Disease relevance of TDO2

• Tryptophanase of fecal flora as a possible factor in the etiology of colon cancer [1].
• Sn-protoporphyrin, in doses (10 mumol/kg body wt) which entirely suppress neonatal hyperbilirubinemia in the experimental animal, leads to a very rapid (approximately 30-60 min) increase in the heme saturation of tryptophan pyrrolase from normal levels of approximately 50-60% to nearly 100% [2].
• Here, we report extensive structural and biochemical studies of the Xanthomonas campestris TDO and a related protein SO4414 from Shewanella oneidensis, including the structure at 1.6-A resolution of the catalytically active, ferrous form of TDO in a binary complex with the substrate l-Trp [3].
• Tryptophanase in sRNA control of the Escherichia coli cell cycle [4].
• Exclusion of the 5-HT1A serotonin neuroreceptor and tryptophan oxygenase genes in a large British kindred multiply affected with Tourette's syndrome, chronic motor tics, and obsessive-compulsive behavior [5].

Psychiatry related information on TDO2

• We have investigated five single nucleotide polymorphisms in the TDO2 gene for association with autistic disorder [6].
• Unlike the results for schizophrenia and bipolar disorder, the increase in TDO2 protein in the major depression group was not associated with an increase in kynurenine concentration [7].
• In CC57BR/Mv mice no relationships were found between alcohol consumption, tryptophan oxygenase activity, and single nucleotide substitutions in intron 6 of the TDO2 gene associated with predisposition to alcoholism in humans [8].
• RESULTS: There was no evidence to support the hypothesis that genetic variation in the serotonin 5-HT1A receptor and tryptophan oxygenase genes causes susceptibility to Tourette's syndrome and chronic multiple tics [5].
• TPH2: an answer for unipolar depression [9]?

High impact information on TDO2

• We have examined this question in liver by studying the heme saturation of tryptophan pyrrolase, the heme-dependent enzyme which controls the first and rate-limiting step in the catabolism of L-tryptophan [2].
• Two sisters with abnormal tryptophan metabolism were given 200 mg L-kynurenine sulfate orally to bypass the effects of tryptophan oxygenase activity [10].
• The results indicated that the higher tryptophanase activity in the feces of rats fed an all-meat diet is due to the inducibility of this enzyme by tryptophan and is not due to any inhibitor in the feces of rats on a normal diet [1].
• The tryptophanase of the indole-positive strains of intestinal anaerobes was inducible by tryptophan and was susceptible to glucose repression [1].
• Triokinase activity is absent in the distal two-fifths of intestine, and tryptophan oxygenase is present only in the distal one-sixth, or most terminal part of the ileum [11].

Chemical compound and disease context of TDO2

• We hypothesize the following ideas: that increased serum L-kynurenine concentrations are mainly due to the increased TDO and decreased kynureninase activities in the liver and increased serum Quin concentrations are due to the decreased ACMSDase activities in the body after renal insufficiency [12].
• This study was conducted in order to assess whether chronic excessive alcohol consumption affects the activity of the liver enzyme tryptophan oxygenase which is rate limiting along the most important pathway of tryptophan catabolism [13].
• In this work, a new disubstituted indigoid generation system was developed with a tryptophanase-deficient Escherichia coli strain as a host to express the human cytochrome P450 2A6 mutant L240C/N297Q, which catalyzes the oxidation of indole to isatin and indoxyl, which in turn react to generate indigoids [14].
• Biotransformations of a series of ortho-, meta- and para-substituted ethylbenzene and propylbenzene substrates have been carried out, using Pseudomonas putida UV4, a source of toluene dioxygenase (TDO) [15].

