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首页> 外文期刊>Biochemistry >Direct Inhibition of the Hexose Transporter GLUT1 by Tyrosine Kinase Inhibitors
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Direct Inhibition of the Hexose Transporter GLUT1 by Tyrosine Kinase Inhibitors

机译：酪氨酸激酶抑制剂对己糖转运蛋白GLUT1的直接抑制

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The facilitative hexose transporter GLUTI is a multifunctional protein that transports hexoses and dehydroascorbic acid, the oxidized form of vitamin C, and interacts with several molecules structurally unrelated to the transported substrates. Here we analyzed in detail the interaction of GLUTI with a group of tyrosine kinase inhibitors that include natural products of the family of flavones and isoflavones and synthetic compounds such as the tyrphostins. These compounds inhibited, in a dose-dependent manner, the transport of hexoses and dehydroascorbic acid in human myeloid HL-60 cells, in transfected Chinese hamster ovary cells overexpressing GLUTI, and in normal human erythrocytes, and blocked the glucose- displaceable binding of cytochalasin B to GLUTI in erythrocyte ghosts. Kinetic analysis of transport data indicated that only tyrosine kinase inhibitors with specificity for A TP binding sites inhibited the transport activity of GLUTI in a competitive manner. In contrast, those inhibitors that are competitive with tyrosine but not with ATP failed to inhibit hexose uptake or did so in a noncompetitive manner. These results, together with recent evidence demonstrating that GLUTI is a nucleotide binding protein, support the concept that the inhibitory effect on transport is related to the direct interaction of the inhibitors with GLUTI. We conclude that predicted nucleotide-binding motifs present in GLUTl are important for the interaction of the tyrosine kinase inhibitors with the transporter and may participate directly in the binding transport of substrates by GLUT1.
机译：促进性己糖转运蛋白GLUTI是一种多功能蛋白，可转运己糖和脱氢抗坏血酸（维生素C的氧化形式），并与在结构上与被转运底物无关的几个分子相互作用。在这里，我们详细分析了GLUTI与一组酪氨酸激酶抑制剂的相互作用，这些抑制剂包括黄酮和异黄酮家族的天然产物以及诸如酪氨酸抑制蛋白的合成化合物。这些化合物以剂量依赖的方式抑制己糖和脱氢抗坏血酸在人骨髓HL-60细胞，过表达GLUTI的转染中国仓鼠卵巢细胞和正常人红细胞中的运输，并阻断了细胞松弛素的葡萄糖可置换结合B到GLUTI中的红细胞鬼影。转运数据的动力学分析表明，只有对A TP结合位点具有特异性的酪氨酸激酶抑制剂以竞争性方式抑制GLUTI的转运活性。相反，那些与酪氨酸竞争而不与ATP竞争的抑制剂不能抑制己糖摄取或以非竞争性方式抑制己糖摄取。这些结果，连同表明GLUTI是核苷酸结合蛋白的最新证据一起，支持了对转运的抑制作用与抑制剂与GLUTI的直接相互作用有关的概念。我们得出结论，GLUT1中存在的预测核苷酸结合基序对于酪氨酸激酶抑制剂与转运蛋白的相互作用很重要，并且可能直接参与GLUT1对底物的结合转运。

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