Biochemistry, Melanin

Fundamentals

Tyrosine is the key precursor for the synthesis of melanin, the pigment responsible for coloration in the skin, hair, and eyes. Melanin biosynthesis begins with the conversion of tyrosine into dihydroxyphenylalanine (L-DOPA) and subsequently into dopaquinone—a critical intermediate—through the action of the enzyme tyrosinase. This enzyme is copper-dependent and tightly regulated, as it catalyzes the rate-limiting step in melanogenesis.

From dopaquinone, the pathway can diverge into the formation of 2 primary types of melanin:

• Eumelanin produces dark brown or black pigment and is generally associated with UV protection, as it effectively absorbs and neutralizes harmful radiation.
• Pheomelanin gives rise to red or yellow pigmentation. The yellowish tone of pheomelanin results from the incorporation of sulfur-containing amino acids, particularly cysteine, which reacts with dopaquinone to form sulfur-rich melanin derivatives.

The balance between eumelanin and pheomelanin in melanocytes determines an individual's natural hair, eye, and skin color, and contributes to variations in sun sensitivity and skin cancer risk.

Disruptions in the melanin biosynthetic pathway, particularly mutations in the TYR gene that encodes tyrosinase, can lead to oculocutaneous albinism. Individuals with oculocutaneous albinism typically produce little to no melanin, resulting in pale skin, light-colored hair, and visual abnormalities, such as nystagmus, reduced visual acuity, and photophobia. Because both eumelanin and pheomelanin synthesis require functional tyrosinase, its deficiency leads to the absence of all melanin pigment types, highlighting its central role in pigmentation biology.[4]

Cellular Level

Eumelanin and pheomelanin are the 2 primary types of melanin pigments produced by specialized cells called melanocytes located in the basal layer of the epidermis. These pigments are synthesized in varying proportions depending on genetic, hormonal, and environmental factors, contributing to the wide range of human skin, hair, and eye colors. Melanocytes originate from melanoblasts, which are derived from the neural crest during embryonic development. Following neural tube closure, melanoblasts migrate to the skin, where they differentiate into mature melanocytes.

Within melanocytes, melanin is synthesized from the amino acid tyrosine through a multi-step enzymatic process that involves key enzymes such as tyrosinase. The resulting melanin is then packaged into small, membrane-bound organelles called melanosomes. Melanosomes are actively transported along dendritic extensions—tentacle-like projections of melanocytes—to neighboring keratinocytes, the predominant cell type in the epidermis. Once transferred, melanosomes are strategically positioned above the nuclei of keratinocytes, forming a protective cap. This arrangement serves a critical photoprotective role by shielding the DNA within the nucleus from damage caused by UV radiation. This tightly regulated system of melanin production, packaging, and transfer plays a fundamental role not only in pigmentation but also in protecting the skin from environmental stressors such as UV exposure.[5][6][5]

Molecular Level

The biosynthesis of both eumelanin and pheomelanin begins through a shared initial pathway. The amino acid tyrosine is first converted into L-DOPA by the enzyme tyrosine hydroxylase, which requires tetrahydrobiopterin as a cofactor. Next, the enzyme tyrosinase oxidizes L-DOPA into dopaquinone. This key intermediate can proceed along different branches to form either eumelanin (a black or brown pigment) or pheomelanin (a red or yellow pigment), depending on the cellular environment and substrate availability.

UV radiation is the primary external stimulus for melanogenesis—the process of melanin production. In response to UV exposure, melanocytes increase the production of pro-opiomelanocortin (POMC). This precursor protein is cleaved into several biologically active peptides, including alpha-melanocyte-stimulating hormone and adrenocorticotropic hormone. These peptides bind to the melanocortin 1 receptor on melanocytes, activating intracellular signaling pathways that enhance eumelanin production, increase melanosome formation, and stimulate the transfer of pigment to keratinocytes, thereby increasing photoprotection to the skin.[7]

Interestingly, individuals with mutations in the POMC gene often exhibit red hair and very fair skin (Fitzpatrick skin type I). This phenotype results from a relative decrease in eumelanin and an increase in pheomelanin, which offers less protection against UV damage. In contrast to cutaneous melanins, neuromelanin is a dark pigment found in specific regions of the brain, such as the substantia nigra and locus coeruleus. Neuromelanin is formed as a byproduct of dopamine and norepinephrine metabolism in dopaminergic and noradrenergic neurons. Although its function is not fully understood, neuromelanin is believed to play a role in neuroprotection by sequestering toxic metabolites and metals. Loss of neuromelanin-containing neurons is a hallmark of Parkinson disease.[8]

