Stipanuk Martha H, Dominy John E, Lee Jeong-In, Coloso Relicardo M
Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
J Nutr. 2006 Jun;136(6 Suppl):1652S-1659S. doi: 10.1093/jn/136.6.1652S.
The mammalian liver tightly regulates its free cysteine pool, and intracellular cysteine in rat liver is maintained between 20 and 100 nmol/g even when sulfur amino acid intakes are deficient or excessive. By keeping cysteine levels within a narrow range and by regulating the synthesis of glutathione, which serves as a reservoir of cysteine, the liver addresses both the need to have adequate cysteine to support normal metabolism and the need to keep cysteine levels below the threshold of toxicity. Cysteine catabolism is tightly regulated via regulation of cysteine dioxygenase (CDO) levels in the liver, with the turnover of CDO protein being dramatically decreased when intracellular cysteine levels increase. This occurs in response to changes in the intracellular cysteine concentration via changes in the rate of CDO ubiquitination and degradation. Glutathione synthesis also increases when intracellular cysteine levels increase as a result of increased saturation of glutamate-cysteine ligase (GCL) with cysteine, and this contributes to removal of excess cysteine. When cysteine levels drop, GCL activity increases, and the increased capacity for glutathione synthesis facilitates conservation of cysteine in the form of glutathione (although the absolute rate of glutathione synthesis still decreases because of the lack of substrate). This increase in GCL activity is dependent on up-regulation of expression of both the catalytic and modifier subunits of GCL, resulting in an increase in total catalytic subunit plus an increase in the catalytic efficiency of the enzyme. An important role of cysteine utilization for coenzyme A synthesis in maintaining cellular cysteine levels in some tissues, and a possible connection between the necessity of controlling cellular cysteine levels to regulate the rate of hydrogen sulfide production, have been suggested by recent literature and are areas that deserve further study.
哺乳动物的肝脏严格调控其游离半胱氨酸池，即使硫氨基酸摄入量不足或过量，大鼠肝脏中的细胞内半胱氨酸仍维持在20至100 nmol/g之间。通过将半胱氨酸水平保持在狭窄范围内，并调节作为半胱氨酸储存库的谷胱甘肽的合成，肝脏既能满足有足够半胱氨酸以支持正常代谢的需求，又能将半胱氨酸水平维持在毒性阈值以下。半胱氨酸分解代谢通过肝脏中半胱氨酸双加氧酶（CDO）水平的调节而受到严格控制，当细胞内半胱氨酸水平升高时，CDO蛋白的周转会显著降低。这是通过CDO泛素化和降解速率的变化来响应细胞内半胱氨酸浓度的变化而发生的。当细胞内半胱氨酸水平因半胱氨酸对谷氨酸 - 半胱氨酸连接酶（GCL）的饱和增加而升高时，谷胱甘肽合成也会增加，这有助于去除多余的半胱氨酸。当半胱氨酸水平下降时，GCL活性增加，谷胱甘肽合成能力的增强有助于以谷胱甘肽的形式保存半胱氨酸（尽管由于缺乏底物，谷胱甘肽合成的绝对速率仍会下降）。GCL活性的这种增加依赖于GCL催化亚基和调节亚基表达的上调，导致总催化亚基增加以及酶的催化效率提高。近期文献表明，半胱氨酸用于辅酶A合成在维持某些组织中的细胞内半胱氨酸水平方面具有重要作用，并且控制细胞内半胱氨酸水平以调节硫化氢产生速率的必要性之间可能存在联系，这些都是值得进一步研究的领域。
