Phenylalanine uptake

Evers, H, Murer, and R. Kinne, Phenylalanine uptake in isolated renal brush border vesicles, Biochim. Biophys. Acta, 426 598-615 (1976). 

We are led by our results to speculate that if an amino acid residue is present in the peptide as the D-isomer, it may render that peptide unavailable for transport regardless of whether the inverted residue is an alanine, phenylalanine or any other amino acid. And each of the other L-residues in the peptide will he denied entry regardless of their identity or degree of racemiza-tlon. So phenylalanine uptake might he decreased as much as alanine uptake because both of these amino acids finds themselves in D-isomer-containing peptides at about the same frequency. 

Figure 18 (a) Polymerization of Cu-IDA complexed to L-phenylalanine. Uptake of D-phenylalanine results in either (b) unfavorable interactions with the substrate and polymer wall or (c) one less binding interaction between the substrate and Cu center. 

Pietz et al. (1999) reported in a pivotal study the positive effects of use of LNAA to block phenylalanine transport into the brain [28], Six male adults with moderate and severe PKU were given a dose of 100 mg L-PHE/kg and assessed with and without LNAAs (150 mg LNAA/kg). Diet was not changed. Mean pre-load blood phenylalanine was 1,000 pmol/L and brain phenylalanine was 250 pmol/L. In response to an oral phenylalanine challenge, without LNAA, brain concentrations of phenylalanine increased to 400 pmol/L. Concurrent LNAA supplementation completely blocked phenylalanine uptake with no noted change in brain... 

While the main function of LNAA is blocking phenylalanine uptake at the brain, a secondary effect may be the reduction of dietary phenylalanine uptake through intestinal mucosa [29, 30]. Sanjurjo and others [30] reported that oral L-threonine supplementation had a blood phenylalanine-reducing effect [30]. Despite the effect of threonine on blood phenylalanine, a mechanism of action could not be confirmed. 

Isochorismis acid is probably the precursor of L-3-carboxyphenylalanine and its derivatives shown in Fig. 147. L-3-Hydroxymethylphenylalanine and l-4-hydroxy-3-hydroxymethylphenylalanine are poisonous to animals by inhibition of L-phenylalanine uptake. They are of significance as feeding deterrents (E 5.5.3). L-3-Carboxyphenylalanine may be an intermediate in the biosynthesis of 3-acetyl-6-methoxybenzaldehyde, a compound involved in the allelopathic interactions between higher plants (E 5.3). 

Phenylalanine uptake Glycine Forebrain 40-90 days No change Silbergeld and Goldberg, 1975... 

The neurotransmitter must be present in presynaptic nerve terminals and the precursors and enzymes necessary for its synthesis must be present in the neuron. For example, ACh is stored in vesicles specifically in cholinergic nerve terminals. It is synthesized from choline and acetyl-coenzyme A (acetyl-CoA) by the enzyme, choline acetyltransferase. Choline is taken up by a high affinity transporter specific to cholinergic nerve terminals. Choline uptake appears to be the rate-limiting step in ACh synthesis, and is regulated to keep pace with demands for the neurotransmitter. Dopamine [51 -61-6] (2) is synthesized from tyrosine by tyrosine hydroxylase, which converts tyrosine to L-dopa (3,4-dihydroxy-L-phenylalanine) (3), and dopa decarboxylase, which converts L-dopa to dopamine. 

In the case of hyperphenylalaninaemia, which occurs ia phenylketonuria because of a congenital absence of phenylalanine hydroxylase, the observed phenylalanine inhibition of proteia synthesis may result from competition between T.-phenylalanine and L-methionine for methionyl-/RNA. Patients sufferiag from maple symp urine disease, an inborn lack of branched chain oxo acid decarboxylase, are mentally retarded unless the condition is treated early enough. It is possible that the high level of branched-chain amino acids inhibits uptake of L-tryptophan and L-tyrosiae iato the brain. Brain iajury of mice within ten days after thek bkth was reported as a result of hypodermic kijections of monosodium glutamate (MSG) (0.5—4 g/kg). However, the FDA concluded that MSG is a safe kigredient, because mice are bom with underdeveloped brains regardless of MSG kijections (106). 

Hu, M. and R. Borchardt. Transport of a large neutral amino acid in a human intestinal epithelial cell line (Caco-2) uptake and efflux of phenylalanine., Biochim. Biophys. Acta 1992, 3335, 233-244... 

Lin, Z., Wang, W., Kopajtic, T., Revay, R. S., and Uhl, G. R. (1999) Dopamine transporter transmembrane phenylalanine mutations can selectively influence dopamine uptake and cocaine analog recognition. Mol. Pharmacol. 56,434 147. 

There are instances in which toxicants have chemical or structural similarities to endogenous chemicals that rely on these special transport mechanisms for normal physiological uptake and can thus utilize the same system for membrane transport. Useful examples of drugs known to be transported by this mechanism include levodopa, which is used in treating Parkinson s disease, and fluorouracil, a cytotoxic drug. Levodopa is taken up by the carrier that normally transports phenylalanine, and fluorouracil is transported by the system that carries the natural pyrimidines, thymine, and uracil. Iron is absorbed by a specific carrier in the mucosal cells of the jejunum, and calcium by a vitamin D-dependent carrier system. Lead may be more quickly moved by a transport system that is normally involved in the uptake of calcium. 

