Melanin

Not to be confused with melamine, melatonin, or Melanotan (disambiguation).

Melanin pigment (dark granular material - center of image) in a pigmented melanoma. Pap stain.

Melanin ⁱ/ˈmɛlənɪn/ (Greek: μέλας, black) is a pigment that is ubiquitous in nature, being found in most organisms (spiders are one of the few groups in which it has not been detected). In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms. All melanins can be considered as derivatives of polyacetylene, since they rely on a polyconiugate structure. Another common form of melanin is pheomelanin, a red-brown polymer of benzothiazine units largely responsible for red hair and freckles. The presence of melanin in the archaea and bacteria kingdoms is an issue of ongoing debate among researchers in the field.

The increased production of melanin in human skin is called melanogenesis. Production of melanin is stimulated by DNA damage induced by UVB-radiation,^[1] and it leads to a delayed development of a tan. This melanogenesis-based tan takes more time to develop, but it is long-lasting.^[2]

The photochemical properties of melanin make it an excellent photoprotectant. It absorbs harmful UV-radiation (ultraviolet) and transforms the energy into harmless heat through a process called "ultrafast internal conversion". This property enables melanin to dissipate more than 99.9% of the absorbed UV radiation as heat^[3] (see photoprotection). This prevents the indirect DNA damage that is responsible for the formation of malignant melanoma and other skin cancers.

In humans

Albinism occurs when melanocytes produce little or no melanin. This albino girl is from Papua New Guinea.

In humans, melanin is the primary determinant of skin color. It is also found in hair, the pigmented tissue underlying the iris of the eye, and the stria vascularis of the inner ear. In the brain, tissues with melanin include the medulla and zona reticularis of the adrenal gland, and pigment-bearing neurons within areas of the brainstem, such as the locus coeruleus and the substantia nigra.

The melanin in the skin is produced by melanocytes, which are found in the basal layer of the epidermis. Although, in general, human beings possess a similar concentration of melanocytes in their skin, the melanocytes in some individuals and ethnic groups more frequently or less frequently express the melanin-producing genes, thereby conferring a greater or lesser concentration of skin melanin. Some individual animals and humans have very little or no melanin in their bodies, a condition known as albinism.

Because melanin is an aggregate of smaller component molecules, there are many different types of melanin with differing proportions and bonding patterns of these component molecules. Both pheomelanin and eumelanin are found in human skin and hair, but eumelanin is the most abundant melanin in humans, as well as the form most likely to be deficient in albinism.

Eumelanin

Part of the structural formula of eumelanin. "(COOH)" can be COOH or H, or (more rarely) other substituents. The arrow denotes where the polymer continues.

Eumelanin polymers have long been thought to comprise numerous cross-linked 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) polymers. However, recent research into the electrical properties of eumelanin has indicated that it may consist of more basic oligomers adhering to one another by some other mechanism. Eumelanin is found in hair, areola, and skin, and the hair colors grey, black, yellow, and brown. In humans, it is more abundant in people with dark skin.

There are two different types of eumelanin. The two types are black eumelanin and brown eumelanin, with black melanin being darker than brown. Black eumelanin is mostly in non-Europeans and aged Europeans, while brown eumelanin is in mostly young Europeans.

A small amount of black eumelanin in the absence of other pigments causes grey hair. A small amount of brown eumelanin in the absence of other pigments causes yellow (blond) color hair.

Pheomelanin

Part of the structural formula of pheomelanin. "(COOH)" can be COOH or H, or (more rarely) other substituents. The arrows denotes where the polymer continues.

Pheomelanin is also found in hair and skin and is both in lighter-skinned humans and darker-skinned humans. Pheomelanin imparts a pink to red hue and, thus, is found in particularly large quantities in red hair.^[4] Pheomelanin also may become carcinogenic when exposed to the ultraviolet rays of the sun. In chemical terms, pheomelanin differs from eumelanin in that its oligomer structure incorporates benzothiazine and benzothiazole units that are produced,^[5] instead of DHI and DHICA, when the amino acid L-cysteine is present.

Neuromelanin

Neuromelanin is the dark pigment present in pigment-bearing neurons of four deep brain nuclei: the substantia nigra (from the Latin black substance) - Pars Compacta part, the locus coeruleus (blue spot), the dorsal motor nucleus of the vagus nerve (cranial nerve X), and the median raphe nucleus of the pons. Both the substantia nigra and locus coeruleus can be easily identified grossly at the time of autopsy because of their dark pigmentation. In humans, these nuclei are not pigmented at the time of birth, but develop pigmentation during maturation to adulthood.

