Amino acid transporters (draft)
Amino acid transporters are categorized into at least 17 distinct classes (Bröer, 2008). Neutral amino acids are considered to be mainly transported by 3 systems: A, ASC, and L (Palacín et al., 1998). Systems A and ASC mainly transport amino acids with short, polar, or linear side chains, such as L-alanine and L-serine. Large, branched, and aromatic amino acids, such as L-tyrosine, mainly enter cells via system L (Saier et al., 1988).
System A (alanine-preferring) amino acid transporters are important in regulation of cell growth. These transporters are sodium-dependent active transporters, that is, able to transport amino acids against their concentration gradients. System A transporters are upregulated in several human cancer types, and provide therefore a target for oncological imaging, using tracers such as [11C]MeAIB (Sutinen et al., 2003; Arimoto et al., 2016).
Alanine-serine-cysteine transporter 2 (ASCT2/SLC1A5) is a sodium-dependent neutral amino acid transporter. Several cancer cell types are dependent on external source of glutamine, and have increased ASCT2 and glutaminase activity. Therefore positron-labelled glutamine analogues are potentially suitable for tumour imaging. [18F]fluciclovine is predominantly transported by ASCT2 and LAT1.
L-type amino acid transporters 1 and 2 (LAT1 and LAT2), the isoforms of system L (leucine-preferring), facilitate the diffusion of large (LAT1/SLC7A5) and smaller (LAT2) neutral amino acids across membranes. The tissue uptake of commonly used PET tracers L-[methyl-11C]methionine, FDOPA, and tyrosine and tryptophan analogues is largely dependent on these transporters.
L-type amino acid transporter 1 (LAT1) is overexpressed in many cancer cells, and is associated with poor prognosis. Non-cancer type isoform LAT2 is ubiquitously expressed in normal tissues. LAT3 and LAT4 prefer phenylalanine over other neutral amino acids.
L-4-borono-2-[18F]fluoro-phenylalanine ([18F]FBPA) prefers LAT1 over LAT2, and therefore tumour imaging using [18F]FBPA does not suffer from the inflammation-induced increase in amino acid uptake, which is the case when using certain other LAT substrates, such as L-[methyl-11C]methionine (Watabe et al., 2017). [18F]fluciclovine is predominantly transported by LAT1 and ASCT2.
While most amino acids are metabolized in the liver, branched-chain amino acids (leucine, isoleucine, and valine) are metabolized mainly in skeletal muscle and white adipose tissue. The first step in the catabolism of BCAAs is catalyzed by mitochondrial branched-chain aminotransferase (BCAT2), which is not expressed in the liver.
Bröer S. Amino acid transport across mammalian intestinal and renal epithelia. Physiol Rev. 2008; 88: 249–286.
Crippa F, Alessi A, Serafini GL. PET with radiolabeled aminoacids. Q J Nucl Med Mol Imaging 2012; 56(2): 151-162.
Juhász C, Dwivedi S, Kamson DO, Michelhaugh SK, Mittal S. Comparison of amino acid positron emission tomographic radiotracers for molecular imaging of primary and metastatic brain tumors. Mol Imaging 2014; 13: 1-16. doi: 10.2310/7290.2014.00015.
Kilbourn MR. Small molecule PET tracers for transporter imaging. Semin Nucl Med. 2017; 47(5): 536-552. doi: 10.1053/j.semnuclmed.2017.05.005.
Langen K-J, Bröer S. Molecular transport mechanisms of radiolabeled amino acids for PET and SPECT. J Nucl Med. 2004; 45(9): 1435-1436.
Mann A, Semenenko I, Meir M, Eyal S. Molecular imaging of membrane transporters’ activity in cancer: a picture is worth a thousand tubes. AAPS J. 2015; 17(4): 788-801.
Palacín M, Estévez R, Bertran J, Zorzano A. Molecular biology of mammalian plasma membrane amino acid transporters. Physiol Rev. 1998; 78: 969–1054.
Saier MH Jr, Daniels GA, Boerner P, Lin J. Neutral amino acid transport systems in animal cells: potential targets of oncogene action and regulators of cellular growth. J Membr Biol. 1988; 104: 1–20.
Created at: 2017-12-03
Updated at: 2018-11-13
Written by: Vesa Oikonen