Activation of deoxycytidine kinase by deoxyadenosine: Implications in deoxyadenosine-mediated cytotoxicity
Activation of deoxycytidine kinase by deoxyadenosine: Implications in deoxyadenosine-mediated cytotoxicity
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DOI：
10.1016/j.abb.2005.01.009
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发表时间：
2005-04-01
影响因子：
3.9
通讯作者：
Staub, M
中科院分区：
文献类型：
--
作者：
Keszler, G;Virga, S;Staub, M
先天性腺苷脱氨酶缺乏的特征是淋巴细胞中积累过量的细胞毒性脱氧腺嘌呤核苷酸。dATP的形成需要脱氧腺苷被脱氧胞苷激酶（dCK）磷酸化，dCK是淋巴细胞中的主要核苷补救酶。先前发现了许多遗传毒性剂（包括2-氯脱氧腺苷，一种脱氨基抗性脱氧腺苷类似物）对dCK的激活。在这里，我们表明，脱氧腺苷本身也是一个有效的激活剂dCK，如果其脱氨基被阻止腺苷脱氨酶抑制剂脱氧coformycin。相反，发现脱氧胞苷可防止各种药物对dCK的刺激。活化形式的dCK对胰蛋白酶消化更具抗性，表明dCK在活化后经历底物非依赖性构象变化。升高的dCK活性伴随着降低的嘧啶核苷酸水平，而细胞毒性dATP池选择性增强。发现生长因子和MAP激酶信号传导下调dCK活性，这为减缓腺苷脱氨酶缺乏症中dATP酸化速率提供了潜在的工具。(c)2005年爱思唯尔公司All rights reserved.
The inborn deficiency of adenosine deaminase is characterised by accumulation of excess amounts of cytotoxic deoxyadenine nucleotides in lyinphocytes. Formation of dATP requires phosphorylation of deoxyadenosine by deoxycytidine kinase (dCK), the main nucleoside salvage enzyme in lymphoid cells. Activation of dCK by a number of genotoxic agents including 2-chlorodeoxyadenosine, a deamination-resistant deoxyadenosine analogue, was found previously. Here, we show that deoxyadenosine itself is also a potent activator of dCK if its deamination was prevented by the adenosine deaminase inhibitor deoxycoformycin. In contrast, deoxycytidine was found to prevent stimulation of dCK by various drugs. The activated form of dCK was more resistant to tryptic digestion, indicating that dCK Undergoes a substrate-independent conformational change Upon activation. Elevated dCK activities were accompanied by decreased pyrimidine nucleotide levels whereas cytotoxic dATP pools were selectively enhanced. dCK activity was found to be downregulated by growth factor and MAP kinase signalling, providing a potential tool to slow the rate of dATP accumlation in adenosine deaminase deficiency. (c) 2005 Elsevier Inc. All rights reserved.