Chemistry of Mixed Melanogenesis—Pivotal Roles of Dopaquinone^†

Abstract

Melanins can be classified into two major groups-insoluble brown to black pigments termed eumelanin and alkali-soluble yellow to reddish-brown pigments termed pheomelanin. Both types of pigment derive from the common precursor dopaquinone (ortho-quinone of 3,4-dihydroxyphenylalanine) which is formed via the oxidation of L-tyrosine by the melanogenic enzyme tyrosinase. Dopaquinone is a highly reactive ortho-quinone that plays pivotal roles in the chemical control of melanogenesis. In the absence of sulfhydryl compounds, dopaquinone undergoes intramolecular cyclization to form cyclodopa, which is then rapidly oxidized by a redox reaction with dopaquinone to give dopachrome (and dopa). Dopachrome then gradually and spontaneously rearranges to form 5,6-dihydroxyindole and to a lesser extent 5,6-dihydroxyindole-2-carboxylic acid, the ratio of which is determined by a distinct melanogenic enzyme termed dopachrome tautomerase (tyrosinase-related protein-2). Oxidation and subsequent polymerization of these dihydroxyindoles leads to the production of eumelanin. However, when cysteine is present, this process gives rise preferentially to the production of cysteinyldopa isomers. Cysteinyldopas are subsequently oxidized through redox reaction with dopaquinone to form cysteinyldopaquinones that eventually lead to the production of pheomelanin. Pulse radiolysis studies of early stages of melanogenesis (involving dopaquinone and cysteine) indicate that mixed melanogenesis proceeds in three distinct stages-the initial production of cysteinyldopas, followed by their oxidation to produce pheomelanin, followed finally by the production of eumelanin. Based on these data, a casing model of mixed melanogenesis is proposed in which a preformed pheomelanic core is covered by a eumelanic surface.

Myosin Vc Interacts with Rab32 and Rab38 Proteins and Works in the Biogenesis and Secretion of Melanosomes

“…4). This result explains the production of pigmented melanosomes in Myosin Vc-deficient MNT-1 cells because tyrosinase is the key enzyme in melanin synthesis, whereas Tyrp1 and Tyrp2 serve modulatory roles (1,3,9). In contrast Rab32 and Rab38 (and AP-3) are involved in the transport of both tyrosinase and Trp1 (11,25,27,31), suggesting that Rab32 and Rab38 serve both MyosinVc-dependent and Myosin Vc-independent functions in melanosome biogenesis.…”

“…The subsequent delivery of integral membrane proteins such as the enzymes tyrosinase, tyrosinase-related protein 1 (Tyrp1), and Tyrp2 initiates the synthesis of melanin pigments that coat the Pmel17-fibrils to form partially pigmented stage III melanosomes (1). Tyrosinase is the key enzyme for melanin synthesis, with Tyrp1 and Tyrp2 serving modulatory roles (1,3,9). Additional melanin synthesis generates fully pigmented stage IV melanosomes (1).…”

Melanocytes and Oxidative Stress

“…It results in a continuous generation of ROS all along the process of melanogenesis: H 2 O 2 during its early stages [17] but also during the redox cycling from indoles to quinones [18], hydroxyl radicals and superoxide anion due to the catalytic activity of tyrosinase [19]. In addition, oxidative intermediates including reactive quinones, which are cytotoxic to proteins and DNA in the cells, are generated during melanogenesis [15].…”

“…In the absence of thiols, DOPAquinone is immediately converted to DOPAchrome and leads to eumelanin production. When glutathione (GSH) and cysteine are present, they can react with DOPAquinone intermediates to divert melanin pigment synthesis from eumelanin to phaeomelanin [15].…”

Inhibitory Effect of Elephantopus mollis H.B. and K. Extract on Melanogenesis in B16 Murine Melanoma Cells by Downregulating Microphthalmia-Associated Transcription Factor Expression

“…13) TRP1 and DCT contribute more to the synthesis of eumelanin than to that of pheomelanin. 14,15) Microphthalmia-associated transcription factor (MITF) is a transcription factor found in a number of cell types and is involved in the regulation of melanocyte differentiation, pigmentation, proliferation, and survival. 16,17) More specifically, MITF is a major transcriptional regulator of the tyrosinase gene family.…”