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It has been known for over 60 years, that the production of melatonin involves the O-methylation of N-acetyl serotonin, by the action of enzyme hydroxyindole-O-methyl transferase, using S-Adenosylmethionine (SAM), as the methyl donor (Axelrod and Weissbach 1960, Weissbach and Axelrod 1960)