Transporters large neutral amino acid

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... 

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. 

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. 

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]. 

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... 

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. 

The proteins whose abundances are altered in the plasma membrane in drug-resistant cells (Table 13.2) include those involved in increased amino acid uptake (4F2 cell-surface antigen heavy chain, large neutral amino acids transporter small subunit-1), reduced glucose uptake (stomatin, facilitated glucose transport... 

Large neutral amino acids transporter small subunit 1 Q01650 7.9 0.6... 

The gradual conversion into MMM results in the release of DMM from depots such as lipid-rich tissues and plasma proteins, and permits its movement through barriers such as the blood-brain and placenta. A cysteine complex of the monomethylated metabolite penetrates the endotheilial cells of the blood-brain barrier by mimicking methionine and using the large neutral amino acid transporter. 

Killian DM, Chikhale PJ. 2001. Predominant functional activity of the large, neutral amino acid transporter LAT1 isoform at the cerebrovasculature. Neurosci. Lett. 306 1 1... 

Methylmercury transport across the blood-brain barrier appears to be mediated by the large neutral amino acid transport system (system L) on the luminal surface of brain capillary endothelial cells (Kerper et al. 1992). Previous in vivo studies had shown that the amino acid, L-cysteine, accelerates methylmercury uptake into brain in vivo, but the mechanism was not identified. Because the methylmercury-L-cysteine complex has close struc-... 

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