5-Hydroxytryptamine serotonin derivatives

Important products derived from amino acids include heme, purines, pyrimidines, hormones, neurotransmitters, and biologically active peptides. In addition, many proteins contain amino acids that have been modified for a specific function such as binding calcium or as intermediates that serve to stabilize proteins—generally structural proteins—by subsequent covalent cross-hnk-ing. The amino acid residues in those proteins serve as precursors for these modified residues. Small peptides or peptide-like molecules not synthesized on ribosomes fulfill specific functions in cells. Histamine plays a central role in many allergic reactions. Neurotransmitters derived from amino acids include y-aminobutyrate, 5-hydroxytryptamine (serotonin), dopamine, norepinephrine, and epinephrine. Many drugs used to treat neurologic and psychiatric conditions affect the metabolism of these neurotransmitters. 

Serotonin is an indolamine neurotransmitter, derived from the amino acid L-tryptophan. Tryptophan is converted to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase. 5-HTP is converted to 5-hydroxytryptamine (serotonin, 5-HT) by aromatic amino acid decarboxylase. In the pineal gland, 5-HT may be further converted to /V-acetyl serotonin by 5-HT /V-acetyltransferase and then to melatonin by 5-hyroxyindole-O-methyltransferase. 5-HT is catabolized by monoamine oxidase, and the primary end metabolite is 5-hydroxyindoleacetic acid (5-HIAA). 

Tryptamine and its Al-methyl and A/Al-dimethyl derivatives (Figure 6.70) are widely distributed in plants, as are simple hydroxylated derivatives such as 5-hydroxytryptamine (serotonin). These are formed (Figure 6.70) by a series of decarboxylation, methylation, and hydroxylation reactions, though the sequences of these reactions are found to vary according to final product and/or... 

The neurohumoral effects of the ergot alkaloids are manifested in an antagonism to adrenaline and noradrenaline on the one hand and to 5-hydroxytryptamine (serotonin) on the other. The adrenolytic elfect accounts for the use of the ergot alkaloids in internal medicine for the treatment of sympathetic overexcitation. The antagonism of the natural alkaloids to serotonin was discovered only in recent years, as it is not present to a marked degree. However, as will be shown subsequently, certain derivatives exhibit a marked and specific antagonism to serotonin. 

Since they are tryptamine derivatives, the indolic hallucinogens are structurally related to the neurohumoral factor serotonin (5-hydroxytryptamine). Serotonin is widely distributed in warmblooded animals. It accumulates in the brain, where it plays a role in the biochemistry of nervous regulations. Consequently, it seems that certain tryptamine structures which occur so frequently in hallucinogens, as well as in the neurohormone serotonin, may be biochemically important in the metabolism of psychic functions. . . ... 

The simplest unsubstituted indole and its methyl derivative, scatol, were found in some Lepiota and Tricholoma species. The probable biogenetic precursor of all indole metabolites is the amino acid tryptophan, widely distributed in fungi, or its derivative tryptamine, found in some species of Coprinus, Inocybe, Panaeolus, Sacrodon, and Boletus (7). Investigation of a strong biological activity characteristic of an animal hormone function revealed the presence 5-hydroxytryptamine (serotonin), which was found in large amounts in some Panaeolus and Amanita species. 

Three important neurotransmitters are derived from aromatic L-amino adds by decarboxylation followed by hydroxylation. Likewise, the ergoline ring system is derived from L-tryptophan, which has been decorated (prenylated and iV-methyl-ated), and decarboxylated in the process. The implication of this similarity in origins is that structures of noradrenaline, dopamine and 5-hydroxytryptamine (serotonin) can be mapped almost entirely onto the ergoline ring structure. This, it is believed, is why many clavine and EA can interact with receptors for all three of these neurotransmitters (102). 

Acetylcholine is formed from choline (which is also an important constituent of phospholipids) and acetyl CoA under the catalytic influence of choline acetyl-ase. It is hydrolised by acetylcholinesterase or choline esterase. Two important steps in the formation of noradrenaline from tyr dopa decarboxylase and dopamine hydroxylase. Adrenaline is formed from noradrenaline by phenyl ethanolamine A -methyltransferase. Both noradrenaline and adrenaline are metabolised by catechol 0-methyl transferase or monoamine oxidase. Some later steps in their metabolism involve aldehyde dehydrogenase and alcohol dehydrogenase (aldehyde reductase), After hydroxylation to its 5-hydroxy derivative, tryptophan is converted by 5-hydroxytryptophan decarboxylase to 5-hydroxytryptamine (serotonin). The major routes of serotonin metabolism involve either monoamine oxidase or hydroxyindole 0-methyltransferase. Histamine is synthesised from histidine by histidine decarboxylase, and is metabolised by either diamine oxidase or histamine Af-methyltransferase. Gamma aminobutyric acid is formed by glutamate decarboxylase and metabolised by... 

