Biochemistry, Melanin

Fundamentals

In humans, melanin exists as three forms: eumelanin (which is subdivided further into black and brown forms), pheomelanin, and neuromelanin.

Cellular Level

Eumelanin and pheomelanin are produced in various amounts in the basal layer of the epidermis within cells called melanocytes. Melanocytes are the mature forms of melanoblasts, which migrate from the neural crest following neural tube closure. As melanin is produced within melanocytes, it is packaged in small, round membrane-bound organelles called melanosomes. Melanosomes are transported from melanocytes to neighboring keratinocytes via tentacle-like dendritic processes. Melanosomes arriving in keratinocytes are positioned superficially to cell nuclei, which serves to protect from incoming ultraviolet (UV) radiation.[4]

Molecular Level

The first step of biosynthesis of both eumelanin and pheomelanin begins the same way. Tyrosine is converted into dihydroxyphenylalanine (DOPA), which requires tyrosine hydroxylase and tetrahydrobiopterin as a cofactor. The enzyme tyrosinase then converts dihydroxyphenylalanine into dopaquinone, which can follow a variety of pathways to form the eumelanin or pheomelanin.

The primary stimulus for melanogenesis and subsequent melanosome production is UV radiation, which upregulates melanocyte production of pro-opiomelanocortin (POMC) and its downstream products, alpha-melanocyte-stimulating hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH). The overall effect is to increase eumelanin production. (Interestingly, people with pro-opiomelanocortin mutations have red hair and Fitzpatrick skin type 1 due to the relative increase in pheomelanin to eumelanin expression).

Neuromelanin is a dark pigment produced by dopaminergic and noradrenergic cells of the substantia nigra and locus coeruleus as a breakdown product of dopamine.[5]

Function

In its various forms, melanin fulfills a variety of biological functions, including skin and hair pigmentation and photoprotection of the skin and eye.

Pigmentation of the skin results from the accumulation of melanin-containing melanosomes in the basal layer of the epidermis. Differences in skin pigmentation result both from the relative ratio of eumelanin (brown–black) to pheomelanin (yellow–red), as well as the number of melanosomes within melanocytes. Pheomelanin accounts for the pinkish skin constituting the lips, nipples, vagina, and glans of the penis. In general, lightly pigmented skin tends to contain melanocytes with clusters of two to three melanosomes, whereas darkly pigmented skin tends to contain individual melanosomes which can melanize neighboring keratinocytes more readily. The overall melanin density correlates with the darkness of skin as well as Fitzpatrick skin type.

The interplay between melanin and UV radiation is complex. Researchers widely believe that melanin production in melanocytes increased as an evolutionary adaptation to the widespread loss of human body hair more than a million years ago. Populations living closer to the equator tended to develop a greater proportion of eumelanin, which is a UV–absorbent, antioxidant, and free radical scavenger. Conversely, populations living further from the equator are relatively richer in pheomelanin, which produces free radicals in response to UV radiation, accelerating carcinogenesis. As the main stimulus for cutaneous vitamin D production is UV light exposure, it follows that dark-skinned individuals also tend to have lower levels of vitamin D and should be screened accordingly.

Less clear is the link between melanin, the sun, and cutaneous immunology. Both acute and chronic UV light exposure induces immunosuppression; UVA light is used therapeutically for a large number of skin conditions, including psoriasis. Intriguingly, melanin is believed to have immunomodulatory and even anti-bacterial properties, although the underlying mechanisms have not yet been fully elucidated. Malignant melanocytes rich in melanin are less sensitive to chemo-, radio-, or photodynamic therapy, and amelanotic melanomas have longer disease-free and overall survival than melanotic ones. Therefore, some have suggested inhibition of melanogenesis as a therapy for malignant melanoma.

Just as melanin protects the skin from photodamage, it also protects the eye. Melanin is concentrated in the iris and choroid, and those with grey, blue, and green eye colors, as well as albinos, have more sun-related ocular issues.

Hair color is determined by the relative proportion of various forms of melanin:

• Black and brown hair results from varying degrees of black and brown eumelanin
• Blonde hair results from a small amount of brown eumelanin in the absence of black eumelanin
• Red hair results from roughly equal amounts of pheomelanin as eumelanin. Strawberry blonde hair results from brown eumelanin in the presence of pheomelanin.

Clinical Significance

Each step in the formation and transport of melanin may be impaired, resulting in a diverse group of diseases:[6][7][8]

• Melanoblast: Waardenburg syndrome, a group of autosomal recessive (AR) and dominant (AD) diseases characterized by a white forelock, skin hypopigmentation, and premature graying of the hair, results from impaired melanoblast migration to their destination tissue (i.e., iris, hair). Various forms also include congenital deafness, heterochromia iridis, synophrys, and dystopia canthorum.
• Melanocyte: Vitiligo, a disease characterized by photosensitive and depigmented white patches surrounded by normally pigmented skin and ophthalmologic issues, results from auto-immune destruction of melanocytes.
• Melanosome: Chédiak-Higashi syndrome, an autosomal recessive disease characterized by partial oculocutaneous albinism, platelet dysfunction, hemophagocytic lymphohistiocytosis (HLH), and immunodeficiency, results from mutations in genes which likely regulate lysosomal trafficking. Griscelli syndrome, an autosomal recessive group of diseases, characterized by hair and skin hypopigmentation, results from mutations in the protein complex responsible for the transfer of mature melanosomes to keratinocytes. Various forms also include neurologic impairment, immunodeficiency, and HLH.
• Tyrosinase: Phenylketonuria, an autosomal recessive disease characterized by intellectual disability, epilepsy, fair, blonde hair and blue eyes, and other skin changes, results from a deficiency of the phenylalanine hydroxylase enzyme. The pigmentary changes are due to competitive inhibition of tyrosinase by phenylalanine buildup. Oculocutaneous albinism, a group of autosomal recessive diseases characterized by hypopigmentation and ocular problems, results from mutations of the tyrosinase (TYR) gene. Vogt-Koyanagi-Harada syndrome, a disease characterized by progression through phases of meningoencephalitis, uveitis, alopecia with vitiligo-like depigmentation, and recurrent uveitis, results from autoimmune destruction of melanosome-bound antigens, possibly including the tyrosinase enzyme itself.
• Dopaminergic neurons: Parkinson disease, a neurodegenerative condition characterized by progressive postural and gait difficulties, results from drop-out of neuromelanin-producing dopaminergic neurons in the brain. Depigmentation of the substantia nigra pars compacta is a pathologic hallmark of the condition.