Melanogenesis

Melanogenesis is the formation of melanin (eu- and pheomelanin).
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 melanogenesis is determined by the gene for the melanocortin receptor 1(MC1R). In humans, the coding MC1R gene is located on chromosome 16, gene locus q24.3.

Three key enzymes are important for melanin synthesis:

Tyrosinase is the key enzyme in melanogenesis. 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.

Dopachrome is converted into DHI-2-carboxylic acid (DHI-carboxylic-acid = DHICA) via the L-dopachrome tautomerase/TYRP2 (DCT, see DCT gene below). Finally, eumelanin is formed via polymerized DHICA.

A reaction with sulphur-containing cysteine or glutathione can lead to the formation of pheomelanin.

The tyrosinase-related protein (tyrosine-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, the 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 tips of the dendrites of the melanocytes(pigment transfer - see different models). In the keratinocytes, they cover the nuclei of the keratinocytes like a polar cap. A melanocyte is connected to 36-40 keratinocytes and together with these forms an organic melanocyte/keratinocyte unit (epidermal melanin unit). The melanocyte/keratinocyte quotient is a fixed value. There are no greater densities in humans, not even in people of different ethnicities and those with different skin types. Morphologically, however, there are differences in the number, shape and size of the pigment cells and especially the melanosomes. The size of the melanosomes varies depending on the type of pigmentation. The darker the skin is pigmented, the larger they are.

The maturation of the melanosomes takes place in the melanocytes in 4 stages. The structural protein MART1 (see also MLANA gene) 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 MC1R protein. MC1R is a receptor that is coupled to a G protein (guanine nucleotide-binding protein) on the surface of melanocytes. The MC1R protein is regulated on the one hand via the stimulating pituitary hormones: melanocyte-stimulating hormone (MSH), beta-lipotropin and ACTH, and on the other hand in an antagonizing manner via the agouti-signalling protein.

The synthesis of melanin can be impaired due to genetic predisposition or genetic damage acquired over time. If production is genetically blocked, depending on the mutation (see oculocutaneous albinism), the melanin pigments in the skin, eyes and other organs may also be missing, which can result in various types of pigmentation disorders (see depigmentation below). An overproduction of melanin (inflammatory, genetic, solar, hormonal) leads to localized or generalized hyperpigmentation.

A potent inhibitor of melanogenesis is hydroquinone (also the obsolete mercury). A naturally occurring hydroquinone derivative is arbutin. See also under bleaching agents.

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4. Ni QZ et al. (2020) Chemoenzymatic elaboration of the Raper-Mason pathway unravels the structural diversity within eumelanin pigments. Chem Sci 11:7836-7841.