Tryptophan metabolism, pathways

Acrodermatitis enteropathica is a metabolic disorder that results in the malabsorption of zinc. However, when patients afflicted with this disorder were treated with human milk, zinc absorption was enhanced (Lombeck et al. 1975). It was reported by Evans (1980) that patients with acrodermatitis enteropathica have an impaired tryptophan metabolic pathway. Picolinic acid, a chief metabolite of tryptophan, is also a constituent of human milk. Picolinic acid is secreted by the pancreas into the intestinal lumen. A study by Boosalis et al. (1983) demonstrated that patients with pancreatic insufficiency had difficulty absorbing zinc administered as zinc sulfate. However, when these pancreatic-insufficient patients were given zinc as zinc picolinate, the extent of zinc absorption was similar to that of healthy controls. Zinc absorption may depend on the bioavailability of picolinic acid. Such a mandatory role of picolinic acid in absorption has not been confirmed (Bonewitz et al. 1982). 

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... 

Tryptophan is a precursor for a series of metabolic reactions. Two tryptophan catabolizing pathways are well characterized (i) tryptophan converts to serotonin (ii) tryptophan is also converted to kynurenine. 

The kynurenine pathway accounts for most of the nonprotein tryptophan metabolism in most tissues. Several metabolites produced by this pathway have been shown... 

Narumiya S, K Takai, T Tokuyama, Y Noda, H Ushiro, O Hayaishi (1979) A new metabolic pathway of tryptophan initiated by tryptophan side chain oxidase. J Biol Chem 254 7007-7015. 

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. 

Nicotinic acid derivatives occur in biologic materials as the free acid, as nicotinamide, and in two coenzymatic forms nicotinamide adenine dinucleotide (NAD), and nicotinamide adenine dinucleotide phosphate (NADP). These coenzymes act in series with flavoprotein enzymes and, like them, are hydrogen acceptors or, when reduced, donors. Several plants and bacteria use a metabolic pathway for the formation of nicotinic acid that is different from the tryptophan pathway used by animals and man (B39). 

Aspects of Disorders of the Kynurenine Pathway of Tryptophan Metabolism in Man... 

Niacin is a generic term which refers to two related chemical compounds, nicotinic acid (6.22) and its amide, nicotinamide (6.23) both are derivatives of pyridine. Nicotinic acid is synthesized chemically and can be easily converted to the amide in which form it is found in the body. Niacin is obtained from food or can be synthesized from tryptophan (60 mg of dietary tryptophan has the same metabolic effect as 1 mg niacin). Niacin forms part of two important co-enzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are co-factors for many enzymes that participate in various metabolic pathways and function in electron transport. 

Botting NP (1995) Chemistry and biochemistry of the kynurenine pathway of tryptophan metabolism. Chem Soc Rev 24, 401-412. 

The catabolism of lysine merges with that of tryptophan at the level of (3-ketoadipic acid. Both metabolic pathways are identical from this point on and lead to the formation of acetoacetyl-CoA (Figure 20.21). Lysine is thus ketogenic. It does not transaminate in the classic way. Lysine is a precursor of carnitine the initial reaction involves the methylation of e-amino groups of protein-bound lysine with SAM. The N-methylated lysine is then released proteolytically and the reaction sequence to carnitine completed. See Equation (19.6) for the structure of carnitine. 

Fig. 2 Metabolic pathways in C. glutamicum for biosynthesis of the aromatic amino acids tryptophan, tyrosine, and phenylalanine (a) and amino acids belonging to the aspartate family including lysine, methionine, threonine, and isoleucine (b). Metabolic regulation by feedback inhibition is indicated by dotted lines...

H) lndole-3-acetaldehyde pathway The natural occurrence of indole-3-acetaldehyde (IAAld) in plants was first described in the extracts of cucumber seedlings98 where the concentration of IAAld was --(I. ngg-1 fresh weight. Possibly arising via IAOx or indole-3-pyruvate (IPyA), IAAld may act as a convergence point for tryptophan-dependent pathways.78 In an early study, the capacity to metabolize [14Ci]tryptophan via IPyA and IAAld was determined.99 Two primarily cytoplasmic enzymes were involved and the process was NAD-dependent. 

