In vivo regulation of cysteine dioxygenase via the ubiquitin-26S proteasome system.
In vivo regulation of cysteine dioxygenase via the ubiquitin-26S proteasome system.
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DOI：
10.1007/978-0-387-33504-9_4
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发表时间：
2006
影响因子：
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通讯作者：
John E. Dominy;L. Hirschberger;R. Coloso;M. Stipanuk
中科院分区：
文献类型：
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作者：
John E. Dominy;L. Hirschberger;R. Coloso;M. Stipanuk
半胱氨酸的细胞内游离氨基酸库在哺乳动物肝脏中受到严格调控。例如，在大鼠中，即使当膳食蛋白质或含硫氨基酸摄入量从低于需求水平变化到高于需求水平时，细胞内半胱氨酸也维持在20至100 μmol/g之间（Lee et al.，2004年）。允许的半胱氨酸浓度的窄范围是两个稳态要求的结果。肝组织必须保持足够高的半胱氨酸水平，以满足蛋白质合成和其他必需分子如谷胱甘肽，辅酶A，牛磺酸和无机硫的生产的需要。然而，与此同时，半胱氨酸浓度也必须保持在细胞毒性阈值以下。有助于调节稳态细胞内半胱氨酸水平的重要酶是半胱氨酸双加氧酶（CDO，EC 1.13. 11.20）。这种Fe 2+金属酶在肝脏中以高水平表达，在肾脏、脑和肺中以较低水平表达，催化分子氧添加到半胱氨酸的巯基，产生半胱氨酸亚磺酸盐。半胱氨酸氧化转化为半胱氨酸亚磺酸盐代表了半胱氨酸从游离氨基酸库中的不可逆损失;半胱氨酸亚磺酸盐穿梭进入许多代谢途径，包括亚牛磺酸/牛磺酸合成，无机硫产生，以及使用碳骨架作为丙酮酸盐用于生物合成或氧化脱羧和细胞呼吸。体内数据表明，肝脏（CDO表达量最高的器官）使用CDO作为处置通过饮食获得的过量半胱氨酸以及提供必需代谢物硫酸盐、亚牛磺酸和牛磺酸的手段（Garcia和Stipanuk，1992）。肝脏CDO蛋白的稳态水平受膳食含硫氨基酸的精细调节。肝脏CDO活性在喂食低蛋白的大鼠中几乎检测不到（即，
The intracellular free amino acid pool of cysteine is tightly regulated in the mammalian liver. In rats, for instance, intracellular cysteine is maintained between 20 and 100 µmol/g even when dietary protein or sulfur amino acid intake is varied from subrequirement to above-requirement levels for this species (Lee et al., 2004). The narrow range of permissible cysteine concentrations is the consequence of two homeostatic requirements. Liver tissue must keep cysteine levels sufficiently high to meet the needs of protein synthesis and the production of other essential molecules like glutathione, coenzyme A, taurine, and inorganic sulfur. At the same time, however, cysteine concentrations must also be kept below the threshold of cytotoxicity. An important enzyme that contributes to the regulation of steady-state intracellular cysteine levels is cysteine dioxygenase (CDO, EC 1.13. 11.20). Expressed at high levels in the liver with lower levels in the kidney, brain, and lung, this Fe2+ metalloenzyme catalyzes the addition of molecular oxygen to the sulfhydryl group of cysteine, yielding cysteinesulfinate. The oxidative catabolism of cysteine to cysteinesulfinate represents an irreversible loss of cysteine from the free amino acid pool; cysteinesulfinate is shuttled into numerous metabolic pathways including hypotaurine/taurine synthesis, inorganic sulfur production, and use of the carbon backbone as pyruvate for gluconeogenesis or oxidative decarboxylation and cellular respiration. In vivo data suggest that the liver, the organ with the highest amount of CDO expression, uses CDO as a means of disposing excess cysteine obtained through the diet as well as to provide the essential metabolites sulfate, hypotaurine, and taurine (Garcia and Stipanuk, 1992). Steady-state levels of hepatic CDO protein are exquisitely regulated by dietary sulfur amino acids. Hepatic CDO activity is barely detectable in rats fed low-protein (ie,