Although the functional nature of neuromelanin is unknown in the brain, the pigment is made from oxyradical metabolites of monoamine neurotransmitters including dopamine and norepinephrine. Luigi Zecca and David Sulzer demonstrated that neuromelanin pigment is an autophagy product that accumulates in lysosomes, which are unable to effectively degrade it.^[6] In this way, the synthesis of neuromelanin, is protective as its encapsulation within the autophagic organelle removes it from reacting with sites in the neuronal cytosol that could lead to neurotoxicity.

While neuromelanin becomes higher throughout life in most people,^[7] the loss of pigmented neurons from specific nuclei is seen in a variety of neurodegenerative diseases. In Parkinson's disease there is massive loss of dopamine-producing pigmented neurons in the substantia nigra. High levels of neuromelanin are also detected in other primates, and in carnivores such as cats and dogs.

In other organisms

Melanins have very diverse roles and functions in various organisms. A form of melanin makes up the ink used by many cephalopods (see cephalopod ink) as a defense mechanism against predators. Melanins also protect microorganisms, such as bacteria and fungi, against stresses that involve cell damage such as UV radiation from the sun and reactive oxygen species. Melanin also protects against damage from high temperatures, chemical stresses (such as heavy metals and oxidizing agents), and biochemical threats (such as host defenses against invading microbes).^[8] Therefore, in many pathogenic microbes (for example, in Cryptococcus neoformans, a fungus) melanins appear to play important roles in virulence and pathogenicity by protecting the microbe against immune responses of its host. In invertebrates, a major aspect of the innate immune defense system against invading pathogens involves melanin. Within minutes after infection, the microbe is encapsulated within melanin (melanization), and the generation of free radical byproducts during the formation of this capsule is thought to aid in killing them.^[9] Some types of fungi, called radiotrophic fungi, appear to be able to use melanin as a photosynthetic pigment that enables them to capture gamma rays^[10] and harness its energy for growth.^[11]

The black feathers of birds owe their color to melanin; they are much more readily degraded by bacteria than white feathers, or those containing other pigments such as carotenes.^[12]

Catechol melanins are plant melanins.

Biosynthetic pathways

L-tyrosine

L-DOPA

L-dopaquinone

L-leucodopachrome

L-dopachrome

The first step of the biosynthetic pathway for both eumelanins and pheomelanins is catalysed by tyrosinase:

Tyrosine → DOPA → dopaquinone

Dopaquinone can combine with cysteine by two pathways to benzothiazines and pheomelanins

Dopaquinone + cysteine → 5-S-cysteinyldopa → benzothiazine intermediate → pheomelanin

Dopaquinone + cysteine → 2-S-cysteinyldopa → benzothiazine intermediate → pheomelanin

Alternatively, dopaquinone can be converted to leucodopachrome and follow two more pathways to the eumelanins

Dopaquinone → leucodopachrome → dopachrome → 5,6-dihydroxyindole-2-carboxylic acid → quinone → eumelanin

Dopaquinone → leucodopachrome → dopachrome → 5,6-dihydroxyindole → quinone → eumelanin

Microscopic appearance

Melanin is brown, non-refractile, and finely granular with individual granules having a diameter of less than 800 nanometers. This differentiates melanin from common blood breakdown pigments, which are larger, chunky, and refractile, and range in color from green to yellow or red-brown. In heavily pigmented lesions, dense aggregates of melanin can obscure histologic detail. A dilute solution of potassium permanganate is an effective melanin bleach.

Genetic disorders and disease states

Melanin deficiency has been connected for some time with various genetic abnormalities and disease states.

There are approximately ten different types of oculocutaneous albinism, which is mostly an autosomal recessive disorder. Certain ethnicities have higher incidences of different forms. For example, the most common type, called oculocutaneous albinism type 2 (OCA2), is especially frequent among people of black African descent. It is an autosomal recessive disorder characterized by a congenital reduction or absence of melanin pigment in the skin, hair, and eyes. The estimated frequency of OCA2 among African-Americans is 1 in 10,000, which contrasts with a frequency of 1 in 36,000 in white Americans.^[13] In some African nations, the frequency of the disorder is even higher, ranging from 1 in 2,000 to 1 in 5,000.^[14] Another form of Albinism, the "yellow oculocutaneous albinism", appears to be more prevalent among the Amish, who are of primarily Swiss and German ancestry. People with this IB variant of the disorder commonly have white hair and skin at birth, but rapidly develop normal skin pigmentation in infancy.^[14]

Ocular albinism affects not only eye pigmentation, but visual acuity, as well. People with albinism typically test poorly, within the 20/60 to 20/400 range. In addition, two forms of albinism, with approximately 1 in 2700 most prevalent among people of Puerto Rican origin, are associated with mortality beyond melanoma-related deaths.

