5-Hydroxytryptophan synthesis

Final examples of applications of our results (91CPB1905, 99H1157) in 1-hydroxytryptophan chemistry come from the work of Boger and co-workers (99JA6197) on the synthesis of HUN 7293 (293, Scheme 46) (96MI69) and from Kitahara and co-workers (200 IHl) on the synthesis of apicidin (301) (96TL8077). 

The precursor for the synthesis of 5-HT is the amino acid L-tryptophan, which is obtained from dietary protein (Fig. 2.2A). L-tryptophan is converted to 5-hydroxytryptophan (5-HTP) in serotonin neurons by the enzyme tryptophan... 

Following the synthesis of 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase, the enzyme aromatic amino acid decarboxylase (also known as 5-HTP or dopa decarboxylase) then decarboxylates the amino acid to 5-HT. L-Aromatic amino acid decarboxylase is approximately 60% bound in the nerve terminal and requires pyridoxal phosphate as an essential enzyme. 

Dietary tryptophan is the source of the formation of serotonin. Enzymes and cofactors necessary for serotonin synthesis are present in both the enterochromaf-lin cells of the gastrointestinal tract and neurons in the brain. Tryptophan is initially hydroxylated to form 5-hydroxytryptophan. Decarboxylation of the latter compound results in the formation of serotonin (Fig. 24.2). 

Before the identification of 5-hydroxytryptamine (5-HT), it was known that when blood is allowed to clot, a vasoconstrictor (tonic) substance is released from the clot into the serum. This substance was called serotonin. Independent studies established the existence of a smooth muscle stimulant in intestinal mucosa. This was called enteramine. The synthesis of 5-hydroxytryptamine in 1951 permitted the identification of serotonin and enteramine as the same metabolite of 5-hydroxytryptophan. 

The hereditary absence of phenylalanine hydroxylase, which is found principally in the liver, is the cause of the biochemical defect phenylketonuria (Chapter 25, Section B).430 4308 Especially important in the metabolism of the brain are tyrosine hydroxylase, which converts tyrosine to 3,4-dihydroxyphenylalanine, the rate-limiting step in biosynthesis of the catecholamines (Chapter 25), and tryptophan hydroxylase, which catalyzes formation of 5-hydroxytryptophan, the first step in synthesis of the neurotransmitter 5-hydroxytryptamine (Chapter 25). All three of the pterin-dependent hydroxylases are under complex regulatory control.431 432 For example, tyrosine hydroxylase is acted on by at least four kinases with phosphorylation occurring at several sites.431 433 4338 The kinases are responsive to nerve growth factor and epidermal growth factor,434 cAMP,435 Ca2+ + calmodulin, and Ca2+ + phospholipid (protein kinase C).436 The hydroxylase is inhibited by its endproducts, the catecholamines,435 and its activity is also affected by the availability of tetrahydrobiopterin.436... 

Serotonin is synthesized via tryptophan and 5-hydroxytryptophan with decarboxylation of the latter (Fig. 25-12). Within the pineal body of the brain and in the retina, serotonin is acetylated to N-acetylseroto-nin,782/783 which is then O-methylated to melatonin, the pineal hormone (Fig. 25-12). A specific inhibitor of serotonin synthesis is p-chlorophenylalanine, and studies with this and other inhibitors suggest that serotonin is required for sleep.784... 

Ribeiro, P. and Webb, R.A. (1 984) The occurrence, synthesis and metabolism of 5-hydroxytryptamine and 5-hydroxytryptophan in the cestode Hymenolepis diminuta. Comparative Biochemistry and Physiology C 79, 159-164. 

Schmidt U, Weinbrenner S (1996) What is the Structure of the Calmodulin Antagonist Konbamide from Theonella sp. Synthesis of Two Isomers by Direct Biomimetic Introduction of Bromine in Hydroxytryptophan-Containing Cyclic Peptides. Angew Chem Int Ed Engl 35 1336... 

Homolytic substitution of heteroaromatic compounds, 16, 123 Hydantoins, chemistry of, 38, 177 Hydrogen cyanide derivatives, synthesis of heterocycles from, 41, 1 Hydrogen exchange base-catalyzed, 16, 1 one-step (labeling) methods, 15, 137 Hydrogenated porphyrin derivatives hydroporphyrins, 43, 73 Hydroxamic acids, cyclic, 10, 199 1 -Hydroxyindoles, 1 -hydroxytryptophans, and 1-hydroxytryptamines,... 

Ribeiro, P. Webb, R. A. (1983a). The synthesis of 5-hydroxytryptamine from tryptophan and 5-hydroxytryptophan in the cestode Hymenolepis diminuta. International Journal for Parasitology, 13 101-6. 

