L-Tryptophan metabolism

Pewnim T, Seifert J. 1993. Structural requirements for altering the L-tryptophan metabolism in mice by organophosphorous and methylcarbamate insecticides. Eur J Pharmacol 248 237-241. 

Seifert J, Pewnim T. 1992. Alteration of mice L-tryptophan metabolism by the organophosphorous acid triester diazinon. Biochem Pharmacol 44(11) 2243-2250. 

Sato, T.. Aoki, J Nagai, Y Dohmae, N Takio, K Doi, T.. Arai, H., and Inoue, K. (1997), Serine phospholipid-specific phospholipase A that is secreted from activated platelets, A new member of the lipase family. J. Biol Chem. 211, 2192-2198. Seifert, J., and Pewnim, T. (1992), Alteration of mice L-tryptophan metabolism by the organophosphorous acid iriester diatrinon. Biochem. Pharmacol. 44, 2243-2250. 

Several alternative pathways of L-tryptophan metabolism diverge from kynurenine (24). In mammals the quantitatively major fate of the benzene ring of the amino acid appears to be its oxidation to carbon dioxide via 3-hydroxyanthranilic acid (25), Figure 4.5. Kynurenine is first hydroxylated by a typical mixed function oxidase and the side chain is then removed, under the... 

A further important pathway of L-tryptophan metabolism also diverges from 2-amino-3-carboxy-m, cis muconic semi-aldehyde (26) the ring fission product of 3-hydroxyanthranilate (25) and this is the biosynthetic pathway which leads to the formation of the pyridine ring of the nicotinamide nucleotides . The first step in this pathway appears to be the recyclisation of the oxidation product (26) to give quinolinic add (27) which is transformed to the pyridine nucleotides, such as NAD (28) in a complex series of reactions. Figure 4.6. 

L-Tryptophan 2,3-dioxygenase (TPO), which catalyzes the ring cleavage of tryptophan to N-formylkynurenine [eq. (14)] [156], is a heme enzyme containing iron porphyrin [157] and plays a key role in the L-tryptophan metabolic pathway. Kotake and Masayama first... 

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. 

For therapeutical purposes selective and unselec-tive 5-HT-receptor agonists and antagonists are used. Furthermore, the serotonin metabolism can be influenced by drugs like re-uptake inhibitors and the substrate of 5-HT synthesis, L-tryptophan. 

The shikimate/arogenate pathway leads to the formation of three aromatic amino acids L-phenylalanine, L-tyrosine, and L-tryptophane. This amino acids are precursors of certain homones (auxins) and of several secondary compounds, including phenolics [6,7]. One shikimate/arogenate is thought to be located in chloroplasts in which the aromatic amino acids are produced mainly for protein biosynthesis, whereas the second is probably membrane associated in the cytosol, in which L-phenylalanine is also produced for the formation of the phenylpropanoids [7]. Once L-phenylalanine has been synthesized, the pathway called phenylalanine/hydroxycinnamate begins, this being defined as "general phenylpropanoid metabolism" [7]. 

The most significant difference between the action of the trp and lac repressors relates to the function of the small-molecule effector. In the case of lac, the effector mol-ecule allolactose acts as an antirepressor (inducer), causing release of repressor from the operator in the case of trp, the effector molecule L-tryptophan acts as a corepressor, stimulating the binding of repressor to the operator. It should be obvious that the difference in action of these small-molecule effectors, the concentrations of which dictate the level of operon activity, is well suited to the different metabolic needs of the cell satisfied by the two operons. 

Bacterial De-Novo Synthesis. The basic idea behind this variant is to use the synthetic potential of bacteria to produce the indole precursor (Scheme 3). Although indole (23) does not occur as an intermediate in bacterial metabolism, it appears as an enzyme-linked intermediate in the biocatalytic transformation ofD-glucose (17) to L-tryptophan (22). The crucial biosynthetic step is the conversion of indole-3-glycerine phosphate (21) to L-tryptophan (22) by the enzyme tryptophan synthase. 

Capuron L, Neurauter G, Musselman DL, Lawson DH, Nemeroff CB, Fuchs D, Miller AH. Interferon-alfa-induced changes in tryptophan metabolism. Relationship to depression and paroxetine treatment. Biol Psychiatry 2003 54 906-14. 

Tryptophan dioxygenase catalyzes the first step in the oxidative metabolism of L-tryptophan. L-Kynurenine is the product. 

