Reduction of tryptophan

The effects of a short-term tryptophan depletion were examined in 15 patients with OCD who had responded to treatment with various SRIs such as CMI, fluvoxamine, and fluoxetine. These patients underwent tryptophan depletion under double-blind, placebo-controlled conditions. Reduction of tryptophan had no significant effects on either obsessions or compulsions, but mean depression ratings were significantly increased during tryptophan depletion [Barr et al. 1994]. 

Scheme XVI. Tritium distribution in pyridoxylalanine derived from sodium [3H]borohydride reduction of tryptophan synthase in the presence of (3/ )-[3-2H]serine and indolepropanol phosphate.

Injection of 5,6-dihydroxytryptamine (5,6-DHT) in laboratory rats, produces profound reduction of tryptophan hydroxylase in the brain and spinal cord. A week following the injection hydroxylase activity returns to normal in most of the brain, but not in the spinal cord. 

Injection of 5,7-dihydroxytryptamine in the rat induced a reduction of tryptophan hydroxylase in all regions of the brain. It also caused depletion of norepinephrine, but did not deplete dopamine. The pretreatment of laboratory animals with desmethylimipramine (desipramine) blocked the neurotoxic reaction to the norepinephrine reuptake system, but did not protect the serotonergic reuptake system. (Lovenburg 1978). 

Neckers, L. M., Bertilsson, L., Koslow, S. H., and Meek, J. L., 1976, Reduction of tryptophan hydroxylase activity and 5-hydroxytryptamine concentration in certain rat brain nuclei after / -chloroamphetamine, /. Pharmacol. Exp. Ther. 196 333-338. 

Y. Kikugawa. Chemistry of amine-boranes. Part 3. Reduction of tryptophan derivatives with pyridine-borane. J. Ghem. Research (5), 1978, 184. 

Tryptophans can also be prepared by reduction of a,(3-dehydrotryptophans. These can be obtained by a classical azlactone type synthesis from derivatives of indole-3-carboxaldehyde. These reactions usually rquire an iV-EW substituent and the yields are modest[15]. 

Niacin was discovered as a nutrient during studies of pellagra. It is not strictly a vitamin since it can be synthesized in the body from the essential amino acid tryptophan. Two compounds, nicotinic acid and nicotinamide, have the biologic activity of niacin its metabolic function is as the nicotinamide ring of the coenzymes NAD and NADP in oxidation-reduction reactions (Figure 45-11). About 60 mg of tryptophan is equivalent to 1 mg of dietary niacin. The niacin content of foods is expressed as mg niacin equivalents = mg preformed niacin + 1/60 X mg tryptophan. Because most of the niacin in cereals is biologically unavailable, this is discounted. 

Typically, neurotoxic effects of drugs on monoamine neurons have been assessed from reductions in brain levels of monoamines and their metabolites, decreases in the maximal activity of synthetic enzymes activity, and decreases in the active uptake carrier. In the present study, the traditional markers described above have been used, including the measurement of the content of monoamines and their metabolites in brain at several different timepoints following drug administration. Since reports in the literature have documented that MDMA and MDA can inhibit the activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis (Stone et al. 1986 Stone et al. 1987). it is unclear whether MDMA-induced reductions in the content of serotonin and its metabolite 5-hydroxyin-doleacetic acid (5-HlAA) may be due to suppressed neurotransmission in otherwise structurally intact serotonin neurons or may represent the eonsequenee of the destruction of serotonin neurons and terminals. 

Hanson, G.R., Gibb, J.W., Metzger, R.R., Kokoshka, J.M., Fleckenstein, A.E. Methamphetamine-induced rapid and reversible reduction in the activities of tryptophan hydroxylase and dopamine transporters oxidative consequences Ann. N.Y.Acad. Sci. 844 103, 1998. 

