title: alpha-MSH can control the essential cofactor 6-tetrahydrobiopterin in melanogenesis.
abstract: In the human epidermis both keratinocytes and melanocytes express POMC m-RNA. Immunohistochemical studies of both cell types demonstrate significantly higher levels of alpha-MSH in melanocytes than in keratinocytes. Both cell types also hold the full capacity for de novo synthesis/recycling of the essential cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (6BH4). 6BH4 is critical for the hydroxylation of the aromatic amino acids L-phenylalanine, L-tyrosine, and L-tryptophan, for nitric oxide production and in various immune modulatory processes. Recently it was shown that tyrosinase activity is regulated by 6BH4 through a specific allosteric inhibition. The tyrosinase/6BH4 inhibition can be activated by 1:1 complex formation between 6BH4 and alpha-MSH, but an excess of alpha-MSH over 6BH4 can inhibit tyrosinase due to complex formation by tyr2 in the alpha-MSH sequence. In both melanocytes and keratinocytes 6BH4 controls the L-tyrosine supply via phenylalanine hydroxylase (PAH). Recently we were able to show that the cellular uptake of L-phenylalanine and its intracellular turnover to L-tyrosine is crucial for melanogenesis. alpha-MSH can promote the production of L-tyrosine via PAH due to activation of the PAH tetramer to the more active dimer by removing 6BH4 from the regulatory binding domain on the enzyme. In conclusion, alpha-MSH can control (1) intracellular L-tyrosine formation from L-phenylalanine in both melanocytes and keratinocytes, and (2) tyrosinase activity, directly, in melanocytes.
authors.affiliation: Clinical and Experimental Dermatology Department of Biomedical Sciences, University of Bradford, United Kingdom. K.Schallreuter@bradford.ac.uk
authors.forename: K U
authors.initials: KU
authors.lastname: Schallreuter
authors.forename: J
authors.initials: J
authors.lastname: Moore
authors.forename: D J
authors.initials: DJ
authors.lastname: Tobin
authors.forename: N J
authors.initials: NJ
authors.lastname: Gibbons
authors.forename: H S
authors.initials: HS
authors.lastname: Marshall
authors.forename: T
authors.initials: T
authors.lastname: Jenner
authors.forename: W D
authors.initials: WD
authors.lastname: Beazley
authors.forename: J M
authors.initials: JM
authors.lastname: Wood
mesh_terms: D000818:Animals; D000975:Antioxidants; D001708:Biopterins / Q000031:analogs & derivatives* / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000502:physiology; D008543:Melanins / Q000096:biosynthesis*; D008544:Melanocytes / Q000502:physiology; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000502:physiology*; D012879:Skin Physiological Phenomena; D012880:Skin Pigmentation / Q000502:physiology*; D014158:Transcription, Genetic; D000521:alpha-MSH / Q000502:physiology*
chemical_list: D000975:Antioxidants; D008543:Melanins; D001708:Biopterins; D000521:alpha-MSH; D011333:Pro-Opiomelanocortin; C003402:sapropterin