Costin GE, Valencia JC, Wakamatsu K et al.Mutations in dopachrome tautomerase (DCT) affect eumelanin/pheomelanin synthesis, but do not affect intracellular trafficking of the mutant protein. Biochem J 391:249-259

Pigment Cell Biology Section, Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Biochemical Journal (Impact Factor: 4.4). 11/2005; 391(Pt 2):249-59. DOI: 10.1042/BJ20042070
Source: PubMed


Dopachrome tautomerase (Dct) is a type I membrane protein and an important regulatory enzyme that plays a pivotal role in the biosynthesis of melanin and in the rapid metabolism of its toxic intermediates. Dct-mutant melanocytes carrying the slaty or slaty light mutations were derived from the skin of newborn congenic C57BL/6J non-agouti black mice and were used to study the effect(s) of these mutations on the intracellular trafficking of Dct and on the pigmentation of the cells. Dct activity is 3-fold lower in slaty cells compared with non-agouti black melanocytes, whereas slaty light melanocytes have a surprisingly 28-fold lower Dct activity. Homology modelling of the active site of Dct suggests that the slaty mutation [R194Q (Arg194-->Gln)] is located in the active site and may alter the ability of the enzyme to transform the substrate. Transmembrane prediction methods indicate that the slaty light mutation [G486R (Gly486-->Arg)] may result in the sliding of the transmembrane domain towards the N-terminus, thus interfering with Dct function. Chemical analysis showed that both Dct mutations increase pheomelanin and reduce eumelanin produced by melanocytes in culture. Thus the enzymatic activity of Dct may play a role in determining whether the eumelanin or pheomelanin pathway is preferred for pigment biosynthesis.

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    • "In our study, IFN-γ promoted the accumulation of melanin in melanocytes, and increased the transcription of some of the melanogenesis-related genes. However, it also significantly decreased the mRNA level of DCT, which encodes a critical enzyme in the synthesis of eumelanin [39]. Thus, IFN-γ might change the eumelanin/pheomelanin ratio in melanocytes. "
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    • "Groups have also shown that mutations in Dct (dopachrome tautomerase) affect eumelanin/pheomelanin synthesis , but do not affect intracellular trafficking of the mutant protein, leading to a mild iris phenotype (Costin et al., 2005). Despite this biological significance, Dct did not fulfill our inclusion criteria. "
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