Tryptophan pyrrolase activity

Tryptophan pyrrolase activity is lacking in fetal liver of rat and rabbit and appears late in gestation in the guinea pig. In the fetus and newborn of these animals the metabolism of tryptophan to nicotinic acid is decreased or completely absent (Nl). 

Badawy, A. A. and Smith, M. J., Changes in liver tryptophan and tryptophan pyrrolase activity after administration of salicylate and tryptophan to the rat, Biochem. Pharmacol., 21[1], 97, 1972. 

Badawy, A. A. B. and Evans, M., The regulation of rat liver tryptophan pyrrolase activity by reduced nicotinamide-adenine dinucleotide (phosphate). Experiments with glucose and nicotinamide, Biochemical., 156, 381, 1976. 

Badawy, A. A., Punjani, N. E, and Evans, M., Enhancement of rat brain tryptophan metabolism by chronic ethanol administration and possible involvement of decreased liver tryptophan pyrrolase activity, Biochem. ]., 178,575,1979. 

Johnson, R. J. and Dyer, I. A., Effect of orally administered tryptophan on tryptophan pyrrolase activity in ovine and bovine, Life Sci., 5, 1121, 1966. 

The alkaloids interfere with a number of enzyme systems. In vitro, lasiocarpine and heliotrine inhibit enzyme systems that need pju idine nucleotides for electron transfer (45). The nicotinamide-adenine dinucleotide pyrophosphorylase activity of nuclei from rat liver that has been treated with heliotrine is reduced significantly below that of controls (46). It has recently been shown that in rats lasiocarpine inhibits RNA synthesis, causes a substantial reduction in tryptophan pyrrolase activity, and decreases the activity of RNA polymerase (47). 

Tryptophan is also the initial substrate for the 5-hydroxytryptamine (serotonin) pathway (Fig. 1). Administration of hydrocortisone to the rat results in decreased serotonin levels in brain and induction of tryptophan pyrrolase activity in the liver (C16, K6). In the gerbil, in which corticosteroids do not induce hepatic tryptophan pyrrolase, hydrocortisone does not result in any change in brain serotonin concentrations (G6). Although these findings are not conclusive proof, they suggest that if tryptophan pyrrolase is induced, particularly in the liver, tryptophan in brain may be diverted from the serotonin pathway to the kynurenine pathway, resulting in decreased serotonin synthesis in brain (C16). 

An estrogen-progestin combination was shown (N3) to reduce brain serotonin concentrations in female rats. Similar changes occur with the estrous cycle (G9). Estrogens may induce tryptophan pyrrolase activity in liver (Bll), and this could divert tryptophan from the 5-hydroxytryp-tamine (serotonin) pathway (C16), as was discussed earlier. 

G8. Greengard, P., Kahnsky, H. J., and Manning, T. J., Tryptophan pyrrolase activity during pregnancy. Biochim. Biophys. Acta 156, 198-199 (1968). 

Psychiatric disorders (in so far as they can be explained by imbalances in neurochemicals) that accompany some of the porph)oias may be caused by a build-up in levels of ALA, which bears a structural resemblance to the neurotransmitter GABA (y-aminobutyric acid), and so could act as a neurotoxin. The heme deficiency that is brought on by the porphyrias, can lead to a reduction in the activity of hepatic (liver) enzymes that require heme. For example, reduction in the level of hepatic tryptophan pyrrolase activity leads to a build-up in levels of the amino acids tryptophan and 5-hydroxy-tryptophan. Thus, a heme-deficient state in the liver could produce biochemical abnormalities capable of leading to neurological dysfunction, while heme deficiency in nerve tissue could directly alter nerve function. This has led to the treatment of severe neurological dysfunction by intravenous administration of heme compounds. 

Table 8. Tryptophan pyrrolase activities in T(1 3) ras homozygotes, and heterozygotes (After Tobler et al., 1971)...

This very elegant hypothesis requires further proof. Mischke et al. (1975) could not induce tryptophane pyrrolase activity in fresh homogenates of the vermilion mutant of D, melanogaster and D. hydei, although the treatment was done in exactly the same manner as by Jacobson (1971). At the same time, enzyme activity could be induced almost to the wild-type level by homogenation of vermilion flies in the presence of 0.02M EDTA, the standard component in mixtures of ribonu-clease. The authors suggested that the tryptophane pyrrolase activity, stimulated by EDTA, is possibly derived from another enzyme (peroxidase, for instance), but not from the tryptophane pyrrolase molecule. 

