Key role of uridine kinase and uridine phosphorylase in the homeostatic regulation of purine and pyrimidine salvage in brain
Key role of uridine kinase and uridine phosphorylase in the homeostatic regulation of purine and pyrimidine salvage in brain
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DOI：
10.1016/j.neuint.2007.06.007
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发表时间：
2007-12-01
影响因子：
4.2
通讯作者：
Ipata, Piero Luigi
中科院分区：
文献类型：
--
作者：
Balestri, Francesco;Barsotti, Catia;Ipata, Piero Luigi
尿苷是一种主要的循环嘧啶核苷，参与许多生理过程的调节，很容易被哺乳动物细胞吸收。细胞内尿苷的合成代谢和分解代谢之间的平衡由尿苷激酶和尿苷磷酸化酶维持，尿苷激酶催化第一步UTP和CTP残余物的合成，尿苷磷酸化酶催化第一步尿苷在肝脏降解为p -丙氨酸。在本研究中，我们报告了这两种酶在脑嘌呤和嘧啶代谢的稳态调节中具有额外的作用，这依赖于从预先形成的核苷和核碱基中挽救合成核苷酸，而不是从简单的前体重新合成。实验在大鼠脑提取物和培养的人星形细胞瘤细胞中进行。脑内嘌呤和嘧啶残基合成相互调节的基本原理是：(1)嘧啶残基途径的最终产物UTP和CTP对尿嘧啶激酶的抑制作用；(2)嘧啶残基发生在核苷水平（主要是尿苷），而嘌呤残基是一个5-磷酸核糖基-1-焦磷酸（PRPP）介导的过程，发生在核碱基水平。因此，在相对较低的UTP和CTP水平下，摄取的尿苷主要被合成代谢为尿苷核苷酸。相反，在相对较高的UTP和CTP水平下，尿苷激酶通道的抑制作用使尿苷走向磷解。然后将核糖-1-磷酸转化为PRPP， PRPP用于嘌呤回收合成。(C) 2007 Elsevier Ltd.版权所有。
Uridine, the major circulating pyrimidine nucleoside, participating in the regulation of a number of physiological processes, is readily uptaken into mammalian cells. The balance between anabolism and catabolism of intracellular uridine is maintained by uridine kinase, catalyzing the first step of UTP and CTP salvage synthesis, and uridine phosphorylase, catalyzing the first step of uridine degradation to P-alanine in liver. In the present study we report that the two enzymes have an additional role in the homeostatic regulation of purine and pyrimidine metabolism in brain, which relies on the salvage synthesis of nucleotides from preformed nucleosides and nucleobases, rather than on the de novo synthesis from simple precursors. The experiments were performed in rat brain extracts and cultured human astrocytoma cells. The rationale of the reciprocal regulation of purine and pyrimidine salvage synthesis in brain stands (i) on the inhibition exerted by UTP and CTP, the final products of the pyrimidine salvage pathway, on uridine kinase and (ii) on the widely accepted idea that pyrimidine salvage occurs at the nucleoside level (mostly uridine), while purine salvage is a 5-phosphoribosyl-1-pyrophosphate (PRPP)-mediated process, occurring at the nucleobase level. Thus, at relatively low UTP and CTP level, uptaken uridine is mainly anabolized to uridine nucleotides. On the contrary, at relatively high UTP and CTP levels the inhibition of uridine kinase channels uridine towards phosphorolysis. The ribose-1-phosphate is then transformed into PRPP, which is used for purine salvage synthesis. (C) 2007 Elsevier Ltd. All rights reserved.