SLC7A5, known as LAT1, belongs to the APC superfamily and forms a heterodimeric amino acid transporter interacting with the glycoprotein CD98 (SLC3A2) through a conserved disulfide. The complex is responsible for uptake of essential amino acids in crucial body districts such as placenta and blood brain barrier. LAT1/CD98 heterodimer has been studied over the years to unravel the transport mechanism and the role of each subunit. Studies conducted in intact cells demonstrated that LAT1/CD98 mediates a Na⁺ and pH independent antiport of amino acids. Some novel insights into the function of LAT1 derived from studies conducted in proteoliposomes reconstituted with the recombinant human LAT1. Using this experimental tool, it has been demonstrated that the preferred substrate is histidine and that CD98 is not required for transport being, plausibly, involved in routing LAT1 to the plasma membrane. Since a 3D structure of LAT1 is not available, homology models have been built on the basis of the AdiC transporter from E.coli. Crucial residues for substrate recognition and gating have been identified using a combined approach of bioinformatics and site-directed mutagenesis coupled to functional assays. Over the years, the interest around LAT1 increased because this transporter is involved in important human diseases such as neurological disorders and cancer. Therefore, LAT1 became an important pharmacological target together with other nutrient membrane transporters. Moving from knowledge on structure/function relationships, two cysteine residues, lying on the substrate binding site, have been exploited for designing thiol reacting covalent inhibitors. Some lead compounds have been characterized whose efficacy has been tested in a cancer cell line.

SLC1A5, known as ASCT2, is a neutral amino acid transporter belonging to the SLC1 family and localized in the plasma membrane of several body districts. ASCT2 is an acronym standing for Alanine, Serine, Cysteine Transporter 2 even if the preferred substrate is the conditionally essential amino acid glutamine, with cysteine being a modulator and not a substrate. The studies around amino acid transport in cells and tissues began in the ‘60s by using radiolabeled compounds and competition assays. After identification of murine and human genes, the function of the coded protein has been studied in cell system and in proteoliposomes revealing that this transporter is a Na⁺ dependent antiporter of neutral amino acids, some of which are only inwardly transported and others are bi-directionally exchanged. The functional asymmetry merged with the kinetic asymmetry in line with the physiological role of amino acid pool harmonization. An intriguing function has been described for ASCT2 that is exploited as a receptor by a group of retroviruses to infect human cells. Interactions with scaffold proteins and post-translational modifications regulate ASCT2 stability, trafficking and transport activity. Two asparagine residues, namely N163 and N212, are the sites of glycosylation that is responsible for the definitive localization into the plasma membrane. ASCT2 expression increases in highly proliferative cells such as inflammatory and stem cells to fulfill the augmented glutamine demand. Interestingly, for the same reason, the expression of ASCT2 is greatly enhanced in many human cancers. This finding has generated interest in its candidacy as a pharmacological target for new anticancer drugs. The recently solved 3D structure of ASCT2 will aid in the rational design of such therapeutic compounds.

Renal proximal tubular cells are high energy-demanding cells mainly relying on fatty acid oxidation. In stress conditions, such as transient hypoxia, fatty acid oxidation (FAO) decreases and carbohydrate catabolism fails to compensate for the energy demand. In this scenario, the surviving tubular cells exhibit the peculiar phenotype associated with fibrosis that is the histological manifestation of a process culminating in chronic and end-stage kidney disease. Genome-wide transcriptome analysis revealed that, together with inflammation, FAO is the top dysregulated pathway in kidney diseases with a decreased expression of key FAO enzymes and regulators. Another evidence that links the derangement of FAO to fibrosis is the progressive decrease of the expression of peroxisome proliferator-activated receptor α (PPARα) in aged people, that triggers the age-associated renal fibrosis. To allow FAO completion, a coordinate network of enzymes and transport proteins is required. Indeed, the mitochondrial inner membrane is impermeable to fatty acyl-CoAs and a specialized system, well known as carnitine shuttle, is needed for translocating fatty acids moieties, conjugated with carnitine, into mitochondrial matrix for the β-oxidation. The first component of this system is the carnitine palmitoyltransferase 1 (CPT1) responsible for transfer acyl moieties to carnitine. Several studies indicated that the stimulation of CPT1 activity and expression has a protective effect against renal fibrosis. Therefore, the network of enzymes and transporters linked to FAO may represent potential pharmacological targets deserving further attention in the development of new drugs to attenuate renal dysfunction.

OCTN is a small subfamily of membrane transport proteins that belongs to the larger SLC22 family. Two of the three members of the subfamily, namely, OCTN2 and O...