Streptonigrin.—Details of a study of the biosynthesis of streptonigrin (139) that had earlier been published in preliminary form (cf. Vol. 9, p. 24 Vol. 10, p. 23) are now available in full papers.51 52 In essence, the new results are that labelled anthranilic acid was not incorporated into streptonigrin (139),51 that l-rather than D-tryptophan was a precursor, and that label from C-7a in tryptophan (94) appeared, it was deduced, at C-8 in (139).52 The exclusive labelling of C-8 by tryptophan indicates that rings A and B do not derive from this amino-acid. These rings do not derive from phenylalanine and tyrosine, and negative results have been obtained with shikimic acid due, at the least, to poor cellular uptake.51... 

In the work of Loomeijer and work on similar lines carried out in the author s laboratory no evidence was found for the presence in important amounts of the common fatty esters, phospholipids, or steroids in purified preparations of elastin in these circumstances there seems to be little reason to classify elastin with the lipoproteins. The uptake of lipophilic dyes, which has been mentioned by several authors as indicating a lipoprotein character, can as well be explained by the presence of massive nonpolar radicals in the fluorescent prosthetic group, as described by Loomeijer, or to interactions with lipophilic sections of the peptide chain due to the large concentrations of nonpolar amino acids such as valine, the leucines, and phenylalanine. 

Finally, using PNA as an affinity capture reagent recently was extended to probing RNA-protein complexes (RNPs) in cells (33). In this application, the PNA is functionalized with a peptide that allows uptake into cells and is complementary to an RNA component of an RNP. The PNA also bears two affinity tags, the first of which is a benzophenone-modifled phenylalanine residue that can photocross-link the PNA to a protein present in the RNP. The second tag is a biotin group, which allows the purification of the cross-linked PNA-protein. Subsequent analysis by mass spectrometry identifies both the protein and its cross-linking site. As is the case for PNA used to deliver a fluorophore to a specific site in an RNA, this method requires that the PNA not disrupt the structure being probed. 

Same laser for Raman and one optical tweezers 785 nm Saccharomyces cerevisia, Escherichia coli (E. coli) Shift of phenylalanine at 1,002 cm to 965 cm, indicates uptake of C-13 Feasibility of studying unculturable microorganisms is demonstrated... 

The process of amino acid accumulation is catalyzed by at least five different Na, amino acid-symporters transporting (i) asparagine and glutamine, (ii) arginine, lysine and histidine, (iii) alanine, glycine, serine and threonine, (iv) valine, leucine, isoleucine and methionine and (v) phenylalanine, tyrosine and tryptophane. One more symporter seems to be involved in the uptake of glutamate and aspartate. Cysteine is not transported and inhibits the transport of other amino acids (reviewed in [30]). 

An increase in the aromatic amino acids phenylalanine and tyrosine occurs due to the lowered hepatic uptake of enterally released amino acids and their restricted catabolism in the liver. They are also released to a greater extent from the muscles in cases of cirrhosis with catabolism. Furthermore, phenylalanine hydroxylase... 

The LAT system has been used for the transport of various compounds to the brain. Variations in the cerebellum to plasma ratio at late times in 6-[18F]fluoro-L-DOPA studies are consistent with competitive binding of large neutral amino acids (LNAAs) for the LAT at the BBB (117). In addition, it was shown that oral administration of phenylalanine inhibited the uptake of an artificial amino acid [(1 lC)-aminocyclohexanecarboxylate] in human brain (118). Melphalan, a nitrogen mustard derivative of the neutral amino acid L-phenylalanine, was transported to the brain via the LAT system at the rat BBB. In addition, it was shown that melphalan competed with phenylalanine for the LAT system (119). 

The presence or absence of phosphate ions plays an important role in the expression and accumulation of some secondary products. Zenk et al. (47) have demonstrated a 50% increase in anthraquinone accumulation in cell cultures of Morinda citrofolia when phosphate was increased to a concentration of 5g7h In suspension cultures of Catharanthus roseus, the overall accumulation of secondary metabolites like tryptamine and indole alkaloids has been shown to occur rapidly when cells were shifted to a medium devoid of phosphate (48,49). A study on the uptake of phosphate and its effect on phenylalanine ammonia lyase and the subsequent accumulation of cinnamoyl putrescine in cell suspension cultures of Nicotiana tabacum demonstrated marked sensitivity to phosphate concentration (5DX Enhanced phenylalanine ammonia lyase activity and increased production of cinnamoyl putrescine was induced by subculture onto phosphate-free medium while suppression of these effects and stimulation of growth was observed with phosphate concentrations of 0.02-0.5uM. Interestingly, phenylalanine ammonia lyase activity is stimulated by increasing phosphate concentrations in cell suspension of Catharanthus roseus (51). 

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