Neutral amino acids, transport

Kanai Y, Hediger MA (2004) The glutamate/neutral amino acid transporter family SLC1 molecular, physiological and pharmacological aspects. Pfliigers Arch 447 469-479... 

Levodopa, a dopamine precursor, is the most effective agent for PD. Patients experience a 40% to 50% improvement in motor function. It is absorbed in the small intestine and peaks in the plasma in 30 to 120 minutes. A stomach with excess acid, food, or anticholinergic medications will delay gastric emptying time and decrease the amount of levodopa absorbed. Antacids decrease stomach acidity and improve levodopa absorption. Levodopa requires active transport by a large, neutral amino acid transporter protein from the small intestine into the plasma and from the plasma across the blood-brain barrier into the brain (Fig. 29-2). Levodopa competes with other amino acids, such as those contained in food, for this transport mechanism. Thus, in advanced disease, adjusting the timing of protein-rich meals in relationship to levodopa doses may be helpful. Levodopa also binds to iron supplements and administration of these should be spaced by at least 2 hours from the levodopa dose.1,8,16,25... 

Fig. n.i. Human duodenal expression variability of peptide and amino acid transporters (our unpublished data). Shaded box indicates 25-75% of expression range, the line within the box marks the median, and error bars indicate 10-90% of expression range. PEPT1, di-, tri-peptide transporter HPT1 (Ll-cadherin) peptide transporter SLC3A1, cystine, dibasic and neutral amino acid transporter y+LATl, cationic amino acid transporter ATBq, neutral... 

Kekuda, R., et al. Cloning of the sodium-dependent, broad-scope, neutral amino acid transporter Bo from a human placental choriocarcinoma cell line. J. Biol. Chem. 1996, 273, 18657-18661. 

Kekuda, R., et al. Molecular and functional characterization of intestinal Na(-Independent neutral amino acid transporter BO. Am. J. Physiol. 1997, 272, G1463-G1472. 

Wells, R. G. and M. A. Hediger. Cloning of a rat kidney cDNA that stimulates dibasic and neutral amino acid transport and has sequence similarity to glucosidases. Proc. Natl. Acad. Sci. U. S. A 1992, 89, 5596-5600. 

Simmons-Willis, T. A., et al. Transport of a neurotoxicant by molecular mimicry the methylmercury-l-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. Biochem. J. 2002, 367, 239-246. 

Cornford EM, Young D, Paxton JW. Melphalan penetration of the blood-brain barrier via the neutral amino acid transporter in tumor bearing brain. Cancer Res 1992 52 138-143. 

Segawa H, Fukasawa Y, Miyamoto K, Takeda E, Endou H, Kanai Y. Identification and functional characterization of a Na+-independent neutral amino acid transporter with broad substrate selectivity. J Biol Chem 1999 274 19745-19751. 

Boado RJ, Li JY, Nagaya M, Zhang C, Partridge WM. Selective expression of the large neutral amino acid transporter at the blood-brain barrier. Proc Natl Acad Sci USA 1999 96 12079-12084. 

Shafqat, S., Tamarappoo, B. K., Kilberg, M. S., Puranam, R. S., McNamara, J. O., Guadano-Ferraz, A., and Fremeau, R. T. (1993) Cloning and expression of a novel Na+-dependent neutral amino acid transporter structurally related to mammalian Na+/glutamate cotransporters. J. Biol. Chem. 268,15351-15355. 

Arriza, J. L., Kavanaugh, M. P., Fairman, W. A., Wu, Y.-N., Murdoch, G. H., North, R. A., and Amara, S. G. (1993) Cloning and expression of a human neutral amino acid transporter with structural similarity to the glutamate transporter gene family. J. Biol. Chem. 268, 15329-15332. 

Utsunomiya-Tate, N., Endo, H., and Kanai, Y. (1996) Cloning and functional characterization of a system ASC-like Na+-dependent neutral amino acid transporter. J. Biol. Chem. 271, 14883-14890. 

