Molecular mechanisms of drug transports via amino acid transporters

本研究的目的是揭示氨基酸转运体转运药物的机制。本研究利用非洲爪蟾卵母细胞表达系统、高表达LAT 1的T24人膀胱癌细胞和稳定表达LAT 1和LAT 2的小鼠S2细胞系研究了L系统转运蛋白LAT 1和LAT 2。研究表明，LAT 1转运芳香族氨基酸衍生物，包括L-多巴，α-甲基多巴，α-甲基酪氨酸，加巴喷丁，甲状腺激素，如三碘甲状腺原氨酸和甲状腺素，以及抗癌药物美法仑。基于实验和半经验的计算分析，有人提出，为了芳香族氨基酸是一个LAT 1底物，它必须有一个游离的羧基和氨基。此外，底物侧链和底物结合位点之间的疏水相互作用似乎对底物结合至关重要。由于这种多特异性，LAT 1已被确定为药物 ...更多信息 已经证明LAT 1在癌细胞中上调，并且其抑制导致癌细胞生长的抑制。基于LATI的药理学特性，我们设计并合成了与LATI具有高亲和力的新化合物（KYT 0193、KYT 0206和KYT 0213），这些化合物有望成为抗癌药物的候选化合物。在本研究中发现，LAT 1和LAT 2运输甲基汞作为半胱氨酸共轭。我们进一步发现，经典的L系统抑制剂BCH挽救了表达LAT 1的T24人膀胱癌细胞免于甲基汞-半胱氨酸缀合物的毒性，表明甲基汞的细胞毒性是由L系统转运蛋白介导的。我们已经鉴定了新的芳香族氨基酸转运蛋白TAT 1（T型氨基酸转运蛋白1）和两个成员的异二聚体氨基酸转运蛋白Asc-2和AGT 1提出了与未知的重链。少

The purpose of this study is to reveal the mechanisms of drug transports via amino acid transporters. In this study, system L transporters LAT1 and LAT2 were investigated using Xenopus oocyte expression system, T24 human bladder carcinoma cells expressing high-level of LAT1 and mouse S2 cell-lines stably transfecting human LAT 1 and LAT2. It was demonstrated that LAT1 transports aromatic-amino-acid derivatives including L-dopa, α-methyldopa, α- methyltyrosine, gabapentin, thyroid hormones such as triiodothyronine and thyroxine, and anti-cancer drug melphalan. Based on the experimental and semi-empirical computational analyses, it is proposed that, in order for an aromatic amino acid to be a LAT1 substrate, it must have a free carboxyl and an amino group. In addition, the hydrophobic interaction between the substrate side chain and the substrate binding site of LAT1 seems to be crucial for the substrate binding. Because of this multispecific property, LAT1 has been established as a drug … More transporter.LAT1 has been demonstrated to be upregulated in cancer cells and its inhibition results in the inhibition of cancer cell growth. Based on the pharmacological properties of LAT1, we have designed and generated new compounds (KYT0193, KYT0206 and KYT0213) with high affinity to LATI, which can be candidates for anti-cancer agents.It has been proposed that the amino acid transporters are the major routes for methylmercury mobilization. In the present study it was found that LAT1 and LAT2 transport methylmercury as a cysteine-conjugate. We have further found that a classical system L inhibitor BCH rescued T24 human bladder carcinoma cells expressing LAT1 form the toxicity of methylmercury-cysteine conjugate, indicating that the cytotoxicity of methylmercury is mediated by system L transporters.In addition, we have identified novel aromatic amino acid transporter TAT1 (T-type amino acid transporter 1) and two members of heterodimeric amino acid transporters Asc-2 and AGT 1 proposed to be associated with unknown heavy chains. Less