title: Action of ellagic acid on the melanin biosynthesis pathway.
abstract: BACKGROUND
  Tyrosinase is an enzyme involved in the first steps of the melanogenesis process. It catalyzes the hydroxylation of monophenols to o-diphenols and the oxidation of the latter to o-quinones. Ellagic acid (EA) is a phenolic compound which has been described as a tyrosinase inhibitor and is used in the cosmetic industry as a whitening agent. However, it has hydroxyl groups in ortho position and could act as a substrate rather than inhibitor. This aspect should be taken into consideration when using this compound as a cosmetic ingredient due to the reactive character of o-quinones.
  
  
  OBJECTIVE
  To determine whether ellagic acid is a substrate or an inhibitor of tyrosinase, to characterize it kinetically and interpret its role in the melanogenesis process.
  
  
  METHODS
  UV-vis spectrophotometry was used to follow the action of tyrosinase on typical substrates and ellagic acid. A chronometric method was chosen for the kinetic characterization of ellagic acid.
  
  
  RESULTS
  Ellagic acid is not an inhibitor per se but an alternative substrate of tyrosinase. It is oxidized by the enzyme to an unstable o-quinone. Its kinetic characterization provided low Michaelis and catalytic constants (KM(EA)=138±13μM and kcat(EA)=0.47±0.02s(-1)). Furthermore, ellagic acid, which is a powerful antioxidant, may chemically reduce the o-quinones (o-dopaquinone) and semiquinones, in this way inhibiting the melanogenesis.
  
  
  CONCLUSIONS
  Ellagic acid is oxidized by tyrosinase, producing reactive o-quinones. As an antioxidant it can inhibit the melanogenesis process. This first aspect should be taken into consideration in its application as a cosmetic ingredient due to the toxicity of o-quinones and its ability to modify the redox status of the cell.
authors.affiliation: GENZ-Group of Research on Enzymology, Department of Biochemistry and Molecular Biology-A, Regional Campus of International Excellence "Campus Mare Nostrum", University of Murcia, E-30100 Espinardo, Murcia, Spain(1).
authors.forename: Carmen Vanessa
authors.initials: CV
authors.lastname: Ortiz-Ruiz
authors.affiliation: Synthetic Organic Chemistry Group, Department of Organic Chemistry Regional Campus of International Excellence "Campus Mare Nostrum", University of Murcia, E-30100 Espinardo, Murcia, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Berna
authors.affiliation: GENZ-Group of Research on Enzymology, Department of Biochemistry and Molecular Biology-A, Regional Campus of International Excellence "Campus Mare Nostrum", University of Murcia, E-30100 Espinardo, Murcia, Spain(1).
authors.forename: Jose
authors.initials: J
authors.lastname: Tudela
authors.affiliation: Department of Physical Chemistry, Technical School of Industrial Engineering, University of Castilla La Mancha, Avda. España s/n. Campus Universitario, E-02071 Albacete, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Varon
authors.affiliation: GENZ-Group of Research on Enzymology, Department of Biochemistry and Molecular Biology-A, Regional Campus of International Excellence "Campus Mare Nostrum", University of Murcia, E-30100 Espinardo, Murcia, Spain(1). Electronic address: canovasf@um.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Garcia-Canovas
mesh_terms: D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D016227:Benzoquinones / Q000378:metabolism; D053898:Biosynthetic Pathways / Q000187:drug effects; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives / Q000378:metabolism; D004610:Ellagic Acid / Q000378:metabolism* / Q000494:pharmacology*; D057075:Enzyme Assays; D006801:Humans; D007700:Kinetics; D008543:Melanins / Q000096:biosynthesis*; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010636:Phenols / Q000378:metabolism; D011809:Quinones / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000201:enzymology; D062327:Skin Lightening Preparations / Q000378:metabolism* / Q000494:pharmacology*; D013056:Spectrophotometry, Ultraviolet / Q000379:methods; D013379:Substrate Specificity
chemical_list: D000975:Antioxidants; D016227:Benzoquinones; D008543:Melanins; D010636:Phenols; D011809:Quinones; D062327:Skin Lightening Preparations; D004610:Ellagic Acid; D004295:Dihydroxyphenylalanine; C035157:dopaquinone; D014442:Monophenol Monooxygenase
keywords: ellagic acid; inhibition; kinetic characterization; melanogenesis; tyrosinase