L-amino acid transporter

There are two distinct pools of HA in the brain (1) the neuronal pool and (2) the non-neuronal pool, mainly contributed by the mast cells. The turnover of HA in mast cells is slower than in neurons it is believed that the HA contribution from the mast cells is limited and that almost all brain histaminergic actions are the result of HA released by neurons (Haas Panula, 2003). The blood-brain barrier is impermeable to HA. HA in the brain is formed from L-histidine, an essential amino acid. HA synthesis occurs in two steps (1) neuronal uptake of L-histidine by L-amino acid transporters and (2) subsequent decarboxylation of l-histidine by a specific enzyme, L-histidine decarboxylase (E.C. 4.1.1.22). It appears that the availability of L-histidine is the rate-limiting step for the synthesis of HA. The enzyme HDC is selective for L-histidine and its activity displays circadian fluctuations (Orr Quay, 1975). HA synthesis can be reduced by inhibition of the enzyme HDC. a-Fluoromethylhistidine (a-FMH) is an irreversible and a highly selective inhibitor of HDC a single systemic injection of a-FMH (10-50 mg/kg) can produce up to 90% inhibition of HDC activity within 60-120 min (Monti, 1993). Once synthesized, HA is taken up into vesicles by the vesicular monoamine transporter and is stored until released. 

Figure 6.1 Histamine synthesis and metabolism in neurons. L-histidine is transported into neurons by the L-amino acid transporter. Once inside the neuron, L-histidine is converted into histamine by the specific enzyme histidine decarboxylase. Subsequently, histamine is taken up into vesicles by the vesicular monoamine transporter and stored there until released. In the absence of a high-affinity uptake mechanism in the brain, released histamine is rapidly degraded by histamine methyltransferase, which is located postsynaptically and in glia, to telemethylhistamine, a metabolite that does not show any histamine-like activity.

Kim, D., et al. Characterization of the system L amino acid transporter in T24 human bladder carcinoma cells. Biochim. Biophys. Acta 2002, 3565, 112. 

Dopamine does not cross the blood-brain barrier and if given into the peripheral circulation has no therapeutic effect in parkinsonism. However, (-)-3-(3,4-dihydroxyphenyl)-L-alanine (levodopa), the immediate metabolic precursor of dopamine, does enter the brain (via an L-amino acid transporter, LAT), where it is decarboxylated to dopamine (see Figure 6-5). Several noncatecholamine dopamine receptor agonists have also been developed and may lead to clinical benefit, as discussed in the text that follows. 

Other examples of polymorphic drug transporter proteins include the dipeptide transporter, organic anion and cation transporters, and L-amino acid transporter. Their effects on drug distribution are the focus of ongoing research. 

Delta, A., Cruickshank, G.S., 2009. L-amino acid transporter-1 and boronophenylalanine-based boron neutron capture therapy of human hrain tumors. Cancer Res. 69, 2126. 

Figure 18.4 Kinetics of F-DOPA. F-DOPA is incorporated into tissue via the L-amino acid transporter. In neuroendocrine tumors it is subsequently decarboxylated by DOPA-decarboxylase to F-dopamine. The inserted image shows increased dopamine retention in liver metastases of a patient with carcinoid (arrow).

Babu E, Kanai Y, Chairoungdua A, Kim do K, Iribe Y, Tangtrongsup S, Jutabha P, Li Y, Ahmed N, Sakamoto S, Anzai N, Nagamori S, Endou H. Identification of a novel system L amino acid transporter structurally distinct from heterodimeric amino acid transporters. J Biol Chem 2003 278 43838-43845. 

Together with dopamine, adrenaline and noradrenaline belong to the endogenous catecholamines that are synthesized from the precursor amino acid tyrosine (Fig. 1). In the first biosynthetic step, tyrosine hydroxylase generates l-DOPA which is further converted to dopamine by the aromatic L-amino acid decarboxylase ( Dopa decarboxylase). Dopamine is transported from the cytosol into synaptic vesicles by a vesicular monoamine transporter. In sympathetic nerves, vesicular dopamine (3-hydroxylase generates the neurotransmitter noradrenaline. In chromaffin cells of the adrenal medulla, approximately 80% of the noradrenaline is further converted into adrenaline by the enzyme phenylethanolamine-A-methyltransferase. 

W. N. Fischer. B. Andre, D. Rentsch, S. Krolkiewicz, M. Tegeder, K. Breitkreuz, and W. B. Frommer, Amino acid transport in plants. Trends Plant Sci. 3 188 (1998), H. Y. Steiner, W. Song, L. Zhang, F. Naider, J. M. Becker, and G. Stacey, An Arahidopsis peptide transporter is a member of a novel family of membrane transport proteins. Plant Cell 6 189 (1994). 

D Burston, DM Matthews. (1972). Intestinal transport of dipeptides containing acidic and basic L-amino acids and a neutral D-amino acid. Clin Sci Mol Med 42 4P. 

The question also arises as to where the chiral molecules came from. Were the L-amino acids or the D-sugars selected on the primeval Earth, or are exuaterresuial sources responsible for the homochirality This second possibility is dealt with by hypotheses on the effect of circularly polarised light, of extraterrestrial origin, on chiral molecules in the molecular clouds from which the solar system was formed. One such hypothesis was proposed by Rubenstein et al. (1983) and developed further by others, particularly A. W. Bonner (Bonner and Rubenstein, 1987) both scientists worked at Stanford University. The authors believe that the actual radiation source was synchrotron radiation from supernovae. The excess of one enantiomeric form generated by this irradiation process would have needed to be transported to Earth by comets and meteorites, probably during the bombardment phase around 4.2-3.8 billion years ago. 

Sawada, K., et al. Recognition of L-amino acid ester compounds by rat peptide transporters PEPT1 and PEPT2. J. Pharmacol. Exp. Ther. 1999, 291, 705-709. 

Uchino, H., et al. Transport of amino add-related compounds mediated by L-type amino acid transporter 1 (LAT1) insights into the mechanisms of substrate recognition. Mol. Pharmacol. 2002, 61, 729—737. 

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. 

Barboiu, M., Luca, C., Popescu, G. and Cot, L. (1996) Facilitated transport of L-amino-adds I. New supramolecular complexes of L-amino-acids. Roumaine Biotechnology Letters, 1 (2), 77-86. 

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