On the significance of an alternate pathway of melatonin synthesis via 5-methoxytryptamine: comparisons across species

Dun Xian Tan, Rüdiger Hardeland, Kyoungwhan Back, Lucien C. Manchester, Moises A. Alatorre-Jimenez, Russel J. Reiter

Research output: Contribution to journalReview articlepeer-review

178 Scopus citations


Melatonin is a phylogenetically ancient molecule. It is ubiquitously present in almost all organisms from primitive photosynthetic bacteria to humans. Its original primary function is presumable to be that of an antioxidant with other functions of this molecule having been acquired during evolution. The synthetic pathway of melatonin in vertebrates has been extensively studied. It is common knowledge that serotonin is acetylated to form N-acetylserotonin by arylalkylamine N-acetyltransferase (AANAT) or arylamine N-acetyltransferase (SNAT or NAT) and N-acetylserotonin is, subsequently, methylated to melatonin by N-acetylserotonin O-methyltransferase (ASMT; also known as hydroxyindole-O-methyltransferase, HIOMT). This is referred to as a classic melatonin synthetic pathway. Based on new evidence, we feel that this classic melatonin pathway is not generally the prevailing route of melatonin production. An alternate pathway is known to exist, in which serotonin is first O-methylated to 5-methoxytryptamine (5-MT) and, thereafter, 5-MT is N-acetylated to melatonin. Here, we hypothesize that the alternate melatonin synthetic pathway may be more important in certain organisms and under certain conditions. Evidence strongly supports that this alternate pathway prevails in some plants, bacteria, and, perhaps, yeast and may also occur in animals.

Original languageEnglish (US)
Pages (from-to)27-40
Number of pages14
JournalJournal of pineal research
StatePublished - Aug 1 2016


  • 5-methoxytryptamine
  • N-acetylserotonin O-methyltransferase
  • antioxidant
  • arylalkylamine N-acetyltransferase
  • hydroxyindole-O-methyltransferase
  • melatonin
  • serotonin
  • serotonin N-acetyltransferase

ASJC Scopus subject areas

  • Endocrinology


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