Function

Skin Pigmentation and Melanin Biology

Skin pigmentation arises from the accumulation of melanin-containing melanosomes within keratinocytes in the basal layer of the epidermis. Melanin is synthesized in melanocytes, which transfer melanosomes to neighboring keratinocytes. The degree and type of pigmentation are influenced by both the relative ratio of eumelanin (brown-black pigment) to pheomelanin (yellow-red pigment) and the number and distribution of melanosomes.

Pheomelanin is responsible for the pinkish hue of specific anatomical areas such as the lips, nipples, vagina, and glans penis. In general, individuals with lighter skin have melanocytes containing clusters of 2 to 3 melanosomes. In contrast, individuals with darker skin tend to have more numerous, individually dispersed melanosomes that are more efficiently transferred to keratinocytes. These factors lead to greater melanin density, which correlates with darker skin tone and a higher Fitzpatrick skin type.

Evolutionary Adaptation and UV Response

The relationship between melanin and UV radiation is complex and deeply rooted in human evolution. Scientists believe that melanin production increased as an adaptive response to the loss of protective body hair, which occurred more than one million years ago.

Populations native to equatorial regions, where UV radiation is intense, have evolved to produce more eumelanin—a pigment that not only absorbs UV radiation but also functions as an antioxidant and free radical scavenger, thereby reducing DNA damage. In contrast, populations in higher latitudes developed a higher proportion of pheomelanin, which, unfortunately, can generate free radicals upon UV exposure, potentially increasing the risk of skin cancer. Given that UV radiation is the primary driver of vitamin D synthesis in the skin, individuals with darker skin—who have higher melanin content—often exhibit lower vitamin D levels and may require routine screening or supplementation, especially in low-UV environments.

Melanin and Cutaneous Immunology

The role of melanin in skin immunity remains less clearly defined. Both acute and chronic UV exposure are known to cause local immunosuppression—a mechanism exploited therapeutically in treatments for conditions such as psoriasis, where UVA phototherapy is commonly used. Emerging evidence suggests that melanin may have immunomodulatory and even antibacterial properties, although the molecular mechanisms behind these effects are not yet fully understood. Interestingly, in melanoma, melanin itself can confer a survival advantage to cancer cells. Melanin-rich (melanotic) melanomas tend to be more resistant to chemotherapy, radiotherapy, and photodynamic therapy. In contrast, amelanotic melanomas, which lack pigment, are associated with better outcomes, including longer disease-free and overall survival. These findings suggest that inhibiting melanogenesis may represent a promising therapeutic strategy for treating malignant melanoma.

Melanin Beyond the Skin: Eyes and Hair

Melanin also plays a protective role in the eye, particularly within the iris and choroid, where it shields ocular tissues from UV damage. Individuals with light-colored eyes, such as gray, blue, or green, and those with albinism, who have reduced ocular melanin, are more susceptible to sun-related eye conditions, including photophobia and retinal damage. Hair color is similarly determined by the type and quantity of melanin produced:

• Black or brown hair results from varying amounts of eumelanin, which is predominantly black or brown.
• Blonde hair is due to small amounts of brown eumelanin with the absence of black eumelanin.
• Red hair arises from a mix of pheomelanin and eumelanin in roughly equal parts.

Mechanism

Melanin synthesis takes place within melanosomes, specialized lysosome-related organelles found in melanocytes. Melanosomes are essential for pigmentation, and their structural and functional integrity is critical not only for melanin production but also for its proper distribution. Defects in melanosome biogenesis or trafficking are responsible for rare genetic disorders such as Chediak-Higashi syndrome and Hermansky-Pudlak syndrome, both of which present with cutaneous hypopigmentation alongside systemic manifestations such as immune dysfunction, bleeding disorders, or neurologic complications.

Within melanosomes, key components required for melanin production are assembled, including:

• Pmel17, also known as gp100, is a structural glycoprotein that forms a fibrillar matrix on which melanin is deposited.
• Melanogenic enzymes, such as tyrosinase, tyrosinase-related protein-1, and dopachrome tautomerase, are sequentially incorporated as the organelle matures.

