title: Molecular evidence that melatonin is enzymatically oxidized in a different manner than tryptophan: investigations with both indoleamine 2,3-dioxygenase and myeloperoxidase.
abstract: The catabolism of melatonin, whether naturally occurring or ingested, takes place via two pathways: approximately 70% can be accounted for by conjugation (sulpho- and glucurono-conjugation), and approximately 30% by oxidation. It is commonly thought that the interferon-induced enzyme indoleamine 2,3-dioxygenase (EC 1.13.11.42), which oxidizes tryptophan, is also responsible for the oxidation of 5-hydroxytryptamine (serotonin) and its derivative, melatonin. Using the recombinant enzyme expressed in Escherichia coli, we show in the present work that indoleamine 2,3-dioxygenase indeed cleaves tryptophan; however, under the same conditions, it is incapable of cleaving the two other indoleamines. By contrast, myeloperoxidase (EC 1.11.1.7) is capable of cleaving the indole moiety of melatonin. However, when using the peroxidase conditions of assay -- with H2O2 as co-substrate -- indoleamine 2,3-dioxygenase is able to cleave melatonin into its main metabolite, a kynurenine derivative. The present work establishes that the oxidative metabolism of melatonin is due, in the presence of H2O2, to the activities of both myeloperoxidase and indoleamine 2,3-dioxygenase (with lower potency), since both enzymes have Km values for melatonin in the micromolar range. Under these conditions, several indolic compounds can be cleaved by both enzymes, such as tryptamine and 5-hydroxytryptamine. Furthermore, melatonin metabolism results in a kynurenine derivative, the pharmacological action of which remains to be studied, and could amplify the mechanisms of action of melatonin.
authors.affiliation: Pharmacologie Moléculaire et Cellulaire, Institut de Recherches SERVIER 125, chemin de Ronde 78290, Croissy-sur-Seine, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Ferry
authors.forename: Caroline
authors.initials: C
authors.lastname: Ubeaud
authors.forename: Pierre-Hervé
authors.initials: PH
authors.lastname: Lambert
authors.forename: Sophie
authors.initials: S
authors.lastname: Bertin
authors.forename: Francis
authors.initials: F
authors.lastname: Cogé
authors.forename: Pascale
authors.initials: P
authors.lastname: Chomarat
authors.forename: Philippe
authors.initials: P
authors.lastname: Delagrange
authors.forename: Bernard
authors.initials: B
authors.lastname: Serkiz
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Bouchet
authors.forename: Roger J W
authors.initials: RJ
authors.lastname: Truscott
authors.forename: Jean A
authors.initials: JA
authors.lastname: Boutin
mesh_terms: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D008550:Melatonin / Q000737:chemistry / Q000378:metabolism*; D008956:Models, Chemical; D015394:Molecular Structure; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity; D014364:Tryptophan / Q000737:chemistry / Q000378:metabolism*
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan; D009195:Peroxidase; D008550:Melatonin