Serotonin or 5-hydroxytryptamine is an important biogenic amine, which is synthesized via 5-hydroxy-tryptophan from the amino acid tryptophan. The highest concentration of serotonin occurs in the wall of the intestine. About 90% of the total amount is present in enterochromaffrn cells, which are derived from the neural crest, similarly to those of the adrenal medulla. 

Inflammation is a non-specific reaction which can be induced by a variety of agents apart fiom microorganisms. Lymphokines and derivatives of arachidonic acid, including prostaglandins, leukotrienes and thromboxanes are probable mediators of the inflammatory response. The release of vasoactive amines such as histamine and serotonin (5-hydroxytryptamine) firm activated or damaged cells also contribute to inflammation. 

More than twenty indole derivatives have been identified from bufonid skin extracts. The indolylalkylamines bufotenidine, bufotenine, de-hydrobufotenine, bufo-tionine and serotonin (5-hydroxytryptamine) (Fig. 39.2b) have been identified in skin secretions of Bufo marinus, while the latter four have been detected in parotoid gland secretions (Erspamer 1994 Maciel, Schwartz, Pires Jr, Sebben, Castro, Sousa, Fontes and Schwartz 2003). The concentration of serotonin in the dried secretion of B. marinus was found to equate to approximately 0.1% of the total composition and primarily acts as a vasoconstrictor (Gregerman 1952 Toledo and Jared 1995). 

Some rather important indole derivatives influence our everyday lives. One of the most common ones is tryptophan, an indole-containing amino acid found in proteins (see Section 13.1). Only three of the protein amino acids are aromatic, the other two, phenylalanine and tyrosine being simple benzene systems (see Section 13.1). None of these aromatic amino acids is synthesized by animals and they must be obtained in the diet. Despite this, tryptophan is surprisingly central to animal metabolism. It is modified in the body by decarboxylation (see Box 15.3) and then hydroxylation to 5-hydroxytryptamine (5-HT, serotonin), which acts as a neurotransmitter in the central nervous system. 

From L-tryptophan, the serotonin synthesis pathway also begins. Serotonin is 5-hydroxytryptamine. It is derived from L-tryptophan, which at first is simply hydroxylated to 5-hydroxy-L-tryptophan, and subsequently to the serotonin (Figure 39). Structurally, serotonin is also a 5-HT monoamine neurotransmitter. 

To measure serotonin (5-hydroxytryptamine), by the internal standard method, a 1 ml aliquot of the unknown solution is added to 1 ml of a solution containing 30 ng of N-methyl-serotonin. This mixture is then treated to remove all other compounds which could interfere with the experiment. The operation performed was an extraction in the solid phase to isolate the serotonin and its methyl derivative, diluted in a suitable medium. 

While both dopamine and norepinephrine are derived from tyrosine, serotonin (5-hydroxytryptamine, 5-HT) is derived from tryptophan. All three transmitters are very important... 

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. 

Nicotinate (also called niacin or vitamin Bg) is derived from tryptophan. Human beings can synthesize the required amount of nicotinate if the supply of tryptophan in the diet is adequate. However, nicotinate must be obtained directly if the dietary intake of tryptophan is low. A dietary deficiency of tryptophan and nicotinate can lead to pellagra, a disease characterized by dermatitis, diarrhea, and dementia. An endocrine tumor that consumes large amounts of tryptophan in synthesizing the hormone and neurotransmitter serotonin (5-hydroxytryptamine) can lead to pellagralike symptoms. 

Serotonin or 5-hydroxytryptamine (5-HT), a monoamine, is widely distributed in many cells of the body and about 1-2% of the entire serotonin body content is found in the CNS. Serotonin is synthesized by the enzyme amino acid decarboxylase from 5-hydroxytryptophan (which is derived from tryptophan via tryptophan hydroxylase). The rate-limiting step is the production of 5-hydroxytryptophan by tryptophan hydroxylase. Serotonin is removed from the synapse by a high-affinity serotonin uptake site that is capable of transporting serotonin in either direction, depending on the concentration. 

Indolealkylamines. GC-MS methods applied in studies of the biochemical pharmacology of indoleamines parallel work on the catecholamines. SIM assays for serotonin (5-hydroxytryptamine), 5-methoxytryptamine, JV-acetylserotonin and melatonin (5-methoxy-N-acetyltryptamine) in rat pineal and brain tissue have been described [453,469]. Pentafluoro-propionyl derivatives and structural homologue standardisation were employed with detection limits in the subpicomole range. Estimation of central indoleamine turnover in man currently depends upon metabolite determination in CSF. Ion monitoring determination of indole-3-acetic acid [454] a metabolite of tryptamine, and isotope dilution assays for 5-hydroxyindoleacetic acid (5-HIAA) [455,458] have been reported. Serotonin is converted by central monoamine oxidase to 5-HIAA and the measurement of this metabolite, formerly by fluorimetry, is of interest in patients with CNS disorders [470]. GC-MS has also contributed to the identification of N,N-dimethyltryptamine in vitro [471] and isotope dilution technique has been applied to the measurement of this metabolite in control subjects and in psychiatric patients [472]. 

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