Biology of the major facilitative folate transporters SLC19A1 and SLC46A1.
Biology of the major facilitative folate transporters SLC19A1 and SLC46A1.
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DOI：
10.1016/b978-0-12-800223-0.00004-9
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发表时间：
2014
影响因子：
--
通讯作者：
Matherly, Larry H.
中科院分区：
文献类型：
--
作者：
Hou, Zhanjun;Matherly, Larry H.
本章重点介绍主要的促进性膜叶酸转运蛋白，还原叶酸载体（RFC）和质子偶联叶酸转运蛋白（PCFT）的生物学。叶酸是必需的维生素，叶酸缺乏会导致各种健康障碍。RFC广泛表达，是哺乳动物细胞和组织中主要的叶酸转运蛋白。PCFT介导膳食叶酸的肠道吸收。临床相关的抗叶酸剂如甲氨蝶呤（MTX）由RFC转运，RFC转运的丧失是MTX耐药的重要机制。PCFT在人类肿瘤中大量表达，并且在与肿瘤微环境相关的pH条件下具有活性。培美曲塞（PMX）是PCFT和RFC的优良底物。正在开发与PMX相关的新型肿瘤靶向抗叶酸剂，其具有通过PCFT而不是RFC的选择性膜转运。RFC和PCFT的分子图像继续发展，涉及膜拓扑结构，N-糖基化，能量学，以及结构和功能上重要的结构域和氨基酸的鉴定。与RFC功能丧失相关的MTX耐药的分子基础，以及罕见的常染色体隐性遗传病，遗传性叶酸吸收不良（HFM），归因于突变型PCFT，已经建立。从结构同源性的细菌转运蛋白GlpT和LacY，同源性模型开发RFC和PCFT，使新的机制的见解和实验验证的假设。RFC和PCFT作为同源寡聚体存在，并且有证据表明RFC和PCFT单体蛋白的同源寡聚化对于细胞内运输和/或转运功能可能是重要的。更好地了解RFC和PCFT的结构和功能，将有助于合理开发新的癌症治疗策略以及HFM。
This chapter focuses on the biology of the major facilitative membrane folate transporters, the reduced folate carrier (RFC), and the proton-coupled folate transporter (PCFT). Folates are essential vitamins, and folate deficiency contributes to a variety of heath disorders. RFC is ubiquitously expressed and is the major folate transporter in mammalian cells and tissues. PCFT mediates intestinal absorption of dietary folates. Clinically relevant antifolates such as methotrexate (MTX) are transported by RFC, and the loss of RFC transport is an important mechanism of MTX resistance. PCFT is abundantly expressed in human tumors and is active under pH conditions associated with the tumor microenvironment. Pemetrexed (PMX) is an excellent substrate for PCFT as well as for RFC. Novel tumor-targeted antifolates related to PMX with selective membrane transport by PCFT over RFC are being developed. The molecular picture of RFC and PCFT continues to evolve relating to membrane topology, N-glycosylation, energetics, and identification of structurally and functionally important domains and amino acids. The molecular bases for MTX resistance associated with loss of RFC function, and for the rare autosomal recessive condition, hereditary folate malabsorption (HFM), attributable to mutant PCFT, have been established. From structural homologies to the bacterial transporters GlpT and LacY, homology models were developed for RFC and PCFT, enabling new mechanistic insights and experimentally testable hypotheses. RFC and PCFT exist as homo-oligomers, and evidence suggests that homo-oligomerization of RFC and PCFT monomeric proteins may be important for intracellular trafficking and/or transport function. Better understanding of the structure and function of RFC and PCFT should facilitate the rational development of new therapeutic strategies for cancer as well as for HFM.