Biological context of TDO2

• Compared to the rat, the regulatory region of the human TDO2 gene had an insertion of approximately 1064 bp of random DNA beginning at -293 bp and extending to -1357 bp [16].
• Haplotype analysis also demonstrated significant difference in the transmission of TDO2 haplotypes to autistic subjects (P = 0.0027) [6].
• Point mutations within 663-666 bp of intron 6 of the human TDO2 gene, associated with a number of psychiatric disorders, damage the YY-1 transcription factor binding site [17].
• Single base mutations G-->A at position 663 and G-->T at position 666 of intron 6 of the human tryptophan oxygenase gene (TDO2) are associated with a variety of psychiatric disorders [Comings, D.E. et al. (1996) Pharmacogenetics 6, 307-318] [17].
• The combined use of cell hybrids and in situ hydridization indicated that human tryptophan oxygenase was localized to chromosome band 4q31 [18].

Anatomical context of TDO2

• For this follow-up study of postmortem anterior cingulate gyrus, we have found evidence of increased TDO2 activity in schizophrenia at three different levels of regulation: mRNA, protein, and metabolic product [7].
• This resulted in suppression of growth, changes in morphology (microvilli and large cytoplasm with developed organelles), and expression of hepatocyte markers (albumin, tyrosine amino transferase, and tryptophan oxygenase) [19].
• Whereas TDO is located in the liver cells, IDO is expressed in a large variety of cells and is inducible by the cytokine interferon-gamma [20].
• Small intestine indole 2,3-dioxygenase (IDO) did not vary significantly among the three groups but was higher in comparison with liver TDO activity [21].
• TDO is located in liver cells, whereas IDO is expressed in a variety of cells including monocyte-derived macrophages and dendritic cells and is preferentially induced by Th1-type cytokine interferon-gamma [22].

Associations of TDO2 with chemical compounds

• A mutation that results in decreased activity of the TDO2 can decrease catabolism of tryptophan and increase the level of whole body serotonin [6].
• The tryptophan oxygenase gene may be important in some human behavior disorders, especially those associated with abnormalities of serotonin metabolism [18].
• Structure--function relationships of rat hepatic tryptophan 2,3-dioxygenase: identification of the putative heme-ligating histidine residues [23].
• The spectroscopic properties of the mutant enzymes are altered and become similar to those of tryptophanase and aspartate aminotransferase, enzymes in which an Asp residue interacts with the pyridine nitrogen of pyridoxal phosphate [24].
• Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia [25].

Other interactions of TDO2

• Quantitative RT-PCR indicated that the relative abundance of TPH-2 mRNA was greater than TPH-1 mRNA [26].
• Repression of GR-mediated expression of the tryptophan oxygenase gene by the SWI/SNF complex during liver development [27].
• IFN-gamma induces a high level of indoleamine dioxygenase (IDO), a tryptophan degrading enzyme, and high cortisol levels induce high tryptophan oxygenase activity, which in turn increases metabolism along the tryptophan-nicotinic acid pathway [28].
• The enzyme responsible for this appears to be different from tryptophan 2,3-dioxygenase and also from indoleamine 2,3-dioxygenase [29].
• Cloning and characterization of the Tribolium castaneum eye-color genes encoding tryptophan oxygenase and kynurenine 3-monooxygenase [30].

Analytical, diagnostic and therapeutic context of TDO2

• Sequence alignment of the rat liver protein with that of known or putative TDO sequences from other organisms reveals that four of the His residues are conserved in eukaryotes, two of which are also conserved in prokaryotes [23].
• Finally, we present evidence that the expression and activity of liver specific transcription factors, CCAAT/enhancer binding proteins and liver specific key enzymes such as tryptophan 2,3-dioxygenase, are improved in hepatocyte/BMSC co-cultures [31].
• Liver L-tryptophan 2,3-dioxygenase activity (TDO), a rate-limiting enzyme of the kynurenine pathway, was increased in proportion to blood urea nitrogen and creatinine levels [12].
• The effects of the administration of oestrogens on the activity of hepatic tryptophan oxygenase have been assessed both directly (by measurement of enzyme activity in vitro) and indirectly (by measurement of urinary excretion of tryptophan metabolites) in rats, and indirectly in menopausal women receiving hormone replacement therapy [32].
• Both adrenalectomy and ovariectomy led to a reduction in the activity of tryptophan oxygenase in homogenates of liver from mature rats; again there was no effect of giving 500 micrograms of oestradiol/kg body wt by intraperitoneal injection [32].

References