Phenylalanine neutral amino acid carrier system

As discussed above, certain nutrients are taken up into the brain by carrier-mediated systems. If a dmg possesses a molecular structure similar to that of a nutrient which is a substrate for carrier-mediated transport (Table 13.1), the pseudo-nutrient dmg may be transported across the BBB by the appropriate carrier-mediated system. For example, the dmg L-dopa crosses the BBB via the neutral amino acid carrier system. Other neutral amino acid dmgs that are transported through the BBB on this transport system are a-methyldopa, a-methylparatyrosine, and phenylalanine mustard. 

Drags which have structures similar to that of endogenous nutrients may be taken up by a specialized transport system (carrier-mediated transport, receptor-mediated transcytosis) existing in the brain endothelium for nutrients. For example, drags having a molecular structure similar to a large neutral amino acid may cross the BBB via the neutral amino acid carrier such drags include melphalan (phenylalanine mustard), L-dopa, a-methyldopa, and p-chlorophenylalanine. 

Like the glucose carrier, the carriers for large neutral amino acids, the so-called L-system - now designated LAT - are present at both sides of the endothelial cell membranes and transport at least 10 essential amino acids. The L-transporter at the BBB has a much higher transport capacity than those in other tissues. Its marked preference for phenylalanine analogs explains why the anticancer drugs melphalan and d,l-NAM-7 are transported by the L-system, as is the L-Dopa used to treat Parkinson s disease [42]. 

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. 

Intracellular metabolism of amino acids requires their transport across the cell membrane. Transport of L-amino acids occurs against a concentration gradient and is an active process usually coupled to Na -dependent carrier systems as for transport of glucose across the intestinal mucosa (Chapter 12). At least five transport systems for amino acids (with overlapping specificities) have been identified in kidney and intestine. They transport neutral amino acids, acidic amino acids, basic amino acids, ornithine and cystine, and glycine and proline, respectively. Within a given carrier system, amino acids may compete for transport (e.g., phenylalanine with tryptophan). Na+-independent transport carriers for neutral and lipophilic amino acids have also been described, d-Amino acids are transported by simple diffusion favored by a concentration gradient. 

In liver failure the plasma concentrations of the aromatic amino acids (AAAs) tyrosine, phenylalanine, and tryptophan increase, probably because they are predominantly broken down in the liver, whereas the plasma levels of BCAAs decrease while they are degraded in excess in muscle as a consequence of hepatic failure-induced catabolism. As AAAs and BCAAs are all neutral amino acids and share a common transporter across the blood-brain barrier (system L carrier), changes in their plasma ratio are reflected in the brain, subsequently disrupting the neurotransmitter profile of the catecholamines and indoleamines (see sections on tyrosine and tryptophan). It has been hypothesized that this disturbance contributes to the multifactorial pathogenesis of hepatic encephalopathy. In line with this hypothesis it has been suggested that normalization of the amino acid pattern by supplementing extra BCAAs counteracts hepatic encephalopathy. 

As expected, system 13 did in fact bind and transport zwitterionic a-amino acids through a model membrane barrier with good selectivity under conditions where the porphyrin-derived control system (14), lacking the carboxylate anion chelation ability inherent in 13, would not. Specifically, it was found that at neutral pH compound 13 acts as a very efficient carrier for the through model membrane (H2O-CH2CI2-H2O) transport of phenylalanine and tryptophan. Further, in direct competition experiments, L-phenylalanine was found to be transported four times faster than L-tryptophan and 1000 times faster than L-tyrosine. As implied above, little or no transport was observed when a porphyrin control (14) was used. Nor was significant transport observed when a mixture of sapphyrin and lasalocid was used. 

High concentrations of blood phenylalanine result in increased uptake of phenylalanine into the brain and concomitant dcCTease in the uptake of other large neutral amino adds (LNAA). Phenylalanine is transported into the brain by one of the LNAA carriers, the 1. -amino add transporter 1 (LAT-1) [45 8]. This transporter also selectively transports the amino adds valine, isoleucine, methionine, threonine, tryptophan, tyrosine, and histidine. The binding of the LNAA to the LAT-1 transporter is a competitive process the rate of transport is proportionate to the blood concentration of all the transported amino acids [49]. This system has the highest affinity for phenylalanine, which in case of its high concentration in the blood, significantly decreases the transport of other LNAA and more phenylalanine is transported into the brain. By influence on the activity of tyrosine and tryptophan hydroxylases, elevated brain phenylalanine concentrations also negatively impact the synthesis of catecholamines and serotonin in the brain due to the altered metabolism of tyrosine and tryptophan [4]. 

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