Glutathione in disease
Glutathione in disease
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DOI：
10.1042/bst0240881
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发表时间：
1996-08-01
影响因子：
3.9
通讯作者：
Ganea, E
中科院分区：
文献类型：
--
作者：
Harding, JJ;Blakytny, R;Ganea, E
谷胱甘肽是细胞内含量最丰富的非蛋白硫醇，参与了许多细胞功能，包括解毒、合成、细胞周期调节、基因表达调节、蛋白质和其他细胞成分的保护以及作为抗氧化剂[L-41]。它能在非酶作用下清除自由基和亲电体，还能通过谷胱甘肽S转移酶反应解毒外源物质。它通过谷胱甘肽过氧化物酶减少过氧化脂质和过氧化氢。氧化将其转化为二硫化物形式(GSSG)。作为一种三肽，γ-谷氨酰半胱氨酸甘氨酸是由其组成的氨基酸分两步合成的，需要三磷酸腺苷。第一步是由γ-谷氨酰半胱氨酸合成酶(y-GCS)催化的，是速率决定的。该酶受最终产物谷胱甘肽的抑制，通过反馈控制。因此，当组织GSH水平下降时，PGCs的抑制作用被释放，促进GSH的进一步合成。通常，谷胱甘肽的合成受到血浆中浓度很低的游离半胱氨酸供应的限制。如果GSH是一种单一的抗氧化剂，那么在转化为氧化形式(GSSG)后，它将通过谷胱甘肽还原酶(GR)反应进行循环(图1)。这个反应需要NADPH，主要在戊糖磷酸途径的初始步骤中产生。如果这个系统超载，GSSG积累，它会与蛋白质形成二硫化物(PSSG)，它可以被从细胞中排出。GSSG水平升高也会使硫醇酶失活。氧化应激增加GSSG，最初可能会耗尽GSH，但一些适应性反应，包括半胱氨酸、谷氨酸和甘氨酸的摄取增加，以及GR和谷胱甘肽过氧化物酶的诱导，最终可能导致GSH浓度升高[L]。
GSH is the most abundant intracellular non-protein thiol and has been implicated in many cellular functions including detoxification, synthesis, cell-cycle regulation, regulation of gene expression, protection of proteins and other cellular components, and as an antioxidant [l-41. It can scavenge free radicals and electrophiles nonenzymically, as well as detoxify xenobiotics via the glutathione S-transferase reaction. It reduces lipid peroxides and hydrogen peroxide via glutathione peroxidase. Oxidation converts it to the disulphide form (GSSG). As a tripeptide, y-glutamylcysteinylglycine, it is synthesized from its constituent amino acids in two steps requiring ATP. The first step is catalysed by y-glutamylcysteine synthetase (y-GCS) and is rate-determining. This enzyme is inhibited by the final product GSH exerting feedback control. Thus when tissue GSH levels fall, the inhibition of pGCS is released promoting further synthesis of GSH. Often GSH synthesis is limited by the supply of free cysteine, present at very low concentrations in plasma. It would be wasteful if GSH were a singleshot antioxidant so after conversion to the oxidized form (GSSG), it is recycled via the glutathione reductase (GR) reaction (Figure 1). This reaction requires NADPH mostly produced in the initial steps of the pentose phosphate pathway. If this system is overloaded and GSSG accumulates it will form disulphides with proteins (PSSG), and it can be expelled from the cell. Raised GSSG levels will also inactivate thiol enzymes. Oxidative stress increases GSSG and may initially deplete GSH, but a number of adaptive responses, including increased uptake of cysteine, glutamate and glycine together with induction of GR and glutathione peroxidase, may eventually lead to elevated concentrations of GSH [l].