Tryptophan hydroxylation

L-Tryptophan provides the anthranilate part of the molecule, most probably via a diversion of the classic pathway which forms 3-hydroxyanthranilate from L-tryptophan. Hydroxylation at C-8 of the antibiotic occurs prior to hydroxylation at C-7 and is accompanied by an NIH shift (27). The 8-methyl group of an-thramycin as well as the 7-methoxy carbon of 1 l-demethyltomaymycin are derived from methionine. 

Nilsson GE, Tottmar O (1989) Effects of disulfiram and coprine on rat brain tryptophan hydroxylation in vivo. Neurochem Res 14 537-540... 

The hydroxylation pathway of tryptophan. The pathway of tryptophan hydroxylation in the 5 position and its products are shown above. These include the formation of serotonin and its degradation product, 5-hydroxyindole acetate, as well as melatonin formation. (See text for more detail.)... 

Bengtsson F, Bugge M, Johansen KH, Butterworth RF. Brain tryptophan hydroxylation in the portacaval shunted rat A hypothesis for the regulation of serotonin turnover in vivo. J. Neurochem., 56, 1069-1074, 1991... 

Lovenberg, W., Tryptophan hydroxylation in mammalian tissues. Symposium Biological Role of Indolealkylamine Derivatives, New York, 1967. 

L-tryptophan by hydroxylation to 5-hydroxy-L-tryptophan by the enzyme, ttyptophan-5-hydroxylase. 5-Hydroxy-L-tryptophan is then rapidly decarboxylated by aromatic-L-amino acid deacarboxylase to 5-HT. The actions of 5-HT as a neurottansmitter ate terminated by neuronal reuptake and metabobsm. 

The first objective was the conversion of L-tryptophan into a derivative that could be converted to pyrroloindoline 3, possessing a cis ring fusion and a syn relationship of the carboxyl and hydroxyl groups. This was achieved by the conversions shown in Scheme 1. A critical step was e. Of many variants tried, the use of the trityl group on the NH2 of tryptophan and the t-butyl group on the carboxyl resulted in stereospecific oxidative cyclization to afford 3 of the desired cis-syn stereochemistry in good yield. 

Following hydroxylation of tryptophan to 5-hydroxy-tryptophan by hver tyrosine hydroxylase, subsequent decarboxylation forms serotonin (5-hydroxytrypta-... 

The first step in the synthesis of 5-HT is hydroxylation of the essential amino acid, tryptophan, by the enzyme tryptophan hydroxylase (Fig. 9.4). This enzyme has several features in common with tyrosine hydroxylase, which converts tyrosine to /-DOPA in... 

Figure 9.4 The synthesis and metabolism of 5-HT. The primary substrate for the pathway is the essential amino acid, tryptophan and its hydroxylation to 5-hydrox5dryptophan is the rate-limiting step in the synthesis of 5-HT. The cytoplasmic enzyme, monoamine oxidase (MAOa), is ultimately responsible for the catabolism of 5-HT to 5-hydroxyindoleacetic acid...

The product of the hydroxylation of tryptophan, 5-hydroxytryptophan, is rapidly decarboxylated to 5-HT by a specific decarboxylase enzyme. This is generally thought to be a soluble enzyme which suggests that 5-HT is synthesised in the cytoplasm, before it is taken up into the storage vesicles. If this is the case, then considerable losses might be incurred from its metabolism by monoamine oxidase before it reaches the storage vesicles. Indeed, this could explain why 5-HT turnover seems to greatly exceed its rate of release. 

Figure 13.7 Synthesis and structure of the trace amines phenylethylamine, /)-tyramine and tryptamine. These are all formed by decarboxylation rather than hydroxylation of the precursors of the established monoamine neurotransmitters, dopamine and 5-HT. (1) Decarboxylation by aromatic L-amino acid decarboxylase (2) phenylaline hydroxylase (3) tyrosine hydroxylase (4) tryptophan hydroxylase...

Oxygenation and hydroxylation of a wide variety of biological materials almost always involves the participation of a metal ion, usually iron and sometimes copper. In one unique case, tryptophane pyrrolase, the iron is present as heme (75). The only dioxygenase enzyme reaction in which a metal ion has not been implicated is one involved in the degradation of vitamin B6 (16). 

The structure of the major trimeric LHCII complex has been recently obtained at 2.72 A (Figure 7.3) (Liu et al., 2004). It was revealed that each 25kDa protein monomer contains three transmembrane and three amphiphilic a-helixes. In addition, each monomer binds 14 chlorophyll (8 Chi a and 6 Chi b) and 4 xanthophyll molecules 1 neoxanthin, 2 luteins, and 1 violaxanthin. The first three xanthophylls are situated close to the integral helixes and are tightly bound to some amino acids by hydrogen bonds to hydroxyl oxygen atoms and van der Waals interactions to chlorophylls, and hydrophobic amino acids such as tryptophan and phenylalanine. 

The functional groups of the enzyme involved in the chemical bonding are the TV-terminal and s-amino groups (from lysine) as well as the carboxy-(aspartic or glutamic acid), sulfhydryl- (cysteine), hydroxyl- (serine, threonine), indole (tryptophan), imidazole (hystidine) and phenolic (tyrosine) functions. 

Serotonin is synthesized from tryptophan in two steps. Tryptophan is hydroxylated by tryptophan hydroxylase, and 5-hydroxytryptophan is decarboxylated to give serotonin. Most serotonin in the body is found in the enterochromaffin cells of the intestinal tract and the pineal gland. Platelets take up and store serotonin but do not synthesize it. 

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]. 

In rare instances, PKU is caused by defects in the metabolism of BH4, which is synthesized from GTP via sepiapterin (Fig. 40-2 reactions 3 and 4) [25]. Even careful phenylalanine restriction fails to avert progressive neurological deterioration because patients are unable to hydroxylate tyrosine or tryptophan, the synthesis of which also requires tetrahydrobiopterin. Thus, neurotransmitters are not produced in sufficient amount. 

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