Visible pigmentation of the skin, hair, and eyes depends primarily on the presence of melanin(s) in those tissues. Melanins are produced by specific cells called melanocytes. Not only is the type of melanin produced important, but also its eventual distribution in the tissue dramatically affects visible color, which ultimately determines the functions of the pigment, such as photoprotection (Gilchrest, 2011). Clearly, the specification, migration, and differentiation during development of melanocyte precursors (‘‘melanoblasts’’) in specific patterns are essential for eventual pigmentation in adults (Kawakami and Fisher, 2011). Following is a synopsis of critical findings that have led to our current understanding of the biochemical pathways and melanogenic factors involved in melanin synthesis. The key enzyme involved in the synthesis of all types of melanins from the initial precursor tyrosine is tyrosinase (EC 1.14.18.1). Tyrosinases have been described in many species, including mammals and lower animals, plants, and even fungi; in fact, the earliest observations of the catalytic function of tyrosinase were made in extracts of mushrooms (Bourquelot and Bertrand, 1895), which are still widely used today as a highly enriched source of that enzyme. All tyrosinases depend on the binding of copper for their catalytic function (Lerner et al., 1950; Lerch et al., 1986), although their substrate specificities and physical properties can differ dramatically depending on the species (Lerner et al., 1951; Hearing et al., 1980). The ratelimiting initial step in the biosynthesis of melanin was initially thought to be the hydroxylation of tyrosine to L-3,4dihydroxyphenylalanine (DOPA) and its immediate subsequent oxidation to DOPAquinone (DQ). In melanocytic cells, the DQ formed will be spontaneously converted to an orangecolored intermediate known as DOPAchrome. In vitro, the DOPAchrome will spontaneously lose its carboxylic acid group to form 5,6-dihydroxyindole (DHI), which can then further oxidize and polymerize to form a dense, highmolecular-weight complex now known as DHI-melanin. This was initially reported by Raper (1926), and the pathway was later refined by Mason (1948); hence, the biosynthetic pathway is frequently referred to as the Raper–Mason pathway. Throughout the 1950s, 1960s, and 1970s, the collaborative research groups at Yale (headed by AB Lerner) and Harvard (headed by TB Fitzpatrick) played key roles in defining the involvement of tyrosinase in the human skin pigmentation (Fitzpatrick et al., 1950), how its activities were confined to melanosomes and how those organelles developed (Seiji et al., 1961; Szabo et al., 1969), and the disruptions that occurred in those processes in many skin pigmentary diseases (Breathnach et al., 1965; Kawamura et al., 1971; Lerner and Nordlund, 1978; Rees, 2011; Spritz, 2011). Those findings, plus the training of many post-doctoral fellows and clinicians in their groups, played a major role in establishing research centers in Asia, Europe, and the Americas, which still have a strong influence on studies of skin pigmentation and related pigmentary diseases. As summarized in Figure 1, recent revisions of this melanogenic pathway have shown that DOPA is not a distinct intermediate produced initially from tyrosine, but is in fact produced later in the pathway owing to the paired reduction of DQ (Riley, 1999), and that downstream tyrosinase-related enzymes can rearrange the DOPAchrome to form a carboxylated intermediate (DHI-2-carboxylic acid) known as DHICA, as discussed below. Analysis of the structures of the high-molecular-weight polymers of melanins depended on the development of new techniques to analyze these intractable pigments, and gradual progress was made in defining those structures, initially by Nicolaus’s group in Naples and Swan’s group in the United Kingdom (Swan, 1963; Nicolaus et al., 1964). In working with melanins found in nature, it quickly became apparent that there were two major types, the brown–black melanins now collectively known as eumelanins, and the yellow–red melanins now collectively known as pheomelanins. Prota’s group in Naples took the lead in defining the structure of pheomelanin and the involvement of sulfur as responsible for its unique color and properties (Prota, 1980). Prota and colleagues, as well as Ito and Wakamatsu in Japan (Ito et al., 1984), developed a series of more sensitive and specific assays for eumelanin and pheomelanin intermediates that gradually formed the basis for our understanding of how they are formed in melanocytes and how they are copolymerized in situ. The critical role of sulfhydryl groups in reacting immediately with DQ upon its formation to form various combinations of cysteinylDOPAs and downstream reactions of those intermediates, via cysteinylDOPA-quinones and benzothiazine intermediates, to produce
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Jul 2, 2012
Johan Strümpfer + 1
