Biosynthesis of serotonin

The biosynthesis of serotonin is similar to that of dopamine and also involves enzymatic hydroxylation and subsequent decarboxylation (Figure 10.2b). 

Cooper JR, Melcer I (1961) The enzymatic oxidation of tryptophan to 5-hydroxytryptophan in the biosynthesis of serotonin. J Pharmacol Exp Ther 132 265-268... 

One theory is that women with PMS are abnormally sensitive to progesterone secreted following ovulation, and that this reduces levels of pyridoxine. Pyridoxine is a coenzyme in the final step of the biosynthesis of serotonin, a neurotransmitter known to have potent effects on mood, and its deficiency may contribute to the depressive symptoms. 

Amino Acids and Their Metabolites as Neurotransmitters and Biological Regulators Biosynthesis of Serotonin and Catecholamines (Diagram, Figure 21.32)... 

FIGURE 13-5 The biosynthesis and catabolism of serotonin. Note that in the pineal gland, serotonin is converted enzymatically to melatonin. 

Eur J Neuropsychopharmacol 6 (suppl 3) 207, 1996 Julius D, McDermott AB, Axel R, et al Molecular characterization of a functional cDNA encoding the serotonin 1C receptor. Science 241 558-564, 1988 Jung-Testas 1, Hu ZY, Beaulieu EE, et al Neurosteroids biosynthesis of pregnenolone and progesterone in primary cultures of rat glial cells. Endocrinology 125 2083-2091, 1989... 

Specific decarboxylases for most of the common amino acids have been isolated. In mammals, a decarboxylase involved in the biosynthesis of neuroactive amines is particularly important. This enzyme decarboxylates 3,4-dihydroxyphenylalanine and 5-hydroxytryp-tophan (both products of tetrahydrobiopterin-dependent hydroxylations—Section 1.10.5.1) to give 3,4-dihydroxyphenethylamine and serotonin (equation 10), respectively (70MI11002). 

Histamine, serotonin and the catecholamines (dopamine, epinephrine and norepinephrine) are synthesized from the aromatic amino acids histidine, tryptophan and phenylalanine, respectively. The biosynthesis of catecholamines in adrenal medulla cells and catecholamine-secreting neurons can be simply summarized as follows [the enzyme catalysing the reaction and the key additional reagents are in square brackets] phenylalanine — tyrosine [via liver phenylalanine hydroxylase + tetrahydrobiopterin] —> i.-dopa (l.-dihydroxyphenylalanine) [via tyrosine hydroxylase + tetrahydrobiopterin] —> dopamine (dihydroxyphenylethylamine) [via dopa decarboxylase + pyridoxal phosphate] — norepinephrine (2-hydroxydopamine) [via dopamine [J-hydroxylasc + ascorbate] —> epinephrine (jV-methyl norepinephrine) [via phenylethanolamine jV-methyltransferase + S-adenosylmethionine]. 

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). 

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. 

Figure 29-2 Biosynthesis of catechoiamines and serotonin, and metabolism of serotonin to melatonin.

Martinez A, Knappskog PM, Haavik J. A structural approach into human tryptophan hydroxylase and its implications for the regulation of serotonin biosynthesis. Curr Med Chem 2001 8 1077-91. 

Other examples of PLP-requiring enzymes are the amino acid decarboxylases that lead to formation of amines, including several that are functional in nervous tissue (e.g., epinephrine, norepinephrine, serotonin, and y-aminobutyrate) cysteine desulfhydrase and serine hydroxymethyltransferase, which use PLP to effect the loss or transfer of amino acid side chains phosphorylase, which catalyzes phosphorolysis of the a-1,4-linkages of glycogen and cystathione beta-synthase in the transsulfiiration pathway of homocysteine. Additionally the biosynthesis of heme depends on the early... 

The fourth class, the pterin-dependent hydroxylases, includes the aromatic amino acid hydroxylases, which use tetrahydrobiopterin as cofactor for the hydroxylation of Phe, Tyr, and Trp. The latter two hydroxylases catalyse the rate-limiting steps in the biosynthesis of the neurotransmitters/hormones dopamine/noradreanalme/ adrenaline and serotonin, respectively. 

It was proposed that c-AMP acts as the messenger in the activity of PGE, on hypothalamic neurons, which in turn leads to fever. Aspirinlike drugs do not abolish the fever produced by PGE, injections into a cat s ventricles, but they will abolish fever caused by similar injections of serotonin and pyrogens in general. This, of course, makes sense if one considers the likelihood of E PGs as mediators of fever and that these drugs inhibit the biosynthesis of PGs rather than antagonizes their effects once formed. 

The elimination of a CO2 molecule from the substrate catalyzed by decarboxylases requires the stabilization of a carbanionic intermediate, a task often performed by enzymatic cofactors. Indeed, decarboxylation reactions on ct-amino acids are catalyzed mainly by PLP-dependent enzymes, with a small fraction of reactions catalyzed by enzymes that use a pyruvoyl cofactor." PLP-dependent decarboxylases are largely widespread among both eukaryotes and prokaryotes where they participate in the biosynthesis of biological amines (e.g., dopamine, histamine, and serotonine) and polyamines. In addition, in prokaryotes, inducible PLP-dependent decarboxylases take part in the regulation of intracellular pH." ... 

---