Tryptophan catabolism

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. 

Colabroy KL, TP Begley (2005) Tryptophan catabolism identification and characterization of a new degradative pathway. J Bacteriol 187 7866-7869. 

Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R, Belladonna ML. Fioretti MC, Alegre ML. Puccetti P Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 2003 4 1206-1212. 

Tryptophan Catabolism and Allergy Fungi Are Next in Line... 

In summary, regulation through tryptophan catabolism appears to be an essential component of host responses to fungi such that its manipulation may allow fungi to either evade or promote immune activation. 

Romani L, Puccetti P Protective tolerance to fungi the role of IL-10 and tryptophan catabolism. Trends Microbiol 2006 14 183-189. 

Mellor AL. Munn DH IDO expression by dendritic cells tolerance and tryptophan catabolism. Nat Rev Immunol 2004 4 762-774. 

Bozza S, Fallarino F. Pitzurra L. Zelante T. Montagnoli C. Bellocchio S. Mosci P. Vacca C, Puccetti P. Romani L A crucial role for tryptophan catabolism at the host/Candida albicans Interface. J Immunol 2005 174 2910-2918. 

Montagnoli C. Fallarino F. Gaziano R. Bozza S, Bellocchio S. Zelante T. Kurup WP, Pitzurra L. Puccetti P. Romani L Immunity and tolerance to Aspergillus involve functionally distinct regulatory T cells and tryptophan catabolism. J Immunol 2006 176 1712-1723. 

Returning to the major tryptophan catabolic pathway, marked by green arrows in Fig. 25-11, formate is removed hydrolytically (step c) from the product of tryptophan dioxygenase action to form kynurenine, a compound that is acted upon by a number of enzymes. Kynureninase (Eq. 14-35) cleaves the compound to anthranilate and alanine (step d), while transamination leads to the cyclic kynurenic acid (step e). Hie latter is dehydroxylated in an unusual reaction to quinaldic acid, a prominent urinary excretion product. 

Lebuhn, M., and Hartmann, A. (1993). Method for determination of indole-3-acetic acid and related compounds of L-tryptophan catabolism in soils. /. Chromat. 629, 255-266. 

Tryptophan catabolism is also associated with several dead-end pathways, for example the formation of kynurenic and xanthurenic acids. Normal urine contains small amounts of hydroxykynurenine, kynurenine, kynurenic acid, and xanthurenic add. When large amounts of tryptophan are fed to animals, the excretion of these compounds increases. Xanthurenic acid is excreted in massive quantities in vitamin B6 deficiency. 

In isolated hepatocytes, after maximum induction of tryptophan dioxygenase by glucocorticoids, the uptake of tryptophan into the cells has a control coefficient of 0.75, whereas the control coefficient of tryptophan dioxygenase falls to 0.25. Therefore, the induction of tryptophan dioxygenase has only a limited effect on tryptophan catabolism and NAD synthesis (Salter and Pogson, 1985 Salter et al., 1986). In isolated perfused liver, although cortisol leads to a several-fold increase in tryptophan dioxygenase activity, there is only a relatively small increase in the rate of clearance of tryptophan from the perfusion medium (Kim and Miller, 1969). 

Mellor AL, Munn D, Chandler P, Bieskin D, Johnson T, Marshall B, Jhaver K, Baban B (2003) Tryptophan catabolism and T cell responses. Adv Exp Med Biol 527 27—35. 

Mellor AL, Muim DH (1999) Tryptophan catabolism and T-cell tolerance Immunosuppression by starvadon Immunol Today 20 469 73. 

The enzyme indoleamine 2,3-dioxygenase (IDO) metabolizes tryptophan to kynurenine, kynurenine is then converted to quinolinic acid via the intermediate 3-HK by the enzyme kynurenine hydroxylase. Both IDO and kynurenine hydroxylase are induced by the type-1 cytokine IFN-y. The activity of IDO is an important regulatory component in the control of lymphocyte proliferation, the activation of the type-1 immune response and the regulation of the tryptophan metabolism (Mellor and Munn, 1999). It induces a halt in the lymphocyte cell cycle due to the catabolism of tryptophan (Munn et al., 1999). In contrast to the type-1 cytokines, the type-2 cytokines IL-4 and IL-10 inhibit the IFN-y-induced IDO-mediated tryptophan catabolism (Weiss et al., 1999). IDO is located in several cell types including monocytes and microglial cells (Alberati et al., 1996). An IFN-y-induced, IDO-mediated decrease of CNS... 

Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL (1999) Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med 189 1363-1372. 

Catabolism of tyrosine and tryptophan begins with oxygen-requiring steps. The tyrosine catabolic pathway, shown at the end of this chapter, results in the formation of fumaric acid and acetoaceticacid, Iryptophan catabolism commences with the reaction catalyzed by tryptophan-2,3-dioxygenase. This enzyme catalyzes conversion of the amino acid to N-formyl-kynurenine The enzyme requires iron and copper and thus is a metalloenzyme. The final products of the pathway are acetoacetyl-CoA, acetyl-Co A, formic add, four molecules of carbon dioxide, and two ammonium ions One of the intermediates of tryptophan catabolism, a-amino-P-carboxyrnuconic-6-semialdchydc, can be diverted from complete oxidation, and used for the synthesis of NAD (see Niacin in Chapter 9). 

At One time it was thought that women taking oral contraceptives were at risk for B deficiency. This notion seem-S to have been in error. The error was due to a misinterpretation of the tryptophan load lest. As mentioned earlier, a deficiency in vitamin B(,can induce the accumulation of specific intermediates of the tryptophan catabolic pathway and enhanced excretion in the urine. Oral contraceptives can also induce ar increase in the formation and excretion of specific intermediates by stimulating the activity of specific enzymes of the tryptophan catabolic pathway, This stimulation was responsible for the false indications of deficiency. Independently of the tryptophan load test, there continues to be some evidence for risk associated with the use of oral contraceptives. Oral contraceptive use may result in lowered levels of plasma vitamin Bf, Tlicsc lowered levels may result in a vitamin deficiency when coupled with pregnancy and lactation. 

Plasma tryptophan concentration is a function of dietary tryptophan intake as well as the extent of removal of tryptophan from blood by tissues. The liver is the main organ influencing plasma tryptophan concentration since it actively metabolizes tryptophan while nonhepatic tissues have only relatively limited ability to act in this manner. Following a meal, in the liver, tryptophan stimulates hepatic tryptophan oxygenase activity, which affects tryptophan catabolism and determines how much tryptophan enters the general circulation. 

Taylor, M. W. and Feng, G. S., Relationship between interferon-gamma, indoleamine 2, 3-dioxygenase, and tryptophan catabolism, FASEB., 5[11], 2516, 1991. 

The first step of tryptophan catabolism is the oxidative cleavage of the indole ring of L-tryptophan, which is catalyzed by members of the family of pyrrole dioxygenases. A key member of this family, indoleamine-2,3-dioxygenase (IDO, see Fig. 1, EC 1.13.11.17), is expressed in all tissues except in the liver and produces the central metabolite kynurenine (KYN). Two different and competing branches of the pathway then further metabolize KYN the first pathway includes a family of enzymes called kynurenine aminotransferases (KATs), which produce kynurenic acid (KYNA) in a terminal branch. In a second arm, KMO (or kynurenine... 

Tryptophan catabolism. The major pathway of tryptophan catabolism is presented above. The early steps are shown in detail, with the formation of niacin and acetyl CoA from 3-hydroxyanthranilate shown with no detail. 

It was discovered in 1998 that expression of IDO activity in the mouse fetus represses the maternal T-cell activity and hence protects the fetus from the maternal immune system. Pregnant mice treated with the IDO inhibitor 1-methyltryptophan rejected the embryos via their immune system, thus either IDO itself or a product of tryptophan catabolism is able to suppress the maternal T-cell activity. IDO is also expressed in response to interferon 7 from activating T-cells, inhibiting T-cell proliferation and contributing toward the antiviral activity of interferon 7. The end product of the L-tryptophan degradation pathway, quinolinic acid, has neurological effects, hence the IDO pathway is implicated in several mammalian regulatory pathways. 

Alanine can be made by several metabolic processes. Most commonly it is made by transfer of an amine group to pyruvate (reaction 2 below). Alanine is also a product of tryptophan catabolism. 

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