Transport of tryptophan

Recently research has focused on the action of lithium on serotonergic function. Lithium has been shown to facilitate the uptake and synthesis of 5-HT, to enhance its release and to increase the transport of tryptophan into the nerve terminal, an effect which probably contributes to the increased 5-HT synthesis. The net effect of these changes is to produce postsynaptic receptor events, which might explain why lithium, in combination with tryptophan and a monoamine oxidase inhibitor or a 5-HT uptake inhibitor, is often effective in therapy-resistant depression. 

Laakso ML, Oja SS Transport of tryptophan and tyrosine in rat brain shces in the presence of lithium. Neurochem Res 4 411-423, 1979... 

The results obtained (M8) suggest that a defective transport of tryptophan is established across the cells of the jejunum and across the proximal renal tubules. The reduced conversion of tryptophan to kynurenine is probably due to a deficiency of tryptophan pyrrolase or to a lower transport of substrate to the enzyme. According to the same authors (M8), the cerebellar ataxia may be ascribable to intoxication by retained indolic acids. 

Calzado JA, Palet C, Jonsson JA, and Valiente M. Metal affinity liquid membrane. II. Facilitated transport of tryptophan. Anal. Chim. Acra 2000 417 159-167. 

Boyadzhiev L and Yordanov B. Pertraction of Indole Alkaloids from Vinca minor L. Sep Sci Tech, 2004 39(6) 1321-1329. Coucouvanis D. Dell Rosa and Jay Pike recognition and transport of amphiphilic molecules by a new class of inorganic ditopic receptors. The synthesis of M- Bu - salphen-3n-cr-n complexes and their use (M = Mn,Fe, n = 6) in the transport of tryptophan and serotonin across bulk liquid membranes. Comptes Rendus Chimie, 2003 6(3) 317-327. 

Albumin also functions as an amino acid source for peripheral tissue. After ingestion and absorption of amino acid-containing foods, albumin transports them to tissue. In addition, pinocytosed albumin itself can serve as a source of amino acids for tissue. The synthesis of albumin by the liver increases after meals, apparently in an attempt to prevent loss or catabolism of essential amino acids. Complexing by albumin appears to be necessary for the transport of some amino acids across membranes, in particular the transport of tryptophan across the blood-brain barrier. 

Niacin (adult RDA = 13 mg = 13 niacin equiv.) 50-250 mg Hartnup disease Intestinal and renal transport of tryptophan (high protein diet needed in addition to niacin to relieve symptoms)... 

Wieczorek, P. (1997). Factors influencing the transport of tryptophan hydrochloride through supported liquid membranes containing macrocyclic carriers. J. Membr. Sci., 127, 87-92. 

A possible consideration in the in vivo experiments where T3 and tryptophan were administered to rats was that T3 may inhibit tryptophan transport to the liver. A mutual competitive inhibition between the transport of tryptophan (mediated by the aromatic amino acid transport system T) and T3 has been reported.149150 Though system T transport activity has been studied mainly in erythrocytes, it is also expressed in hepatocytes.151 Interactions between thyroid hormone and tryptophan transport in rat liver have been reported to be modulated by thyroid status.152 For this reason, whether the administration of T3 and tryptophan under selected experimental conditions would affect free tryptophan levels in liver was investigated. The results revealed that rats tube-fed tryptophan and given T3 intraperitoneally at 0 time and killed after 1 h148 had the same increase (10%) in free tryptophan levels in liver as that of rats tube-fed tryptophan alone. 

A number of studies have reported that the plasma free tryptophan levels in infants are indicative of brain serotonin synthesis.41-42 They also reported that in gestationally malnourished rats or human infants the plasma free tryptophan was elevated and considered that an increased transport of tryptophan to the brain caused a possible enhancement of serotonin synthesis. 

A number of genetic diseases that result in defects of tryptophan metabolism are associated with the development of pellagra despite an apparently adequate intake of both tryptophan and niacin. Hartnup disease is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan, resulting in large losses due to intestinal malabsorption and failure of the renal resorption mechanism. In carcinoid syndrome there is metastasis of a primary liver tumor of enterochromaffin cells which synthesize 5-hydroxy-tryptamine. Overproduction of 5-hydroxytryptamine may account for as much as 60% of the body s tryptophan metabolism, causing pellagra because of the diversion away from NAD synthesis. 

Another important function of albumin is its ability to bind various ligands. These include free fatty acids (FFA), calcium, certain steroid hormones, bilirubin, and some of the plasma tryptophan. In addition, albumin appears to play an important role in transport of copper in the human body (see below). A vatiety of drugs, including sulfonamides, penicilhn G, dicumarol, and aspirin, are bound to albumin this finding has important pharmacologic implications. 