PAH, a nonheme iron-containing enzyme, is a member of a larger BI Independent amino acid hydroxylase family. In addition to PAH, the enzyme family includes tyrosine hydroxylase and tryptophan hydroxylase. The enzymes in this family participate in critical metabolic steps and are tissue specific. PAH catabolizes excess dietary PA and synthesizes tyrosine. In adrenal and nervous tissue, tyrosine hydroxylase catalyzes the initial steps in the synthesis of dihydrox-yphenylalanine. In the brain, tryptophan is converted to 5-hydroxytryptophan as the first step of serotonin synthesis. Consequently, these enzymes are highly regulated not only by their expression in different tissues but also by reversible phosphorylation of a critical serine residue found in regulatory domains of the three enzymes. Since all three enzymes are phosphorylated and dephosphorylated by different kinases and phosphatases in response to the need for the different synthetic products, it is not unexpected that the exact regulatory signal for each member of the enzyme family is unique. 

In saprophytic cultures of the Pennisetum ergot fungus, only tryptophan, deuterated in the 5 or 6 position, was used for the synthesis of the clavine alkaloids without loss of the deuterium. Deuterium in the 4 position was lost. These experiments showed that the hypotheses, according to which 5-hydroxytryptophan would be an intermediate stage in the biosyntheses (126, 127), could not be correct (128). 

The other characteristic feature of pellagra is the development of a depressive psychosis, superficially similar to schizophrenia and the organic psychoses, but clinically distinguishable by the sudden lucid phases that alternate with the most florid psychiatric signs. The mental symptoms may be the result of tryptophan depletion, and hence a lower availability of tryptophan for synthesis of the neurotransmitter serotonin (5-hydroxytryptophan). But the role of cADP-ribose and NAADP in controlling calcium release in response to neurotransmitters (Section 8.4.4) and impaired energy-yielding metabolism in the central nervous system as a result of depletion of NAD (P) may also be important. 

Pyridoxine plays a role in (1) the control of the hypothalamo-pituitary end-organ system, (2) melatonin synthesis, and (3) convulsive seizure activity. Neurological deficits resulting from pyridoxine deficiency can largely be explained by decreased activity of glutamic acid decarboxylase, 5-hydroxytryptophan decarboxylase, and ornithine decarboxylase (Dakshinamurti et al., 1990). The products of these... 

The synthesis of 5-HT from tryptophan in serotonergic neurons occurs in two steps. First, the enzyme tryptophan hydroxylase catalyzes the conversion of tryptophan to 5-hydroxytryptophan (5-HTP). Then, the enzyme aromatic amino acid decarboxylase catalyzes the conversion of 5-FlTP to serotonin. 

Catecholamines are synthesized from the amino acid tyrosine, and serotonin from tryptophan as shown in Figure 29-2. The rate-limiting step in catecholamine biosynthesis involves conversion of tyrosine to 3,4-dihydroxyphenylalanine (L-dopa) by the enzyme, tyrosine hydroxylase. A related enzyme, tryptophan hydroxylase, catalyzes conversion of tryptophan to 5-hydroxytryptophan in the first step of serotonin synthesis. 

D. Because of the DHPR deficiency, the activities of Phe hydroxylase and Tyr hydroxylase are low, hence the synthesis of catecholamine neu-rotransmitters are depressed. The synthesis of the indoleamine neurotransmitter serotonin is also depressed because BH is required for the hydroxylation of tryptophan. The best treatment is to decrease the Phe load by a low-Phe diet and provide the precursors for the catecholamine and indoleamine neurotransmitters that occur after the enzymes affected by the deficiency of BH, which would be L-dopa and 5-hydroxytryptophan. 

Tetrahydrobiopterin (BH4) is required in the synthesis of neurotransmitters such as norepinephrine and serotonin, which are produced in brain. BH4 is required in the reaction catalyzed by tyrosine hydroxylase in which tyrosine is hydrox-ylated to form L-dopa (a precursor of several neurotransmitters including dopamine and norepinephrine), and the reaction catalyzed by tryptophan hydroxylase in which tryptophan is hydroxylated to form 5-hydroxytryptophan. L-Dopa and 5-hydroxytryptophan must be supplied to individuals lacking the capacity to synthesize BH4 because the latter molecule does not cross the blood-brain barrier. 

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). 

Fig (2). Aromatic L-amino acid decarboxylase also known as tryptophan decarboxylase, catalyses the synthesis of 5-bydnoxyiriplaminc (serotonin) from 5-hydroxytryptophan. lire reaction consists of a decarboxylation activity that is found in many human tissue cells... 

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