Various minor hematological effects have been noted in animals. Rats exposed to 50-800 ppm of trichloroethylene continuously for 48 or 240 hours showed time- and dose-related depression of delta-aminolevulinate dehydratase activity in liver, bone marrow, and erythrocytes (Fujita et al. 1984 Koizumi et al. 1984). Related effects included increased delta-aminolevulinic acid (ALA) synthetase activity, reduced heme saturation of tryptophan pyrrolase and reduced cytochrome P-450 levels in the liver and increased urinary excretion of... 

The focus of this chapter is the reaction site of oxygenases (hemo-proteins) having heme as the prosthetic group. We discuss the oxygen activation in tryptophan pyrrolase (TPO) and cytochrome P-450 based on our experimental results using iron-porphyrin complexes as the model for the active site of these enzymes. 

Tryptophan Pyrrolase Model Reaction and Activation of Oxygen... 

Kim JH and Miller LL (1969) The functional significance of changes in activity of the enzymes, tryptophan pyrrolase and tyrosine transaminase, after induction in intact rats and in the isolated, perfused rat liver./owma/ of Biological Chemistry 244,1410-16. 

I.I. Newborn. It is known that some mammalian enzymes are absent in fetal life or may display a low activity only at the end of gestation whereas after birth their activity is enhanced to adult levels more or less rapidly. This is the case with tryptophan pyrrolase, a liver enzyme catalyzing the conversion of tryptophan to N -formylkynurenine, the first step of the kynurenine pathway. 

This fact has been explained (V4) in different ways. One possibility is that tryptophan pyrrolase is more active in the growing organism than in the adult. An accumulation of kynurenine can also be the result of relative insufiSciency of the later steps of enzyme activity in the kynuren-ine-nicotinic acid chain. 

This model has been applied to the inhibition of cholinesterase (9), the inhibition of water reabsorption by loop diuretics such as furosemide (9), tryptophan-mediated increase in hepatic activity of tryptophan pyrrolase (28), and the accumulation of lymphocytes in the peripheral lymphoid tissues by prednisolone (26). 

Figure 1. Absorption spectra of tryptophan pyrrolase. 0.96 mg. of tryptophan pyrrolase (specific activity 5.7) and 200 fxmoles of potassium phosphate buffer, pH 7.0, in 1.6 ml.

Valence State of Heme in Active Tryptophan Pyrrolase. The purified enzyme was found to be active in its ferrous form, whereas it was almost inactive in its ferric form. The ferric enzyme could be activated by adding an appropriate amount of ascorbate (Figure 2) or hydrogen peroxide in the presence of tryptophan as originally reported (16). These... 

Figure 2. Effect of ascorbate (Asc) on the activity of tryptophan pyrrolase. Fe, ferric enzyme Fe, ferrous enzyme...

We reported previously that the enzyme was reduced and activated by light under anaerobic conditions (7, 8). This finding was confirmed by Maeno and Feigelson (14). Using this phenomenon, we examined fmther the above-mentioned relationship between the redox state of the heme and the activity. As represented in Figure 3, reduction of the heme resulted in a proportional increase in the activity. Thus, the ferrous form is an active species of tryptophan pyrrolase. 

Figure 3. Relationship of the redox state of the heme in tryptophan pyrrolase to the activity of the enzyme...

Figure 5. Conversion of the ferric enzyme to cyanide complex in the presence and absence of tryptophan. Reaction mixture contained tryptophan pyrrolase, 0.47 mg. (specific activity 2.5) potassium phosphate buffer, pH 7.0, 1.1. mmoles i.-tryptophan, 0.28 mmoles in a jfinal volume of 28 ml. Cyanide was added in the presence (O) and absence ( X) of tryptophan as indicated...

The mechanism of hydroxylation of aromatic compounds catalyzed by peroxidase in the presence of DHF and Oo has been discussed by Mason et al. (i, 14, 15). Probably, the activated species of O2 is per-hydroxyl ion in this reaction (I), but the possible transfer of an oxygen atom from III to the organic molecule as suggested by Mason, may not be excluded (15). The similarity of this enzyme to tryptophan pyrrolase has been discussed. Now it is found that tryptophan pyrrolase shows... 

There is evidence that estrogen administration results in increased activity of tryptophan pyrrolase. This enzyme activity has been shown to be elevated in the livers of pregnant rats (A8, G8). There is some evidence also that a mestranol-norethynodrel combination has a greater stimulatory effect on tryptophan pyrrolase than does estradiol, and that progesterone alone is an inhibitor of the enzyme in rat liver (R15). 

Estrogens may modify the activity of enzymes in the kynurenine pathway other than the rate-limiting enzyme tryptophan pyrrolase. Mason and co-workers (M9, M12) have presented in vitro and in vivo evidence that estrogens may effect binding of PLP to the apoenzyme of kynurenine transaminase. 

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