Tryptophan degradation

Suzuki, T., H. Kawamichi, and K. Imai (1998). A myoglobin evolved from indoleamine 2,3-dioxy-genase, a tryptophan degrading enzyme. Comp. Biochem. Physiol. 121B 117-128. 

Figure 23.30. Tryptophan Degradation. The pathway for the conversion of tryptophan into alanine and acetoacetate. 

There is a mutual inhibitory effect of TDO and IDO a decrease in TDO activity occurs concomitantly with IDO induction, resulting in a coordinate shift in the site (and cell types) of tryptophan degradation (Takikawa et al., 1986). While it has been known for a long time that IDO is expressed in different types of CNS cells, TDO was thought for many year s to be restricted to Uver tissue. It is kno W n today, however, that TDO is also expressed in CNS cells, probably restricted to astrocytes (Miller et al., 2004). 

Takikawa O, Yoshida R, BHdo R, Hayaishi O (1986) Tryptophan degradation in mice initiated by indoleamine 2,3-dioxygenase. J Biol Chem 261 3648-3653. 

Weiss G, Muir C, Zoller H, Haun M, Widner B, Ludescher C, Fuchs D (1999) Modulation of neopterin formation and tryptophan degradation by Thl- and Th2-derived cytokines in human monocytic cells. Clin Exp Immunol 116 435 140. 

Jenny M, Winkler C, Spetea M, Schennach H, Schmidhammer H, Fuchs D (2008) Non-peptidic 5-opioid receptor antagonists suppress mitogen-induced tryptophan degradation in peripheral blood mononuclear cells in vitro. Immunol Lett 118 82-87... 

VIII. Tryptophan Degradation by the Enter.a.mine-Serotonin Pathway ... 

IX. Routes for Tryptophan Degradation used Principally BY Microorganisms... 

Gisslen et al.27 described that tryptophan concentrations increased in CSF and blood after zidovudine treatment of patients with HIV-1 infection. Their data suggested an association between decreased immune stimulation and reduced tryptophan degradation in patients treated with zidovudine. A decrease in neopterin during the antiviral treatment correlated with an increase in tryptophan. 

G., Dierich, M. P., and Wachter, H., Tryptophan degradation in patients infected by human immunodeficiency virus, Biol. Chem. Hoppe-Seyler, 369, 337, 1988. 

Aune, T.M. and Pogue, S. L., Inhibition of tumor cell growth by interferon-gamma is mediated by two distinct mechanisms dependent upon oxygen tension Induction of tryptophan degradation and depletion of intracellular nicotinamide adenine dinucleotide,. Clin. Invest., 84, 863, 1989. 

Thomas and Stocker118 recently reported on studies supporting the proposal that induction of tryptophan degradation along the kynurenine pathway in human monocytes and macrophages by interferon-y represents a novel extracellular antioxidant defense that acts to prevent inadvertent oxidative damage to host tissue during inflammation. 

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. 

The neurotoxic activity of HK seems to be well ascertained [93-95]. In fact, the substance showed neurotoxic properties when added to neuronal cell cultures [91] and provoked seizures when injected intracerebroven-tricularly [93]. As a significant and substantial increase of HK concentrations in brain samples taken post mortem from Huntington s disease patients was observed, a metabolic disorder of tryptophan degradation was associated with the disease. This disorder seems to be relatively specific to Huntington s disease, and normal levels of HK were found under the same conditions in Alzheimer s disease patients. 

Evidence of protein damage shows up in many diseases, particularly those associated with aging. In patients with cataracts, proteins in the lens of the eye exhibit free radical damage and contain methionine sulfoxide residues and tryptophan degradation products. 

If the dietary levels of niacin and tryptophan are insufficient, the condition known as pellagra results. The symptoms of pellagra are dermatitis, diarrhea, dementia, and, finally, death. In addition, abnormal metabolism of tryptophan occurs in a vitamin B6 deficiency. Kynurenine intermediates in tryptophan degradation cannot be cleaved because kynureninase requires PLP derived from vitamin B6. Consequently, these intermediates enter a minor pathway for tryptophan metabolism that produces xanthurenic acid, which is excreted in the urine. 

The simple quinazoline derivatives produced by Pseudomonas are formed in the course of tryptophan degradation ( quinazoline pathway ). Tryptophan is first converted to formylkynurenine and then to A-formylaminoacetophenone, which forms 4-methylquinazoline with ammonia or loses the formyl group to give 2-aminoacetophenone. After reacylation and cyclization with ammonia this latter product yields the other derivatives of 4-methylquinazoline (58,59). 

The antibiotic tryptanthrin (53) has been biosynthesized from 1 mol of tryptophan and 1 mol of anthranilic acid. Upon feeding tryptophan and substituted anthranilic acids, or substituted tryptophans and anthranilic acid, the expected derivatives of 53 were isolated. The enzymes involved in the biosynthesis of 53 had no specificity for these substrates, with the exception of bromotryptophan. The anthranilic acid moiety used during biosynthesis results from tryptophan degradation 131,172). 

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