Transporters for Amino Acids

The low-affinity allosteric site influences the dissociation of uptake inhibitors, such as paroxetine, and citalopram from the primary site, when it is occupied by serotonin. Escitalopram has been shown to stabilize its own binding to the primary site, an effect counteracted by R-citalopram, which is therefore by no means an inactive compound. Clinical data have demonstrated a faster onset of escitalopram action compared to SSRIs. The superiority of escitalopram may be ascribed to this unique interaction with the allosteric site [8]. 

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Interesting as it is, the study of transporters for amino acids and other nitrogenous nutrients in Saccharomyces cerevisiae is a tricky field. Many difficulties must be circumvented to avoid trivial errors. These practical problems are linked with several features of eukaryotic uptake systems, the first being the multiplicity of permeases which transport a given substrate. In relation to this, a major point is to make certain that one is not studying more than one uptake system at a time, and this can hardly be done without genetics. Once individual uptake systems have been identified and separated with the help of genetics, a second difficulty arises, which... 

The extent of NO3 absorption by soil-grown plants will depend on its rate of formation and loss in the rhizosphere (this is considered in Section 6.5). Transporters for amino acids have also been found in plant roots, and concentrations of amino acids in the soil solution in flooded soils can be appreciable. Therefore it seems likely that some N is also absorbed as amino acids, but as yet we do not have the necessary data to quantify this. 

The most efficient rectal absorption enhancers, which have been studied, include surfactants, bile acids, sodium salicylate (NaSA), medium-chain glycerides (MCG), NaCIO, enamine derivatives, EDTA, and others [45 17]. Transport from the rectal epithelium primarily involves two routes, i.e., the paracellular route and the transcellular route. The paracellular transport mechanism implies that drugs diffuse through a space between epithelial cells. On the other hand, an uptake mechanism which depends on lipophilicity involves a typical transcellular transport route, and active transport for amino acids, carrier-mediated transport for (3-lactam antibiotics and dipeptides, and endocytosis are also involved in the transcellular transport system, but these transporters are unlikely to express in rectum (Figure 8.7). Table 8.3 summarizes the typical absorption enhancers in rectal routes. 

Neighboring RPE cells are connected by tight]unctions that help to create the blood/retinal barrier separating the neuro-sensory retina from fenestrated capillaries in the choroid. The basement membrane of RPE, together with the adjacent basement membrane of the choroid, forms a structure known as Bruch s membrane. RPE cells possess a number of organic and ion transporters to help move polar molecules across the blood retinal barrier. These include transporters for amino acids, folate, ascorbic acid, myo-inositol, organic anions, glucose and lactate. 

Fig. 3. Initial conditions of the transport for amino acid derivatives and dicarboxylic acids...

Substrate specificity is determined by high affinity for the cognate neurotransmitter substrate. However, low affinity uptake does also have a part in the clearance of transmitters from the interstitial space (e.g., in uptake mediated by the extraneuronal monoamine transporter, EMT) and in the intestinal absoiption of glycine and glutamate. It is obvious that there is an evolutionary relation of neurotransmitter transporters and amino acid and cation transporters in epithelia. 

Feedback inhibition of amino acid transporters by amino acids synthesized by the cells might be responsible for the well known fact that blocking protein synthesis by cycloheximide in Saccharomyces cerevisiae inhibits the uptake of most amino acids [56]. Indeed, under these conditions, endogenous amino acids continue to accumulate. This situation, which precludes studying amino acid transport in yeast in the presence of inhibitors of protein synthesis, is very different from that observed in bacteria, where amino acid uptake is commonly measured in the presence of chloramphenicol in order to isolate the uptake process from further metabolism of accumulated substances. In yeast, when nitrogen starvation rather than cycloheximide is used to block protein synthesis, this leads to very high uptake activity. This fact supports the feedback inhibition interpretation of the observed cycloheximide effect. 

Transport of amino acids across a chloroform liquid membrane with these carriers also revealed a high specificity (Scheme 2). For efficient transport, an aromatic side chain must be present and the distance between the aryl and ammonium functions is optimal in the P-aryl systems. Neither oe-phenyl-glycine 42 nor y-phenyl-butyrine 43 are transported to significant extents 25a>. These results are shown in Table 2. The selectivity with 13 contrasts sharply for that observed with typical detergents wherein side chain hydrophobicity determines the relative transport rates. 

T. Hatanaka, M. Haramura, Y. J. Fei, S. Miyauchi, C. C. Bridges, P. S. Ganapathy, S. B. Smith, V. Ganapathy, and M. E. Ganapathy. Transport of amino acid-based prodrugs by the Na" - and Cl -coupled amino acid transporter ATB° + and expression of the transporter in tissues amenable for drug delivery. J Pharmacol Exp Ther 308 1138-1147(2004)... 

The transport of amino acids into the brain (i.e. across the blood-brain barrier) requires a specific transporter, as for transport of amino acids in other tissues. The transporter that transports tyrosine and tryptophan into the brain also transports the branched-chain amino acids (Table 8.8). Hence, the branched-chain amino acids can compete with... 

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]. 

Fluoro amino acids have been incorporated into peptides, in order to ease the transport or reduce the systemic toxicity. Thus, trifluoroalanine, a powerful inhibitor of alanine racemase, is an essential enzyme for the biosynthesis of the cell wall of bacteria. It has a low antibiotic activity because of its very poor transport. In order to facilitate this transport, the amino acid has been incorporated into a peptide. This delivery allows a reduction of the doses, and thus the toxicity of the treatment is lowered.3-FIuorophenylaIanine (3-F-Phe) is a substrate of phenylalanine hydroxylase, which transforms it into 3-F-Tyr. 3-F-Tyr has a high toxicity for animals, due to its ultimate metabolization into fluorocitrate, a powerful inhibitor of the Krebs cycle (cf. Chapter 7). 3-F-Phe has a low toxicicity toward fungus cells, but when delivered as a tripeptide 3-F-Phe becomes an efficient inhibitor of the growth of Candida albicans. This tripeptide goes into the cell by means of the active transport system of peptides, where the peptidases set free the 3-F-Phe. ... 

Of this list, hb interactions can be sensitive to steric effects. This has been established for amino acid transport parameters such as the hydrophobicities and partition coefficients. There is some evidence that charge transfer interactions are also subject to steric effects. 

All clinical forms of the disease are due to a defect in the lysosomal membrane transporter for sialic acid necessary for the export of sialic acid out of the lysosome [11]. The gene coding for this transporter, SLC17A5, contains 11 exons and encodes a 495-amino-acid transmembrane protein, sialin [20]. 

Simple lipophilic cations, like ammonium ions bearing long hydrocarbon chains, allow anion extraction into an organic phase and render liquid membranes permeable to anions by an anion exchange (antiport) process. Such carriers effect, for instance, selective transport of amino acid carboxylates [6.3] against inorganic anions like chloride. 

Your liver is also a site for amino acid synthesis such as Serine, Glycine, Glutamic acid and Glutamine. This means that the liver will hang on to some amino acids for bio-synthesis while passing others onto the general circulation for transportation to other organs and tissue. 

Table 3 First- order rates observed for the transport of amino acids fascilitated by 32-34 over a liquid membrane...

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