5- Hydroxytryptamine biosynthesis

Ashley, D. V., Fleury, M. O., Golay, A., Maeder, E., and Leathwood, P. D. (1985). Evidence for diminished brain 5-hydroxytryptamine biosynthesis in obese diabetic and non-diabetic humans. Am. J. Clin. Nutr. 42,1240-1245. 

Rudolph, G. Wioland, N., Kempf., and Bonaventure, N. 1990. EOG and ERG modifications induced in the chicken eye after blockade of catecholamine and 5-hydroxytryptamine biosynthesis. Doc. Qphthal. 76 47-53. 

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... 

Purines and pyrimidines are derived largely from amino acids. The biosynthesis of these precursors of DNA, RNA, and numerous coenzymes will be discussed in detail in Chapter 25. The reactive terminus of sphingosine, an intermediate in the synthesis of sphingolipids, comes from serine. Histamine, a potent vasodilator, is derived from histidine by decarboxylation. Tyrosine is a precursor of the hormones thyroxine (tetraiodothyronine) and epinephrine and of melanin, a complex polymeric pigment. The neurotransmitter serotonin (5-hydroxytryptamine) and the nicotinamide ring of NAD + are synthesized from tryptophan. Let us now consider in more detail three particularly important biochemicals derived from amino acids. 

Tryptophan (fig. 8) is one of the twenty amino acids used by all of life on Earth to build proteins. Although plants, fungi, bacteria, and some other organisms can biosynthesize tryptophan from smaller carbon molecules, humans cannot and must ingest tryptophan as part of their diet. That is, tryptophan is one of the essential amino acids. In fungi and plants, tryptophan is the chemical precursor for the biosynthesis of tryptamines such as DMT and psilocybin. In humans and other animals, tryptophan is the precursor for the synthesis of the neurotransmitter serotonin, 5-hydroxytryptamine (5-HT fig. 9). 

Bone EA, Best LC, Jones PBB, et al. 1980. The effects of strontium and calcium ions on 5-hydroxytryptamine secretion and thromboxane B2 biosynthesis in washed human platelets. Biochem Soc Trans 8(5) 530-531. 

Serotonin, or 5-hydroxytryptamine (5-HT), is another monoamine whose important central effects have only been recognized recently. It had previously been known as a vasoconstrictor in the plasma. Once identified chemically, it was found to be widely distributed in the body. After determination of significant brain levels in the hypothalamus, medulla, midbrain, and other areas (Table 12-3), and after establishing its biosynthetic paths, serotonin became recognized as a neurotransmitter. 5-HT is presently less well understood than are the catecholamines. Figure 12-3 outlines its biosynthesis from the essential amino acid tryptophan. Try enters the brain by active transport (as is L-dopa) and is hydroxylated there by tryptophan hydroxylase, which is an enzyme similar to if not identical to, tyrosine hydroxylase. 

DDC catalyzes the conversion of L-3,4-dihydroxyphenylalanine (l-DOPA) into dopamine (Figure 10), a neurotransmitter found in the nervous system and peripheral tissues of both vertebrates and invertebrates and also in plants where it is implicated in the biosynthesis of benzylisoquinoline alkaloids. " DDC also catalyzes the decarboxylation of tryptophan, phenylalanine, and tyrosine and of 5-hydroxy-L-tryptophan to give 5-hydroxytryptamine (serotonin), and, therefore, is also referred to as aromatic amino acid decarboxylase. Inhibitors of DDC, for example, carbiDOPA and benserazide, are currently used in the treatment of Parkinson s disease to increase the amount of l-DOPA in the brain. 

The latter possibility was reconsidered more recently by Stijve (755, 765). According to his observations, psilocybin in Psilocybe semilance-ata ind in five Inocybe species was accompanied by its precursor baeo-cystine, which may indicate that during biosynthesis phosphorylation precedes methylation in conformity with the sequence tryptophan tryptamine — 4-hydroxytryptamine norbaeocystine baeocystine ... 

Tyrosine is either used for the biosynthesis of proteins, thyroxine, epinephrine, or melanin, or catabo-lized to yield fumaryl acetoacetate. The biosynthesis of proteins and thyroxine is discussed elsewhere this discussion is restricted to epinephrine and melanin synthesis and tyrosine catabolism. Dopa 3,4-dihydroxy-phenylalanine is an intermediate common to epinephrine and melanin. To yield epinephrine, dopa is first decarboxylated by an enzyme called dopa decarboxylase. This enzyme is present in several mammalian tissues, including the adrenal medulla, where the reaction yields hydroxytryptamine chloride. From this... 

It is really difficult to interpret and match the data obtained through submerged cultural condition with that of fruit bodies grown in wild to ascertain the biosynthesis mechanism. Some observations indicate that surface cultures of Psilocybe semilanceata have a high hydroxylation and phosphorylation capacity, although the ability to methylate tryptamine derivatives is low. These findings are in accordance with the earlier mentioned hypothesis that the fungus may have alternate route to convert 4-hydroxytryptamine to psilocybin. 

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