Broer, A., Wagner, C., Lang, F., and Broer, S. (2000) Neutral amino acid transporter ASCT2 displays substrate-induced Na+ exchange and a substrate-gated anion conductance. Biochem. J. 346, 705-710. 

The transport of amino acids at the BBB differs depending on their chemical class and the dual function of some amino acids as nutrients and neurotransmitters. Essential large neutral amino acids are shuttled into the brain by facilitated transport via the large neutral amino acid transporter (LAT) system [29] and display rapid equilibration between plasma and brain concentrations on a minute time scale. The LAT-system at the BBB shows a much lower Km for its substrates compared to the analogous L-system of peripheral tissues and its mRNA is highly expressed in brain endothelial cells (100-fold abundance compared to other tissues). Cationic amino acids are taken up into the brain by a different facilitative transporter, designated as the y system, which is present on the luminal and abluminal endothelial membrane. In contrast, active Na -dependent transporters for small neutral amino acids (A-system ASC-system) and cationic amino acids (B° system), appear to be confined to the abluminal surface and may be involved in removal of amino acids from brain extracellular fluid [30]. Carrier-mediated BBB transport includes monocarboxylic acids (pyruvate), amines (choline), nucleosides (adenosine), purine bases (adenine), panthotenate, thiamine, and thyroid hormones (T3), with a representative substrate given in parentheses [31]. 

Hartnup disorder Is a rare condition caused by impaired resorption of neutral amino acids (especially tryptophan, alanine, threonine, glutamine, and histidine) In the renal tubules and malabsorption In the Intestine, resulting from mutations that lead to defective function of a neutral amino acid transporter. 

Carrier proteins (e.g., large neutral amino acid transporter, NaVglucose-cotransport protein)... 

The other major class of transporter protein is the carrier protein. A prototypic example of a carrier protein is the large neutral amino acid transporter. An important function of the LNAA transporter is to transport molecules across the blood-brain barrier. As discussed previously, most compounds cross the BBB by passive diffusion. However, the brain requires certain compounds that are incapable of freely diffusing across the BBB phenylalanine and glucose are two major examples of such compounds. The LNAA serves to carry phenylalanine across the BBB and into the central nervous system. Carrier proteins, such as the LNAA transporter, can be exploited in drug design. For example, highly polar molecules will not diffuse across the BBB. However, if the pharmacophore of this polar molecule is covalently bonded to another molecule which is a substrate for the LNAA, then it is possible that the pharmacophore will be delivered across the BBB by hitching a ride on the transported molecule. 

Transport Via the Large Neutral Amino Acid Transporter Is Affected by Diet... 

Sanchez del Pino MM, Hawkins RA, Peterson DR. Neutral amino acid transport by the blood-brain barrier. Membrane vesicle studies. J Biol Chem 1992 267 25951-25957. 

Audus KL, Borchardt RT. Characterization of the large neutral amino acid transport system of bovine brain micro vessel endothelial cell monolayers. J Neurochem 1986 47 484-488. 

A direct K+ requirement for translocation has, however, been reported for glutamic acid transport in brain (Kanner and Schuldiner, 1987 Carlson et al., 1989). The dicarboxylic amino acids appear to be transported largely by specific transporters which do not participate in neutral amino acid transport. Recent studies, both in reconstituted systems and the expression of the cloned transporter, have confirmed the K+ requirement (see below). 

Doyle, F.A. McGivan, J.D. (1992). Reconstitution and identification of the major Na+-dependent neutral amino acid-transport protein from bovine renal brush-border membrane vesicles. Biochem. J. 281, 95-102. 

Le Cam, A. Freychet, P. (1976). Glucagon stimulates the A system for neutral amino acid transport in isolated hepatocytes of adult rat. Biochem. Biophys. Res. Commun. 72, 893-901. 

Lever, J.E. (1977). Membrane potential and neutral amino acid transport in plasma membrane vesicles from simian virus transformed mouse fibroblasts. Biochemistry 16, 4328-4334. 

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