Amino acid carrier

Kerper LE, Ballatori N, Clarkson TW. 1992. Methylmercury transport across the blood-brain barrier by an amino acid carrier. Am J Physiol 262 R761-R765. 

Note that the strength of the correlations is increased by the fact that the citric acid pathway is today isolated in mitochondria derived from a distinct early life form and linked to both aspartate and glutamate, in which A and C are dominant amino-acid carriers, while glycolysis and the pentose shunt are cytoplasmic, where U and G are more dominant amino-acid carriers. 

Davis, K. E., Straff, D. J., Weinstein, E. A., Bannerman, P. G., Correale, D. M., Rothstein, J. D and Robinson, M. B. (1998) Multiple signaling pathways regulate cell surface expression, and activity of the excitatory amino acid carrier 1 subtype of Glu transporter in C6 glioma. J. Neurosci. 18,2475-2485. 

The inhibition of amino-acid transport has been regarded as the main toxic effect of mercury compounds [82], The biochemical mechanism underlying the inhibition is unclear. In unfertilized sea-urchin eggs an interaction with the amino-acid carrier was found, whereas in fertilized eggs inhibition of amino-acid transport was indirect and might result from an elevation of the Na + content of the egg caused by the inhibition of the Na+ pump [83]. The action on the diffusional process could be mediated by an effect on membrane phospholipids or on membrane proteins, or by interaction with Ca2+ which stabilizes membrane structure. Mercuric chloride in skate liver cells inhibited amino acid transport, decreased Na + /K + -ATPase (adenosinetriphosphatase) activity, impaired volume regulatory mechanisms and increased the permeability of the plasma membrane to potassium [84]. It has been suggested that... 

E. Carvalho, J. Iley, M. J. Perry, E. Rosa, Triazene Drug Metabolites Part 15. Synthesis and Plasma Hydrolysis of Anti cancer Triazenes Containing Amino Acid Carriers , Pharm. Res. 1998, 15, 931-935. 

L-Dopa. Dopamine itself cannot penetrate the blood-brain barrier however, its natural precursor, L-dihydroxy-phenylalanine (levodopa), is effective in replenishing striatal dopamine levels, because it is transported across the blood-brain barrier via an amino acid carrier and is subsequently decarboxy-lated by DOPA-decarboxylase, present in striatal tissue. Decarboxylation also takes place in peripheral organs where dopamine is not needed, likely causing undesirable effects (tachycardia, arrhythmias resulting from activation of Pi-adrenoceptors [p. 114], hypotension, and vomiting). Extracerebral production of dopamine can be prevented by inhibitors of DOPA-decarboxylase (car-bidopa, benserazide) that do not penetrate the blood-brain barrier, leaving intracerebral decarboxylation unaffected. Excessive elevation of brain dopamine levels may lead to undesirable reactions, such as involuntary movements (dyskinesias) and mental disturbances. 

Fig. 6. Examples of attachment of 5-fluorouracil to cysteine residues in poly(amino acid) carriers (according to [146])...

A conjugate of a poly(aminoacid) and a D03A chelate [177] has been reported to have a pH dependent relaxivity. Here, this originates from conformational changes of the poly( amino acid) carrier as the pH varies from 4 to 8, which affect overall and local rotational motions in the macromolecule. 

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. 

The kidney, liver, and spleen had the highest specific activity after administration of labeled melphalan to rats and mice [68,98], while in dogs and monkeys the highest levels of drug were in the bile [3,75,99]. No significant concentrations in the tumor were noted, and the inhibition of the tumor growth could not be attributed to interactions with proteins, DNA, or RNA within the tumor cell [68]. Cellular transport of melphalan by amino acid carrier systems has been reported [100—105]. 

Greig NH, Momma S, Sweeney DJ, et al. Facilitated transport of melphalan at the rat blood-brain barrier by the large neutral amino acid carrier system. Cancer Res 1987 47 1571-1576. 

Differences in affinity of the carriers for their substrates in peripheral and neural tissues may account for the differences in ease of carrier purification. Na+-linked amino acid carriers in peripheral tissues have Km values in the mM range, while theNa+-K+ glutamate and NaCl-glycineand GABA transporters in neuronal tissues have Km values less than 10 pM. This higher affinity may have favored the development of the elegant and sensitive reconstitution assays used during purification of these carriers. 

A putative Na+-coupled amino acid carrier from LLC-PK cells (A system transporter) (Kong et al., 1993) showed a surprising 76% identity and 89% similarity with the amino acid sequence of the Na+-glucose cotransporter from the same cell line (LLC-PKi cells). Transcripts for this transporter were detected in liver, skeletal muscle, and spleen, tissues that do not express high affinity Na+/glu-cose cotransporter. This putative amino acid transporter has now been identified as a low affinity glucose transporter (Mackenzie et al., 1994). 

The ionization state of the substrate can affect BBB transport of carrier-mediated substrates. For example, histidine is an imidazole amino acid that is highly charged under acidic conditions and crosses the BBB via the basic amino acid carrier. However, under neutral conditions, histidine is 90% neutral and traverses the BBB via the neutral amino acid carrier. 

Hexose carrier Neutral amino acid carrier Monocarboxylic acid (MCA) carrier Adenosine carrier D-glucose (but not L-glucose), mannose, galactose phenylalanine (and 13 other neutral amino acids) lactate, pyruvate, and the ketone bodies /Fhydroxybutyrate and acetoacetate adenosine... 

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. 

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. 

Gonzalez MI, Susarla BTS, Fournier KM, Sheldon AL, Robinson MB. 2007. Constitutive endocytosis and recycling of the neuronal glutamate transporter, excitatory amino acid carrier 1. J Neurochem 103 1917-1931. 

Like the transporters for the catecholamines and serotonin, those for their precursor amino acids are not of very high specificity. This has been exploited in various ways for pharmacotherapy. A very important example is the use of L-DOPA as a pre-drug to substitute dopamine to the brain in patients with Parkinson s disease (Figure 10.18a). Dopamine itself cannot cross the blood brain barrier. However, L-DOPA is accepted by an amino acid carrier that normally transports aromatic amino acids. It can thus enter the brain and there be decarboxylated to dopamine. 

Lash LH, Hueni SE, Putt DA, et al. Role of organic anion and amino acid carriers in transport of inorganic mercury in rat renal basolateral membrane vesicles influence of compensatory renal growth. Toxicol Sci 2005 88(2) 630-44. 

Zunino F, Savi G, Giuliani F, et al. Comparison of antitumor effects of daunorabicin covalently linked to poly-L-amino acid carriers. Eur J Cancer Clin Oncol 1984 20 421-425. 

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