Melanin

In vertebrates, melanin is formed in the melanocytes of the skin and in the retina of the eye. Melanin significantly determines skin and hair color as well as the individual risk of melanoma. It occurs in humans primarily in two variants:

• Brown/blackish (eumelanin)
• Light yellowish (pheomelanin).

However, there are also chemically well-defined variants of other colors (trichromes).

The extent of melanin synthesis is determined by the gene for the melanocortin receptor 1(MC1R). In humans, the MC1R gene is encoded on chromosome 16, gene locus q24.3.

Three key enzymes are important for melanin synthesis:

Tyrosinase is the key enzyme in melanin production. It catalyzes two different reactions. First it converts tyrosine into dopa and then dopa into DOP-quinone. The rate of melanin synthesis is largely controlled by systems that regulate the production and activity of tyrosinase. The synthesis process takes place in the rough endoplasmic reticulum and in the Golgi apparatus of the melanocytes. DOPAquinone is oxidized and polymerized to pheomelanin.

Dopachrome tautomerase (see DCT gene below) is an enzyme that converts DOPAchrome into DHI-2-carboxylic acid (DHI-carboxylic-acid = DHICA) and in a further step converts it into the polymerization product eumelanin.

Tyrosinase-related-protein-1 (TYRP1) is an enzyme that is crucial for the transport of tyrosine to the melanosomes

After synthesis, melanin is stored in intracellular granules called melanosomes. Melanosomes are intracellular, lysosome-like organelles in which melanin pigments are synthesized and stored before they are distributed to the surrounding keratinocytes via the dendrites of the melanocytes. A melanocyte is connected to around 36 keratinocytes and together they form a melanocyte/keratinocyte unit(epidermal melanin unit) The size of these granules varies depending on the type of pigmentation. The darker the skin pigmentation, the larger they are.

The maturation of the melanosomes takes place in the melanocytes in 4 stages. The structural protein MART1 is essential for the transformation of stage I melanosomes into stage II melanosomes.

Melanin is increasingly formed in the skin when exposed to sunlight (see chromophores below) and serves as light protection against the harmful effects of UV radiation. Furthermore, the proliferation and differentiation of melanocytes and thus melanin is increased by growth factors that are produced by keratinocytes and fibroblasts in the skin. The Dickkopf-1 protein (DKK-1) has an antagonistic effect via the WNT/beta-catein signaling pathway (see catenins below), which is produced in large quantities in the fibroblasts of the palms.

The pigment phenotype itself is subject to a complex genetic program. Essentially, pigmentation is controlled by the melanocortin-1 receptor (MC1R) gene, which in turn codes for the MC1 receptor, a receptor that is coupled to a G protein (guanine nucleotide-binding protein) on the surface of the melanocytes. The regulation of MC1-R takes place on the one hand via the stimulating pituitary hormones. Primarily, the MC1 receptor protein is stimulated via melanocyte-stimulating hormone (MSH), beta-lipotropin and ACTH, which in turn are cleaved from the precursor hormone proopiomelanocortin ( Clark AJ 2016).

The synthesis of melanin can be impaired due to genetic predisposition or genetic damage acquired over time. If production is blocked, the pigments in the skin and eyes are also missing, which can result in different types of pigment defects (see depigmentation below). An analogously induced overproduction of melanin leads to the pathological condition of hyperpigmentation.

The antidiabetic drug metformin inhibits melanogenesis both in vitro and in vivo (by downregulating cAMP). The studies suggest that metformin can also be used in the topical treatment of hyperpigmentation. Glutathione also appears to reduce eumelanotic melanogenesis.

1. Brenner M et al. (2010) Basics of skin pigmentation. Dermatology 61: 554-560
2. Clark AJ (2016) 60 YEARS OF POMC: The proopiomelanocortin gene: discovery, deletion and disease. J Mol Endocrinol 56:T27-37.
3. Giehl K et al. (2010) Genetically caused pigmentary disorders. Dermatology 61: 567-577
4. Lehraiki A et al. (2014) Inhibition of melanogenesis by the antidiabetic metformin. J Invest Dermatol 134:2589-2597