Melatonin, biosynthesis

H. S. Y uand R. J. Reiter,Melatonin Biosynthesis, Physiological Ejfects and Clinical Applications, CRC Press, Boca Raton, 1993. 

Soon after the identification of melatonin, Axelrod and co-workers demonstrated that the pinealocytes have the necessary enzymatic components for the biosynthesis of melatonin (Axelrod and Wurtman 1966 Axelrod 1974 p. 282). The sequence of events for the biosynthesis of melatonin is as follows (Fig. 10.1) ... 

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

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

IPA has a pivotal role in liver reducing tryptophan-2,3-dioxygenase and thereby increases free tryptophan availability to the brain. In brain, it can detoxify cells from free-radicals, reducing activity of excitatory amino acids and stimulating biosynthesis of melatonin. 

Methylation is an important reaction in the biosynthesis of endogenous compounds such as adrenaline and melatonin, in the inactivation of biogenic amines such as the catecholamines, serotonine and histamine, and in modulating the activities of macromolecules, such as proteins and nucleic acids. The number of xenobiotics that are methylated is comparatively modest, yet this reaction is seldom devoid of pharmacodynamic consequences (toxication or detoxication). Reactions of methylation imply the transfer of a methyl group from the onium-type cofactor S-adeno-sylmethionine (SAM) to the substrate by means of a methyltransferase. The activated methyl group from SAM is transferred to the acceptor molecules R — XH or RX, as shown in Fig. 31.30. 

Serotonin, or 5-HT, is biosynthesized (3) from its dietary precursor L-tryptophan (Fig. 14.1). Serotonergic neurons contain tryptophan hydroxylase (L-tryptophan-5-monooxygenase) that converts tryptophan to 5-hydroxytryptophan (5-HTP) in what is the rate-limiting step in 5-HT biosynthesis and aromatic L-amino acid decarboxylase (previously called 5-HTP decarboxylase) that decarboxylates 5-HTP to 5-HT. This latter enzyme also is responsible for the conversion of L-DOPA to dopamine (see Chapter 12). The major route of metabolism for 5-HT is oxidative deamination by monoamine oxidase (MAO-A) to the unstable 5-hydroxyindole-3-acetaldehyde, which is either reduced to 5-hydroxytryptophol ( 15%) or oxidized to 5-hydroxyindole-3-acetic acid ( -85%). In the pineal gland, 5-HT is acetylated by 5-HT N-acetyltransferase to N-acetylserotonin, which undergoes O-methylation by 5-hydroxyindole-O-methyltransferase to melatonin. 

Biosynthesis Like other aromatic amino acids, e.g., Phe and Tyr, Trp is formed on the shikimic acid pathway. There is a branching point at chorismic acid one branch leads to Phe and Tyr, the other to Trp choris-mic acid - anthranilic acid (anthranilic acid synthase, EC 4.1.3.27)- A-(5 -0-phosphoribosyl)-anthranilic acid (anthranilic acid phosphoribosyl transferase, EC 2.4.2.18)- 1 -o-carboxyphenylamino-1 -deoxyribu-lose 5-phosphate [A-(5 -phosphoribosyl)anthranilic acid isomerase]- indole-3-glycerol phosphate (in-dole-3-glycerol phosphate synthase, EC 4.1.1.48) - indole (tryptophan synthase, EC 4.2.1,20)+serine - Trp. Many biologically active indole compounds are derived from Trp, e. g., 5-hydroxytryptophan, 5-hydroxy-tryptamine ( serotonin), and melatonin as well as many indole alkaloids. 

From which amino acid are serotonin and melatonin synthesized, and what types of reactions are involved in their biosynthesis ... 

Fig. 3. Biosynthesis and catabolism of melatonin. MAO monoamine oxidase HIOMT hydroxyindole-O-methyl transferase.

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