A purine-selective nucleobase/nucleoside transporter in PK15NTD cells.
A purine-selective nucleobase/nucleoside transporter in PK15NTD cells.
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PK15NTD 细胞中的嘌呤选择性核碱基/核苷转运蛋白。
DOI：
10.1152/ajpregu.00016.2008
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Tse,Chung-Ming
中科院分区：
文献类型：
--
作者：
Hoque,KaziMirajul;Chen,Linxi;Leung,GeorgePH;Tse,Chung-Ming
核苷和核碱基转运蛋白对于嘌呤和嘧啶的抢救以及它们的类似物药物进入细胞的转运是重要的。然而，哺乳动物细胞中的核碱基易位的途径还没有得到很好的表征。我们在核苷转运蛋白缺陷的PK 15 NTD细胞中鉴定了一个Na非依赖性嘌呤选择性核碱基/核苷转运系统。该转运系统对核碱基的亲和力比核苷高1，000倍，[3 H]腺嘌呤的Km值为2.5 ± 0.7 μM，[3 H]鸟嘌呤为6.4 ± 0.5 μM，[3 H]鸟苷为1.1 ± 0.1 mM，[3 H]腺苷为4.2 ± 0.5 mM。[3 H]鸟嘌呤（0.05 μM）的摄取被其他核碱基和核碱基类似物药物（0.5-1 mM，效力顺序）抑制：6-巯基嘌呤=硫鸟嘌呤=鸟嘌呤>腺嘌呤>胸腺嘧啶=氟尿嘧啶=尿嘧啶。胞嘧啶和甲基胞嘧啶没有影响。在2′和/或5位修饰的核苷类似物药物（均为1 mM）在竞争[3 H]鸟嘌呤摄取方面比腺苷更有效：2-氯-2 ′-脱氧腺苷> 2-氯腺苷> 2′3′-双脱氧腺苷= 2′-脱氧腺苷> 5-脱氧腺苷>腺苷。2-氯-2 ′-脱氧腺苷和2-氯腺苷抑制[3 H]鸟嘌呤摄取，IC 50值分别为68 ± 5和99 ± 10 μM。核碱基/核苷转运蛋白对硝基苄基硫代肌苷{6-[（4-硝基苄基）巯基]-9-β-d-呋喃核糖基嘌呤}、双嘧达莫和地拉卓具有抗性，但可被罂粟碱、有机阳离子转运蛋白抑制剂decyphine-22（IC 50为101 μM）和酸性pH（pH = 5.5）抑制。总之，我们已经确定了哺乳动物嘌呤选择性核碱基/核苷转运蛋白具有高亲和力的嘌呤核碱基。这种转运蛋白对于将天然存在的嘌呤和嘌呤类似物药物转运到细胞中具有潜在的重要性。
Nucleoside and nucleobase transporters are important for salvage of purines and pyrimidines and for transport of their analog drugs into cells. However, the pathways for nucleobase translocation in mammalian cells are not well characterized. We identified an Na-independent purine-selective nucleobase/nucleoside transport system in the nucleoside transporter-deficient PK15NTD cells. This transport system has 1,000-fold higher affinity for nucleobases than nucleosides withKmvalues of 2.5 ± 0.7 μM for [3H]adenine, 6.4 ± 0.5 μM for [3H]guanine, 1.1 ± 0.1 mM for [3H]guanosine, and 4.2 ± 0.5 mM [3H]adenosine. The uptake of [3H]guanine (0.05 μM) was inhibited by other nucleobases and nucleobase analog drugs (at 0.5–1 mM in the order of potency): 6-mercaptopurine = thioguanine = guanine > adenine >>> thymine = fluorouracil = uracil. Cytosine and methylcytosine had no effect. Nucleoside analog drugs with modification at 2′ and/or 5 positions (all at 1 mM) were more potent than adenosine in competing the uptake of [3H]guanine: 2-chloro-2′-deoxyadenosine > 2-chloroadenosine > 2′3′-dideoxyadenosine = 2′-deoxyadenosine > 5-deoxyadenosine > adenosine. 2-Chloro-2′-deoxyadenosine and 2-chloroadenosine inhibited [3H]guanine uptake with IC50values of 68 ± 5 and 99 ± 10 μM, respectively. The nucleobase/nucleoside transporter was resistant to nitrobenzylthioinosine {6-[(4-nitrobenzyl) thiol]-9-β-d-ribofuranosylpurine}, dipyridamole, and dilazep, but was inhibited by papaverine, the organic cation transporter inhibitor decynium-22 (IC50of ∼1 μM), and by acidic pH (pH = 5.5). In conclusion, we have identified a mammalian purine-selective nucleobase/nucleoside transporter with high affinity for purine nucleobases. This transporter is potentially important for transporting naturally occurring purines and purine analog drugs into cells.
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