Mortality also is increased in patients with Hermansky-Pudlak syndrome and Chediak-Higashi syndrome. Patients with Hermansky-Pudlak syndrome have a bleeding diathesis secondary to platelet dysfunction and also experience restrictive lung disease (pulmonary fibrosis), inflammatory bowel disease, cardiomyopathy, and renal disease. Patients with Chediak-Higashi syndrome are susceptible to infection and also can develop lymphofollicular malignancy.^[14]

The role that melanin deficiency plays in such disorders remains under study.

The connection between albinism and deafness is well known, though poorly understood. E.g., in his 1859 treatise On the Origin of Species, Charles Darwin observed that "cats which are entirely white and have blue eyes are generally deaf".^[15] In humans, hypopigmentation and deafness occur together in the rare Waardenburg's syndrome, predominantly observed among the Hopi in North America.^[16] The incidence of albinism in Hopi Indians has been estimated as approximately 1 in 200 individuals. It is interesting to note that similar patterns of albinism and deafness have been found in other mammals, including dogs and rodents. However, a lack of melanin per se does not appear to be directly responsible for deafness associated with hypopigmentation, as most individuals lacking the enzymes required to synthesize melanin have normal auditory function.^[17] Instead the absence of melanocytes in the stria vascularis of the inner ear results in cochlear impairment,^[18] though why this is, is not fully understood. It may be that melanin, the best sound-absorbing material known, plays some protective function.^{[citation needed]} in alternate fashion, melanin may affect development, as Darwin suggests.

In Parkinson's disease, a disorder that affects neuromotor functioning, there is decreased neuromelanin in the substantia nigra as consequence of specific dropping out of dopaminergic pigmented neurons. This results in diminished dopamine synthesis. While no correlation between race and the level of neuromelanin in the substantia nigra has been reported, the significantly lower incidence of Parkinson's in blacks than in whites has "prompt[ed] some to suggest that cutaneous melanin might somehow serve to protect the neuromelanin in substantia nigra from external toxins.".^[19] Also see Nicolaus^[20] review article on the function of neuromelanins

In addition to melanin deficiency, the molecular weight of the melanin polymer may be decreased by various factors such as oxidative stress, exposure to light, perturbation in its association with melanosomal matrix proteins, changes in pH or in local concentrations of metal ions. A decreased molecular weight or a decrease in the degree of polymerization of ocular melanin has been proposed to turn the normally anti-oxidant polymer into a pro-oxidant. In its pro-oxidant state, melanin has been suggested to be involved in the causation and progression of macular degeneration and melanoma.^[21]

Higher eumelanin levels also can be a disadvantage, however, beyond a higher disposition toward vitamin D deficiency. Dark skin is a complicating factor in the laser removal of port-wine stains. Effective in treating white skin, in general, lasers are less successful in removing port-wine stains in people of Asian or African descent. Higher concentrations of melanin in darker-skinned individuals simply diffuse and absorb the laser radiation, inhibiting light absorption by the targeted tissue. In similar manner, melanin can complicate laser treatment of other dermatological conditions in people with darker skin.

Freckles and moles are formed where there is a localized concentration of melanin in the skin. They are highly associated with pale skin.

Nicotine has an affinity for melanin-containing tissues because of its precursor function in melanin synthesis or its irreversible binding of melanin and nicotine. This has been suggested to underlie the increased nicotine dependence and lower smoking cessation rates in darker pigmented individuals.^[22]

Human adaptation

Melanocytes insert granules of melanin into specialized cellular vesicles called melanosomes. These are then transferred into the other skin cells of the human epidermis. The melanosomes in each recipient cell accumulate atop the cell nucleus, where they protect the nuclear DNA from mutations caused by the ionizing radiation of the sun's ultraviolet rays. In general, people whose ancestors lived for long periods in the regions of the globe near the equator have larger quantities of eumelanin in their skins. This makes their skins brown or black and protects them against high levels of exposure to the sun, which more frequently results in melanomas in lighter-skinned people.