Melanosome development proceeds through 4 maturation stages as follows:

• Stage I: Formation of the fibrillar matrix without pigment.
• Stages II and III: Acquisition of melanogenic enzymes and initiation of pigment deposition.
• Stage IV: Fully melanized, mature melanosomes.

The proper acquisition and function of these enzymes depend on several regulatory proteins, including membrane-associated transporter protein. Mutations in the gene encoding membrane-associated transporter protein (SLC45A2) result in oculocutaneous albinism type 4, characterized by reduced pigmentation and visual deficits.

Once melanin synthesis is complete, mature melanosomes are actively transported from the perinuclear region of the melanocyte toward its dendritic extensions, which interface with surrounding keratinocytes. This bidirectional movement is mediated by the microtubule network, involving motor proteins such as kinesin for anterograde transport and dynein for retrograde transport, ensuring melanosome delivery to the appropriate cellular regions.[9]

Clinical Significance

Disorders of Melanin Synthesis and Transport

Melanin production and distribution is a complex, multi-step process involving melanoblast migration, melanocyte function, melanosome formation and transport, and enzyme-mediated synthesis. Disruptions at any stage can lead to a wide range of pigmentation disorders and systemic conditions. Several important melanin-associated disorders are outlined below.

Melanoblast defects: Waardenburg syndrome is a group of autosomal dominant or recessive disorders characterized by:

• Pigmentary anomalies: White forelock, patchy skin depigmentation, and premature graying
• Ocular signs: Heterochromia iridis
• Facial features: Dystopia canthorum and synophrys
• Neurologic findings: Congenital sensorineural deafness

These manifestations result from the impaired migration of melanoblasts (precursors to melanocytes) during embryonic development, which prevents the proper colonization of tissues such as the iris, skin, and hair.

Melanocyte destruction: Vitiligo is an autoimmune condition characterized by:

• Depigmented white patches of skin with sharp borders
• Photosensitivity
• Possible ocular involvement

Vitiligo arises from the immune-mediated destruction of melanocytes, leading to areas devoid of melanin.

Melanosome formation and transport: Chédiak-Higashi syndrome is a rare autosomal recessive disorder involving:

• Partial oculocutaneous albinism
• Platelet dysfunction and bleeding
• Immunodeficiency
• Hemophagocytic lymphohistiocytosis

Chédiak-Higashi syndrome is caused by mutations in lysosomal trafficking regulator genes. This syndrome affects the formation and function of melanosomes, leading to impaired pigment deposition.

Griscelli syndrome is another autosomal recessive disorder characterized by:

• Silvery-gray hair
• Skin hypopigmentation

Chédiak-Higashi syndrome is associated with neurologic deficits, immunodeficiency, or hemophagocytic lymphohistiocytosis (depending on subtype). The syndrome results from mutations affecting the protein complex involved in melanosome transport from melanocytes to keratinocytes.

Tyrosinase activity and melanin synthesis: Phenylketonuria is an autosomal recessive metabolic disorder featuring:

• Intellectual disability and seizures, if untreated
• Fair skin, blonde hair, and blue eyes

Phenylketonuria is caused by a deficiency of phenylalanine hydroxylase, leading to phenylalanine buildup. High levels of phenylalanine competitively inhibit tyrosinase, disrupting melanin synthesis.

Oculocutaneous albinism is a group of autosomal recessive conditions caused by mutations in the TYR (tyrosinase) gene or other genes involved in melanin production, characterized by:

• Hypopigmentation of the skin, hair, and eyes
• Visual impairments such as nystagmus, photophobia, reduced acuity

Vogt-Koyanagi-Harada syndrome is a multisystem autoimmune disease, with phases including:

• Meningoencephalitis
• Bilateral uveitis
• Alopecia and vitiligo-like depigmentation
• Recurrent ocular inflammation

This syndrome is believed to result from autoimmune targeting of melanocyte-associated antigens, including tyrosinase.

Neuromelanin and the central nervous system: Parkinson disease is a progressive neurodegenerative disorder marked by:

• Resting tremor, bradykinesia, rigidity, and postural instability
• Depigmentation of the substantia nigra pars compacta, reflecting the loss of neuromelanin-producing dopaminergic neurons

This pigment loss is a pathological hallmark of the disease and correlates with motor symptoms.