Eumelanin Biosynthesis

CPD-12379 is a common type of melanin pigment, which is found in hair and skin. There are two types of eumelanin, black and brown, which differ by their pattern of polymer bonds. A small amount of black eumelanin in the absence of other pigments causes grey hair, while a small amount of brown eumelanin in the absence of other pigments causes yellow (blond) color hair. Spectroscopic studies of the biosynthesis of eumelanin showed that it takes place in three chromophoric phases. The first phase corresponds to the formation of the red pigment L-dopachrome (λmax 475 nm) (see L-dopachrome biosynthesis). The second phase corresponds to a purple intermediate, which was designated melanochrome, with a broad absorption maximum at 540 nm, and the third phase is characterized by a general absorption due to eumelanin (NAPOLITANO85). The oxidation of L-dopachrome to melanochrome occurs spontaneously in vitro but has been shown to be under enzymatic control in vivo. L-dopachrome is converted into two compounds - a spontaneous decarboxylation to 5,6-dihydroxyindole, and an enzymatic tautomerization to 5,6-dihydroxyindole-2-carboxylate. Both of these products are then oxidized to quinones, which are polymerized to form melanochrome and eventually eumelanin. The pathway involves the activities of three related proteins, all members of the tyrosinase gene family: tyrosinase ( TYR ), tyrosinase-related protein 1 ( Tyrp1 ) and tyrosinase-related protein 2 ( Dct ). The enzymatic activities of tyrosinase and tyrosinase-related protein 2 ( L-dopachrome tautomerase ) are well established. HS01248-MONOMER is the initial, rate-limiting enzyme of melanogenesis, catalyzing the first two steps from L-tyrosine via L-dopa to dopaquinone, which goes through a series of spontaneous reactions yielding L-dopachrome (see L-dopachrome biosynthesis ). Subsequently, the Dct -encoded L-dopachrome tautomerase converts L-dopachrome into 5,6-dihydroxyindole-2-carboxylate (DHICA). The role of the third family member, Tyrp1 , is less clear. Despite its structural similarity to Tyr and Dct, the enzymatic function of Tyrp1 is controversial and might be species-specific. A 5,6-dihydroxyindole-2-carboxylate monooxygenase (DHICA oxidase) activity has been demonstrated for the murine Tyrp1 protein, but in humans TYR and not TYRP1 performs this function. As Tyr and Tyrp1 are part of the 'melanogenic complex' and are known to form heterodimers, it is possible that the main function of human Tyrp1 is to stabilize tyrosinase. The two products of L-dopachrome oxidation, indole-5,6-quinone and indole-5,6-quinone-2-carboxylate, polymerize to form a mixture of different dimers and trimers, known under the name melanochrome . The polymerization can be induced by the presence of certain metal ions such as Ni²⁺ or Zn²⁺ (NAPOLITANO85), but could also be catalyzed enzymatically by tyrosinase or by peroxidases. Different routes were shown to result in the formation of different compounds. Defects in TYR result in various forms of albinism. Mutations in TYRP1 in mice result in brown fur, but mutations in the human gene result in a form of oculocutaneous albinism (OCA3).