In animal studies, high levels of cortisol have been shown to induce (increase) the activity of the enzyme tryptophan 2,3-dioxygenase in the liver, thereby decreasing the bioavailability of tryptophan to the brain. It is interesting to note that low acute doses of a number of different antidepressants inhibit the activity of this enzyme and, as a result, increase brain tryptophan concentrations, thus stimulating 5-HT synthesis (Badawy and Evans, 1982). In this way a link between the two key monoamine neurotransmitters and the hormone may be seen namely, reduced brain NA activity leads to decreased inhibition of the HPA axis, while increased levels of cortisol reduce 5-HT activity in the brain. Activation of the HPA axis has also been shown to result in tissue atrophy, in particular of the limbic system s hippocampus, and a reduction in the levels of neurotrophic factors responsible for the maintenance and optimal function of brain neurons (Manji et al., 2001). In conclusion, manipulation of the HPA axis (Nemeroff, 2002) and stimulation of neurotrophic factor activity (Manji et al., 2001) might open up new avenues for the treatment of affective disorders. 

There is always interest in the photochemistry of the pyrimidine nucleic acid bases and related simple pyrimidinones, due to its importance in genetic mutation. In addition to damaging DNA, photo-induced reactions may also repair the damage, as in the reduction, by FADH, of the thymine glycol 64 back to thymine <06JACS10934>. Another report related to repair of DNA involved a model study, by means of the linked dimer 65, of the involvement of tryptophan in the electron-transfer leading to reversion of thymine oxetane adducts <06OBC291>. 

There is probably one more mechanism of MPO-mediated lipid peroxidation. Kettle and Candaeis [174] have studied the oxidation of tryptophan by neutrophil MPO. They suggested that tryptophan, which is present in plasma at the similar concentration as tyrosine and has a similar one-electron reduction potential, can contribute to oxidative stress at inflammation sites. It was proposed that the formed tryptophan free radicals may stimulate oxidative stress during inflammation. 

The initial hydroxylation of tryptophan, rather than the decarboxylation of 5-HTP, appears to be the rate-limiting step in serotonin synthesis. Therefore, the inhibition of this reaction results in a marked depletion of the content of 5-HT in brain. The enzyme inhibitor most widely used in experiments is parachlorophenylalanine (PCPA). In vivo, PCPA irreversibly inhibits tryptophan hydroxylase, presumably by incorporating itself into the enzyme to produce an inactive protein. This results in a long-lasting reduction of 5-HT levels. Recovery of enzyme activity, and 5-HT biosynthesis, requires the synthesis of new enzyme. Marked increases in mRNA for tryptophan hydroxylase are found in the raphe nuclei 1-3 days after administration of PCPA [6]. 

An interesting example of asymmetric induction has been used for the synthesis of (—)-l from L-tryptophan. Pictet-Spengler cyclization of the corresponding amide (127) with 5-chloropentanal afforded (—)-128 as the sole product. Removal of the unwanted carboxamide function was achieved in good yield by sodium borohydride reduction of die corresponding a-amino nitrile (—)-129, resulting in (—)-l (98). 

Tyrosine fluorescence emission in proteins and polypeptides usually has a maximum between 303 and 305 nm, the same as that for tyrosine in solution. Compared to the Stokes shift for tryptophan fluorescence, that for tyrosine appears to be relatively insensitive to the local environment, although neighboring residues do have a strong effect on the emission intensity. While it is possible for a tyrosine residue in a protein to have a higher quantum yield than that of model compounds in water, for example, if the phenol side chain is shielded from solvent and the local environment contains no proton acceptors, many intra- and intermolecular interactions result in a reduction of the quantum yield. As discussed below, this is evident from metal- and ionbinding data, from pH titration data, and from comparisons of the spectral characteristics of tyrosine in native and denatured proteins. 

Other groups within the protein may affect excited states. Disulfide bonds quench the excited states of tryptophan. For instance, at 77 K the phosphorescence lifetime of native lysozyme is low, 1.4s reduction of the disulfide bonds or denaturation gave the typical phosphorescence lifetime of 5.6 s.(49) Therefore, the absence of phosphorescence at room temperature from this protein is likely to be due to quenching of both the singlet and the triplet state. 

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