It is now well established that the primary metabolic target of glyphosate is an enzyme of the shikimic acid metabolic pathway, enolpyruvyl shikimate-3-phosphate synthase (2.f ). Via this action, glyphosate blocks the synthesis of the end products of this pathway, notably phenylalanine and tryptophan, but also various subsequent products (Figure 1) ( ,i). It has seemed logical to conclude that the herbicidal effect of glyphosate is a direct result of its effect on the shikimic acid pathway. 

As shown in Figure 8.2, NAD(P) can be synthesized from the tryptophan metaboUte quinolinic acid. The oxidative pathway of tryptophan metabolism is shown in Figure 8.4. Under normal conditions, almost aU of the dietary intake of tryptophan, apart from the small amount that is used for net new protein synthesis, is metabolized by this pathway, and hence is potentially available for NAD synthesis. About 1% of tryptophan metabolism is by way of 5-hydroxylation and decarboxylation to 5-hydroxytryptarnine (serotonin), which is excreted mainly as 5-hydroxyindoleacetic acid. 

A number of inborn errors of metabolism of the tryptophan oxidative pathway (see Figure 8.4) have been reported, aU of which result in the development of pellagra that responds to high doses of niacin. These conditions include vitamin Be-responsive xanthurenic aciduria, caused by a defect of kynureni-nase (Section 9.4.3) hydroxykynureninuria, apparentiy caused by a defect of kynureninase tryptophanuria, apparentiy caused by tryptophan dioxygenase deficiency a hereditary pellagra-like condition, apparentiy caused by an increase in activity of picoUnate carboxylase and Hartnup disease. 

Carcinoid is a tumor of the enterochromaffin cells that normally synthesize 5-hydroxytrytophan and 5-hydroxytryptamine. The carcinoid syndrome is seen when there are significant metastases of the primary tumor in the liver. It is characterized by increased gastrointestinal motility and diarrhea, as well as by regular periodic flushing. These symptoms can be attributed to systemic release of large amounts of serotonin and can be controlled with inhibitors of tryptophan hydroxylase, such as p-chlorophenylalanine. The synthesis of 5-hydroxytryptamine in advanced carcinoid syndrome may be so great that as much as 60% of the body s tryptophan metabolism proceeds by this pathway, compared with about 1% under normal conditions. A significant number of... 

Quinolinate has been known for more than 25 years to produce HD-like pathology in rodents (e.g., Beal et al., 1986). Thus, it has been suggested that the genetic defect in HD may result in heightened neuronal susceptibility to excitotoxic injury. Guidetti et al. (2004) have shown that the levels of quinolinate (an endogenous neuroactive metabolite of the kynurenine pathway of tryptophan metabolism) and... 

Figure 8.4. Pathways of tryptophan metabolism. Tryptophan dioxygenase, EC 1.13.11.11 formylkynurenine formamidase, EC 3.5.1.9 kynurenine hydroxylase, EC 1.14.13.9 kynttreninase, EC 3.7.1.3 3-hydroxyanthranilate oxidase, EC 1.10.3.5 picolinate carboxylase, EC 4.1.1.45 kynurenine oxoglutarate aminotransferase, EC 2.6.1.7 kynurenine glyoxylate aminotransferase, 2.6.1.63 tryptophan hydroxylase, EC 1.14.16.4 and 5-hydroxytryptophan decarboxylase, EC 4.1.1.26. Relative molecular masses (Mr) tryptophan, 204.2 serotonin, 176.2 kynurenine, 208.2 3-hydroxykynurenine, 223.2 kynurenic acid, 189.2 xanthurenic acid, 205.2 and quinolinic add 167.1. CoA, coenzyme A...

The production of KYNA is regulated by IDO and tryptophan 2,3-dioxygenase (TDO). Both enzymes catalyze the first step in the pathway, the degradation from tryptophan to kyn-urenine. Type-1 cytokines, such as IFN-y and IL-2 stimulate the activity of IDO (Grohmann etal., 2003). Figure 36.1 shows the relationship betw een cytokines, enzymes of the tryptophan metabolism, and formation of neuroactive intermediates. 

ASPECTS OF DISORDERS OF THE KYNURENINE PATHWAY OF TRYPTOPHAN METABOLISM IN MAN... 

Finally, it was found (B7) that the excretion of 5-hydroxyindoleacetic acid, which is taken as an index of tryptophan metabolism by the serotonin pathway, is affected by the administration of tryptophan neither in normal nor in schizophrenic subjects. 

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