased and increased renal levels of 5-oxoproline. Administration of a specific inhibitor of gamma-glutamylcysteine synthetase, such as buthionine sulphoximine, leads to a rapid decline in the glutamylcysteine synthetase, such as buthionine sulphoximine, leads to a rapid decline in the glutathione level of the kidney and other tissues, reflecting the appreciable rate of glutathione utilization. When gamma-glutamyl transpeptidase is inhibited in vivo by injection of L- or D-gamma-glutamyl-(o-carboxy)phenylhydrazide, there is extensive glutathionuria and the blood plasma level of glutathione increases. Studies in which inhibitors of glutathione synthesis and transpeptidation were given to mice showed that transport of intracellular glutathione to membrane-bound transpeptidase is a discrete step in the gamma-glutamyl cycle, and that the level of plasma glutatione reflects (a) synthesis of glutathione and its export by liver, muscle, and other tissues and (b) utilization of glutatione by kidney and other tissues. Studies on several lymphoid cell lines show that these cells also actively translocate glutathione out of the cell. A summary scheme is given for the metabolism of glutathione in which glutathione is translocated to the cell membrane where it may be utilized as such or oxidized to glutathione disulphide. Oxidation is inhibited, and transpeptidation is promoted by the presence of amino acids that are substrates of the transpeptidase. Glutathione exported from cells that have membrane-bound transpeptidase may be recovered by the cell transport of gamma-glutamyl amino acids and free amino acids...