Recent advances in the understanding of the mechanism of membrane transport of folates and antifolates.
Recent advances in the understanding of the mechanism of membrane transport of folates and antifolates.
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发表时间：
1999-04
影响因子：
4
通讯作者：
Sierra Ee;Goldman Id
中科院分区：
文献类型：
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作者：
Sierra Ee;Goldman Id
叶酸和反叶酸在大多数细胞中的转运是由还原叶酸载体介导的，这是一种阴离子交换浓缩过程，而与能量代谢直接耦合的独立出口泵(S)则相反。这些过程的平衡控制细胞内游离叶酸水平，叶酸是叶基多谷氨酸合成酶的底物，并决定许多叶酸和反叶酸对多谷氨酸衍生物的代谢率。RFCI对新一代抗叶酸有很高的亲和力，但所有这些化合物的转运和多谷氨酰化之间的关系尚未确定。对RFCI突变的分析表明，结合亲和力和/或载体迁移率发生了高度选择性的功能变化，这增加了以下可能性：(1)天然叶酸的增强运输和积累可以通过阻止嘌呤和嘧啶合成的抗叶酸抑制剂与活性衍生物的多谷氨酰化反应，或通过在目标酶位置的竞争而不显著改变抗叶酸运输，从而导致对抗叶酸抑制剂的抗药性，以及(2)与运输相关的抗药性可能不会对另一种抗叶酸抑制剂产生类似的交叉耐药性。出口泵功能受损，导致叶酸在细胞内积累增加，并抑制抗叶酸多谷氨酰化，是对新一代抗叶酸产生抵抗的另一种潜在机制。叶酸受体介导的转运是叶酸和抗叶酸进入细胞的另一种途径，但其重要性尚未很好地确定。最后，在多种哺乳动物细胞系中存在低pH转运机制。然而，它与RFCI和其他低pH上皮转运蛋白的关系以及它运输新一代抗叶酸的能力仍有待确定。
Transport of folates and antifolates in most cells is mediated by the reduced folate carrier (RFCI), an anion exchanging concentrative process, which is opposed by independent exit pump(s) that are directly coupled to energy metabolism. The balance of these processes governs the free intracellular folate level that is the substrate for folylpolyglutamate synthetase and determines the rate of metabolism of many folates and antifolates to polyglutamate derivatives. The RFCI has a high affinity for new-generation antifolates, but the relationship between transport and polyglutamylation for all these compounds has not, as yet, been defined. Analysis of mutations in RFCI indicate highly selective functional changes in binding affinity and/or carrier mobility, raising the possibilities that (1) enhanced transport and accumulation of natural folates can result in resistance to antifolate inhibitors of purine and pyrimidine synthesis by blocking their polyglutamylation to active derivatives, or by competition at the target enzyme site without substantial changes in antifolate transport, and (2) transport-related resistance to one antifolate might not produce comparable cross-resistance to another. Impaired export pump function, which results in enhanced accumulation of folates in cells and inhibition of antifolate polyglutamylation, represents another potential mechanism of resistance to new-generation antifolates. Folate receptor-mediated transport is another route of entry of folates and antifolates into cells, but its importance has not been well-defined. Finally, a low pH transport mechanism is present in a variety of mammalian cell lines. However, its relationship to RFCI and other low pH epithelial transporters and its ability to transport new-generation antifolates remain to be established.