Additional evidence for conformational changes in the transporter has come from measurement of the intrinsic fluorescence of the protein tryptophan residues, of which there are six, in the presence of substrates and inhibitors of transport. The fluorescence emission spectrum of the transporter has a maximum at about 336 nm, indicating the presence of tryptophan residues in both non-polar environments (which would emit maximally at about 330 nm) and in polar environments (which would emit at 340-350 nm) [154], The extent of quenching by the hydrophilic quencher KI indicates that more than 75% of the fluorescence is not available for quenching, and so probably stems from tryptophan residues buried within the hydrophobic interior of the protein or lipid bilayer [155]. Fluorescence is quenched... 

Serretti, A., Zanardi, R., Rossini, D. etal. (2001b). Influence of tryptophan hydroxylase and serotonin transporter genes on fluvoxamine antidepressants activity. Mol. Psychiatry, 6, 586-92. 

Hanson, G.R., Gibb, J.W., Metzger, R.R., Kokoshka, J.M., Fleckenstein, A.E. Methamphetamine-induced rapid and reversible reduction in the activities of tryptophan hydroxylase and dopamine transporters oxidative consequences Ann. N.Y.Acad. Sci. 844 103, 1998. 

The amino acid L-tryptophan is the precursor for the synthesis of 5-HT. The synthesis and primary metabolic pathways of 5-HT are shown in Figure 13-5. The initial step in the synthesis of serotonin is the facilitated transport of the amino acid L-tryptophan from blood into brain. The primary source of tryptophan is dietary protein. Other neutral amino acids, such as phenylalanine, leucine and methionine, are transported by the same carrier into the brain. Therefore, the entry of tryptophan into brain is not only related to its concentration in blood but is also a function of its concentration in relation to the concentrations of other neutral amino acids. Consequently, lowering the dietary intake of tryptophan while raising the intake of the amino acids with which it competes for transport into brain lowers the content of 5-HT in brain and changes certain behaviors associated with 5-HT function. This strategy for lowering the brain content of 5-HT has been used clinically to evaluate the importance of brain 5-HT in the mechanism of action of psychotherapeutic drugs. 

In biological systems, therefore, the behavior of Li+ is predicted to be similar to that of Na+ and K+ in some cases, and to that of Mg2+ and Ca2+ in others [12]. Indeed, research has demonstrated numerous systems in which one or more of these cations is normally intrinsically involved, including ion transport pathways and enzyme activities, in which Li+ has mimicked the actions of these cations, sometimes producing inhibitory or stimulatory effects. For example, Li+ can replace Na+ in the ATP-dependent system which controls the transport of Na+ through the endoplasmic reticulum Li+ inhibits the activity of some Mg2+-dependent enzymes in vitro, such as pyruvate kinase and inositol monophosphate phosphatase Li+ affects the activity of some Ca2+-dependent enzymes— it increases the levels of activated Ca2+-ATPase in human erythrocyte membranes ex vivo and inhibits tryptophan hydroxylase. 

Kleinberger-Doron, N. and Kanner, B. I. (1994) Identification of tryptophan residues critical for the function and targeting of the gamma-aminobutyric acid transporter (subtype A)../. Biol. Chem. 269, 3063-3067. 

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... 

Enhanced synthesis and transport of neurotransmitter synthesizing enzymes (e.g. tyrosine and tryptophan hydroxylase). 

Figure 7. A serotonergic synapse including a depiction of the acute tryptophan depletion method discussed in the text. All large neutral amino acids (SLNAAs) share a common blood-brain barrier transporter. The serotonergic precursor, tryptophan, essentially competes with the other LNAAs for transport. Thus tryptophan is uniquely susceptible to acute dietary manipulation. Numerous serotonergic receptor types exist, including presynaptic S-HTm and (somatodendritic) 5-HTia autoreceptors and postsynaptic 5-HTia, 5-HTid, 5-HT2a 5-HT2c 5-HT3 and 5-HT4 receptors. Additional modulation of serotonin activity can occur via the action of selective serotonin re-uptake inhibitors (SSRls) including fluoxetine, fluvoxamine, and citalopram.

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. 

The production of serotonin requires the absorption of the amino acid tryptophan from your food. Transport of this amino acid is influenced by the level of other amino acids in your blood that level, in turn, is also influenced by what you eat. Within the neurons of your brain, tryptophan is converted to 5-hydroxy-tryptophan by tryptophan hydroxylase, an enzyme that is usually not saturated with substrate. Therefore, if you eat less tryptophan, your brain generally produces less serotonin. Conversely, providing additional tryptophan in the diet may lead to increased production of serotonin within neurons. It is worth noting, however, that simply producing more of any neurotransmitter does not guarantee that the neuron will actually release it. If too much serotonin is produced, then the excess is simply discarded. Studies have shown that only extreme depletion or supplementation of this amino acid in the diet can influence serotonin-controlled brain processes such as mood and sleep. 

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