Tryptophan hydroxylase TPH

This similarity between MDMA and PCA is also observed in vivo in that PCA produces both an acute and long-term depletion of 5-HT (Fuller et al. 1975 Steranka et al. 1977). Like PCA, the acute decrease in 5-HT concentrations produced by MDMA is associated with a decrease in the activity of the rate-limiting enzyme for 5-HT synthesis, tryptophan hydroxylase (TPH). The timecourse of this change in cortical enzyme activity is also shown in figure 1. More detailed analysis of this acute effect of MDMA and kinetic analysis of TPH activity reveals that the decrease in enzyme activity actually precedes the decline in transmitter levels and is due to a reduction in the activity of the enzyme (Schmidt and Taylor 1987 Schmidt and Taylor 1988). As shown for the cortex in figure 3, the decrease in 5-HT... 

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. 

The first step of 5-HT biosynthesis is catalyzed by the rate-hmiting enzyme tryptophan hydroxylase (TPH). Two isoforms, TPHl and TPH2, have been identified in the periphery and in 5-HT neurons, respectively. Both isoforms are members of the aromatic amino acid hydroxylase gene family, together with phenylalanine (PAH) and tyrosine hydroxylases (TH). The human TPHl gene located on chromosome llplS.l, spans a region of 30 kb, contains at... 

Genes encoding for the biosynthesis and catabolism of neurotransmitters Tryptophan hydroxylase (TPH)... 

The aromatic amino add hydroxylases (AAHs) are a family of pterin-dependent enzymes comprising phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH), and tryptophan hydroxylase (TPH, with two gene products TPH1 and TPH2). The AAHs perform the hydroxylation of aromatic amino adds and play an important role in mammalian metabolism and in the biosynthesis of... 

One of the best characterized physiological functions of (6R)-tetrahydrobio-pterin (BH4, 43) is the action as a cofactor for aromatic amino acid hydroxylases (Scheme 28). There are three types of aromatic amino acid hydroxylases phenylalanine hydroxylase [PAH phenylalanine monooxygenase (EC 1.14.16.1)], tyrosine hydroxylase [TH tyrosine monooxygenase (EC 1.14.16.2)] and tryptophan hydroxylase [TPH tryptophan monooxygenase (EC 1.14.16.4)]. PAH converts L-phenylalanine (125) to L-tyrosine (126), a reaction important for the catabolism of excess phenylalanine taken from the diet. TH and TPH catalyze the first step in the biosyntheses of catecholamines and serotonin, respectively. Catecholamines, i.e., dopamine, noradrenaline and adrenaline, and serotonin, are important neurotransmitters and hormones. TH hydroxylates L-tyrosine (126) to form l-DOPA (3,4-dihydroxyphenylalanine, 127), and TPH catalyzes the hydroxylation of L-tryptophan (128) to 5-hydroxytryptophan (129). The hydroxylated products, 127 and 129, are decarboxylated by the action of aromatic amino acid decarboxylase to dopamine (130) and serotonin (131), respectively. 

HT has long been associated with emotion and anxiety (37). 5-HT is synthesized from tryptophan by the rate-limiting enzyme tryptophan hydroxylase (TPH) in serotonergic neurons in the raphe. Release of 5-HT is controlled by the 5-HTia and 5-HTib autoreceptors located at the somatodendritic compartment and axon terminals, respectively. In addition, the synaptic and extracellular levels of 5-HT are regulated by the 5-HT transporter (5-HTT). Genetic risk for anxiety has been associated with all of these macromolecules. 

Not only is methamphetamine administration toxic to the dopaminergic system, but the serotonergic system in the various brain areas is also altered. Hotchkiss and Gibb (1980) reported that methamphetamine, administered as described above, decreased tryptophan hydroxylase (TPH) activity in the serotonergic nerve terminal of rat brain and spinal cord. Similarly, the content of 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindole acetic acid (5-HIAA) were also severely depressed. In contrast to the effects in the dopaminergic system, these serotonergic parameters were decreased by methamphetamine within 15 minutes after a single dose... 

The synthesis of serotonin from tryptophan is carried out in two steps controlled by two enzymes tryptophan hydroxylase (TPH) and aromatic L-amino acid decarboxylase (AADC). The second enzyme, A ADC, is also known as DOPA carboxylase or 5-hydroxytryptophan carboxylase when it acts specifically in 5-HT synthesis. In the first step, the TPH adds a hydroxyl chemical group (OH) to tryptophan to make 5-hydroxytryptophan, Fig (1). In the second step, AADC removes the carboxyl group (-COOH) from 5-hydroxy tryptophan to make serotonin. Fig (2). 

We have mentioned in the second section of this review that tryptophan hydroxylase (TPH) is the rate limiting enzyme in the synthesis of 5-HT. The human TPH gene was localized to chromosome Ilpl4-pl5.3. The enzyme is tetrameric [88]. A polymorphism within intron 7 has been detected and that may influence 5-HT metabolism in the brain [89]. Hong et al [90] described an association between the TPH gene polymorphism (A218C) and schizophrenia. At present there are no association studies of autism and this polymorphism. However, the fact that the ontogeny of... 

Fig. 1.1. Biosynthesis and regeneration of tetrahydrobiopterin including possible metabolic defects and catabolism of phenylalanine. l.l=phenylalanine-4-hydroxylase (PAH) 1.2/1.6 = GTP cyclohydrolase I (GTPCH), 1.3 = 6-pyruvoyl-tetra-hydropterin synthase (PTPS), 1.4 = dihydropteridine reductase (DHPR), 1.5 = pterin-4a-carbinolamine dehydratase (PCD), 1.7 = sepiapterin reductase SR, carbonyl reductase (CR), aldose reductase (AR), dihydrofolate reductase (DHFR), aromatic amino acid decarboxylase (AADC), tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), nitric oxide synthase (NOS). Pathological metabolites used as specific markers in the differential diagnosis are marked in squares. n.e.=non-enzymatic...

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