What is melanogenesis - Melanogenesis pathway

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What is melanogenesis?

Melanogenesis is the biochemical process of melanin production. Melanogenesis pathway is catalyzed by the tyrosinase enzyme.

Melanin pigment producing cells are known as melanocytes. Melanocytes are located in the basal layer of epidermis. Normally about 5-10% of the cells present in the stratum basale layer are melanocytes. The rest of cells in the basal layer are basal keratinocytes. Each melanocyte is in contact with nearly 40 neighboring keratinocytes in the basal and suprabasal layers via dendrites. Synchronizing with the rate of skin turnover, the melanogenesis process continuously goes on to pigment the newly forming keratinocytes.

Web definition of melanogenesis

merriam-webster.com defines as: "the formation of melanin."

Drugs.com defines as: "formation of melanin."

Collinsdictionary.com defines as: "the production of melanin."

Mechanisms regulating melanogenesis and its pathways

Melanin production takes place in the melanosomes, which are membrane-bound organelles located inside the melanocytes. Melanosomes are synthesized in the melanocytes. They are sites of synthesis, storage and transport of melanin.

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When the melanosomes are full with melanin bundles, they are transferred to the surrounding keratinocytes via dendrites. Cytoplasmic dynein (a motor protein involved in the organelle transport) present in the cytoplasm of the keratinocyte, moves the melanosomes to the center to hide the cell nucleus from UV radiation.

A base level melanogenesis is carried on continuously in the melanosomes to keep up with the genetically determined level of melanin. Exposure to UV radiation enhances the melanin production by activating tyrosinase enzyme for melanogenesis.

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Intrinsic factors like melanocyte-keratinocyte interaction, hormones, enzymes, melanocyte-stimulating hormone, inflammatory and neuronal components can affect the melanogenesis and its pathway. Extrinsic factors like ultraviolet radiation and certain medications and chemicals can also interfere with melanogenesis pathway.

Tyrosinase regulation of melanogenesis

Tyrosinase, a glycoprotein, is the principal enzyme involved in the melanin production. The tyrosinase is a single membrane-spanning transmembrane protein, spanning the entirety of the melanosomal membrane. It span from one side of the melanosomal membrane through to the other side of the membrane and is permanently attached. Most of the tyrosinase protein is present inside the melanosomal vesicle, which is the catalytic region of melanogenesis pathway. Only a small part of tyrosinase traverses the melanosomal membrane and projects into cytoplasm. The histidine residues present in the catalytic region bind to copper ions for tyrosinase activation.

Melanogenesis pathway

L-tyrosine is a non-essential amino acid as it can be synthesized by the body. Being a proteinogenic amino acid, it is the building block as well as the pathway in the synthesis of many cellular proteins, enzymes and catalysts. L-tyrosine [L-2-Amino-3-(4-hydroxyphenyl)propanoic acid] is the precursor to the melanin.

L-phenylalanine to l-tyrosine pathway
L-tyrosine has to reach the melanosomes only by the process of spontaneous passive transport which leads its insufficiency in the melanogenesis pathway.

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However, the human body has found a way out of this situation. L-phenylalanine, an essential amino acid, is actively transported through the melanosomal membrane. Inside the organelle, l-tyrosine is created from l-phenylalanine by hydroxylation by the phenylalanine hydroxylase enzyme. This synthetic pathway ensures sufficiency of the base material for the melanogenesis.

L-phenylalanine ››› intracellular phenylalanine hydroxylase (PAH) enzyme ››› L-tyrosine

L-dopaquinone synthesis pathway
In the melanogenesis pathway, tyrosinase enzyme catalyses the hydroxylation of l-tyrosine to l-dihydroxyphenylalanine (L-DOPA) and the subsequent oxidation of L-DOPA to l-dopaquinone. With the formation of dopaquinone, the melanogenesis pathway is bifurcated into synthesis of the eumelanin and pheomelanin.

L-tyrosine ››› tyrosinase catalyst ››› L-dihydroxyphenylalanine (L-DOPA) ››› tyrosinase catalyst ››› L-dopaquinone

Eumelanogenesis pathway
In this intermediate melanogenesis pathway, l-dopaquinone reacts with cysteine (which is actively transported across melanosomal membrane) to form either 5-S-cysteinyl-dopa or 2-S-cysteinyl-dopa. Both these cysteinyl-dopa intermediates, convert to benzothiazine intermediate and then polymerize to pheomelanin at the end of the melanogenesis pathway.

Dopaquinone + cysteine ››› 5-S-cysteinyldopa ››› benzothiazine intermediate ››› polymerization ››› pheomelanin

Dopaquinone + cysteine ››› 2-S-cysteinyldopa ››› benzothiazine intermediate ››› polymerization ››› pheomelanin

Pheomelanogenesis pathway
In this intermediate melanogenesis pathway, l-dopaquinone is converted spontaneously into from leucodopachrome and then dopachrome. Dopachrome is either converted spontaneously into 5,6-dihydroxyindole (indole) or convert to 5,6-dihydroxyindole-2-carboxylic acid by the enzymatic action of dopachrome tautomerase (DCT). Both these intermediates convert to quinone and then polymerize to eumelanin.

Dopaquinone ››› spontaneous conversion ››› leucodopachrome ››› spontaneous conversion ››› dopachrome ››› dopachrome tautomerase (DCT) catalyst ››› 5,6-dihydroxyindole-2-carboxylic acid ››› quinone ››› polymerization ››› eumelanin

Dopaquinone ››› spontaneous conversion ››› leucodopachrome ››› spontaneous conversion ››› dopachrome ››› spontaneous conversion ››› 5,6-dihydroxyindole ››› quinone ››› polymerization ››› eumelanin

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Reference: 1.Inês Ferreira dos Santos Videira, Daniel Filipe Lima Moura, Sofia Magina. Mechanisms regulating melanogenesis. An Bras Dermatol. 2013 Jan-Feb; 88(1): 76–83. 2.Park HY, Kosmadaki M, Yaar M, Gilchrest BA. Cellular mechanisms regulating human melanogenesis. Cell Mol Life Sci. 2009 May;66(9):1493-506. 3.Gillbro, J. M. Olsson, M. J. The melanogenesis and mechanisms of skin-lightening agents – existing and new approaches. International Journal of Cosmetic Science, 33: 210–221. 4.Agar N, Young AR. Melanogenesis: a photoprotective response to DNA damage? Mutat Res. 2005 Apr 1;571(1-2):121-32. Epub 2005 Jan 23.

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