Unit of Biochemistry and Molecular Biotechnology, Department DiBEST (Biologia, Ecologia, Scienze della Terra), University of Calabria, Via P. Bucci 4C, 87036 Arcavacata di Rende, Italy.
CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council, Via Orabona 4, 70126 Bari, Italy.
Molecules. 2021 Oct 29;26(21):6562. doi: 10.3390/molecules26216562.
The localization of membrane transporters at the forefront of natural barriers makes these proteins very interesting due to their involvement in the absorption and distribution of nutrients and xenobiotics, including drugs. Over the years, structure/function relationship studies have been performed employing several strategies, including chemical modification of exposed amino acid residues. These approaches are very meaningful when applied to membrane transporters, given that these proteins are characterized by both hydrophobic and hydrophilic domains with a different degree of accessibility to employed chemicals. Besides basic features, the chemical targeting approaches can disclose information useful for pharmacological applications as well. An eminent example of this picture is the histidine/large amino acid transporter SLC7A5, known as LAT1 (Large Amino Acid Transporter 1). This protein is crucial in cell life because it is responsible for mediating the absorption and distribution of essential amino acids in peculiar body districts, such as the blood brain barrier and placenta. Furthermore, LAT1 can recognize a large variety of molecules of pharmacological interest and is also considered a hot target for drugs due to its over-expression in virtually all human cancers. Therefore, it is not surprising that the chemical targeting approach, coupled with bioinformatics, site-directed mutagenesis and transport assays, proved fundamental in describing features of LAT1 such as the substrate binding site, regulatory domains and interactions with drugs that will be discussed in this review. The results on LAT1 can be considered to have general applicability to other transporters linked with human diseases.
膜转运蛋白定位于天然屏障的前沿，由于其参与营养物质和外源性物质（包括药物）的吸收和分布，因此这些蛋白质非常有趣。多年来，已经采用了几种策略（包括暴露的氨基酸残基的化学修饰）来进行结构/功能关系研究。鉴于这些蛋白质具有不同程度的疏水性和亲水性区域，并且对所使用的化学物质具有不同的可及性，因此这些方法对于膜转运蛋白非常有意义。除了基本特征外，化学靶向方法还可以揭示对药理学应用有用的信息。这种情况的一个突出例子是组氨酸/大氨基酸转运蛋白 SLC7A5，称为 LAT1（大氨基酸转运蛋白 1）。该蛋白在细胞生命中至关重要，因为它负责介导必需氨基酸在特殊身体区域（如血脑屏障和胎盘）中的吸收和分布。此外，LAT1 可以识别多种具有药理兴趣的分子，并且由于其在几乎所有人类癌症中的过度表达，也被认为是药物的热门靶标。因此，化学靶向方法与生物信息学、定点诱变和转运测定相结合，对描述 LAT1 的特征（如底物结合位点、调节域以及与药物的相互作用）至关重要，这并不奇怪。本综述将讨论这些结果。关于 LAT1 的结果可以被认为具有普遍适用性，可以应用于与人类疾病相关的其他转运蛋白。