No 3-carboxy-substituted TBCs, derived from L-tryptophan by the Pic-tet-Spengler route, have yet been isolated from mammalian tissues. The same is also true for the dicarboxylic acid 23a derived from the condensation of L-tryptophan with pyruvic acid (36). The 1-carboxy-substituted TBCs 37 and 38, on the other hand, occur in mammalian systems (70,71) and are metabolically decarboxylated (65,S5). Whether a direct enzymatic decarboxylation of racemic material, occurring with the (S) and (R) enantiomers at a different rate, could account for the formation of unequal amounts of the enantiomers of TBC has not been investigated so far. The pyruvic acid route to optically active TBC (Fig. 12) leading from TBC 38a to TBC 29a via DBC 34 is at tifie moment the preferred pathway (85,86,89), although the enzymes involved in the asymmetric reduction leading to TBC 29a and the hydroxylated metabolites TBCs 30a and 33a have been neither isolated nor characterized. 

Bender DA and Totoe L (1984a) High doses of vitamin Be in the rat are associated with inhibition of hepatic tryptophan metabolism and increased uptake oftryptophan into the btmn. Journal of Neurochemistry 43,733-6. 

Bender DA and Totoe L (1984b) Inhibition of tryptophan metabolism by oestrogens in the rat a factor in the aetiology of pellagra. British Journal of Nutrition 51,219-24. 

Tryptophan metabolism was investigated in neurological diseases (V5, Cl) in which the xanthurenic acid excretion was measured after ingestion of L-tryptophan (100 mg/kg). The greater amounts of xanthurenic acid excreted by certain patients suggested an alteration of tryptophan metabolism, probably related to pyridoxine deficiency. 

Harris et al. (H4) reported a case of an adult patient with hematological abnormalities unresponsive to the usual hematopoietic agents and characterized by a hypochromic anemia, leucocytosis, high serum iron, and high percent iron-binding protein saturation. Measurements of the urinary excretion of kynurenine, kynurenic acid, acetylkynurenine, xanthurenic acid, o-aminohippuric acid before and after an oral dose of 4 g L-tryptophan indicated abnormalities of tryptophan metabolism. This alteration was partially normalized on a 1-mg pyridoxine dose and completely normalized at the 10-mg level. Also the clinical and laboratory abnormalities disappeared and hematological remission followed the pyridoxine administration. 

It has been observed (D6) Aat addition of vitamin Be to insulin therapy allowed the employment of lower doses of insuhn and, in one subject, the total cessation of insulin administration. Finally, Oka and Leppanen (04) studied the tryptophan metabolism in 10 patients with diabetes mellitus and in 12 control subjects by determining the urinary excretion of 5-hydroxyindoleacetic acid, kynurfenine, and anthranilic, 3-hydroxyanthranilic, and xanthurenic acids before and after a load of 2 g L-tryptophan. The authors noted a markedly increased excretion of... 

In view of the hypoglycemic and insulinase-inhibitory action of l-tryptophan, it seemed pertinent to Mirsky to study the effect of various metabolic products of tryptophan on the blood sugar of normal and diabetic rats (M9), A statistically significant hypoglycemic response was produced after oral administration of anthranilic acid, niacin, indole-3-acetic acid, 5-hydroxytryptophan, and serotonin. A hypoglycemic fol-... 

The disease is a rare inherited disorder characterized by a progressive degeneration of the lenticular nucleus in the brain and by cirrhosis of the liver. Barbeau et al. (Bl) studied a case of Wilson s disease which presented normal ceruloplasmin and serum copper values but increased excretion of kynurenine, 3-hydroxykynurenine, and conjugated anthra-nilic acid in xurine after an oral dose of 2 g L-tryptophan. This defect in tryptophan metabolism could be related to that of other amino acids and to the actual content of ceruloplasmin in Wilson s disease (Bl). These findings corroborated Marver s (M2) investigations demonstrating a definite excretion of kynurenine and 3-hydroxykynurenine in abnormal proportions after a tryptophan load in a case of Wilson s disease. 

Metabolic studies by Milne et al. (M8) showed that in Hartnup disease the renal aminoaciduria is more constant than the excessive excretion of indican and indolic acids (indoleacetic acid, indolelactic acid, and indoleacetylglutamine). After ingestion of L-tryptophan in this disease there is usually delayed and incomplete absorption from the gut of the amino acid which is partly converted, by intestinal bacteria, to indole... 

---