With humans, exposure to sunlight stimulates the skin to produce vitamin D. Because high levels of cutaneous melanin act as a natural sun screen, dark skin can be a risk factor for vitamin D deficiency in regions of the Earth known as cool temperate zones, i.e., above 36 degrees latitude in the Northern hemisphere and below 36 degrees in the Southern hemisphere. As a result of this, health authorities in Canada and the USA have issued recommendations for people with darker complexions (including people of southern European descent) to consume between 1000-2000 IU (International Units) of vitamin D, daily, through Autumn to Spring.

The most recent scientific evidence indicates that all humans evolved in Africa,^[23] then populated the rest of the world through successive radiations. It seems likely that the first modern humans had relatively large numbers of eumelanin-producing melanocytes. In accordance, they had darker skin as with the indigenous people of Africa today. As some of these original peoples migrated and settled in areas of Asia and Europe, the selective pressure for eumelanin production decreased in climates where radiation from the sun was less intense. Of the two common gene variants known to be associated with pale human skin, Mc1r^[24] does not appear to have undergone positive selection, while SLC24A5^[25] has.

As with peoples having migrated northward, those with light skin migrating toward the equator acclimatize to the much stronger solar radiation. Most people's skin darkens when exposed to UV light, giving them more protection when it is needed. This is the physiological purpose of sun tanning. Dark-skinned people, who produce more skin-protecting eumelanin, have a greater protection against sunburn and the development of melanoma, a potentially deadly form of skin cancer, as well as other health problems related to exposure to strong solar radiation, including the photodegradation of certain vitamins such as riboflavins, carotenoids, tocopherol, and folate.

Melanin in the eyes, in the iris and choroid, helps protect them from ultraviolet and high-frequency visible light; people with gray, blue, and green eyes are more at risk for sun-related eye problems. Further, the ocular lens yellows with age, providing added protection. However, the lens also becomes more rigid with age, losing most of its accommodation — the ability to change shape to focus from far to near — a detriment due probably to protein crosslinking caused by UV exposure.

Recent research by J.D. Simon et al.^[26] suggests that melanin may serve a protective role other than photoprotection. Melanin is able to effectively ligate metal ions through its carboxylate and phenolic hydroxyl groups, in many cases much more efficiently than the powerful chelating ligand ethylenediaminetetraacetate (EDTA). Thus, it may serve to sequester potentially toxic metal ions, protecting the rest of the cell. This hypothesis is supported by the fact that the loss of neuromelanin observed in Parkinson's disease is accompanied by an increase in iron levels in the brain.

Physical properties and technological applications

In terms of structure and electronics, melanins are "rigid-backbone" conductive polymers composed of polyacetylene, polypyrrole, and polyaniline "Blacks" and their mixed copolymers. The simplest melanin is polyacetylene, and some fungal melanins are pure polyacetylene.

In 1963, D.E Weiss and coworkers reported^[27][28][29] high electrical conductivity in a melanin, iodine-doped and oxidized polypyrrole "Black". They achieved the quite high conductivity of 1 Ohm/cm. A decade later, John McGinness, and coworkers reported a high conductivity "ON" state in a voltage-controlled solid-state threshold switch made with DOPA melanin. Further, this material emitted a flash of light—electroluminescence—when it switched. Melanin also shows negative resistance, a classic property of electronically-active conductive polymers. Likewise, melanin is the best sound-absorbing material known,^[30] because of its strong electron-phonon coupling. This might explain part of the reason behind melanin's presence in the inner ear.

Melanin voltage-controlled switch, an "active" organic polymer electronic device from 1974. Smithsonian Chip collection.

These early discoveries were "lost" until the recent emergence of such melanins in device applications, in particular, electroluminescent displays. In 2000, the Nobel Prize in Chemistry was awarded to three scientists for their subsequent 1977 (re)discovery and development of such conductive organic polymers. In an essential reprise of the work by Weiss et al., these polymers were oxidized, iodine-doped "polyacetylene black" melanins. There is no evidence that the Nobel committee was aware of the almost identical prior report by Weiss et al.^[27][28][29] of passive high conductivity in iodinated polypyrrole black or of switching and high electrical conductivity in DOPA melanin and related organic semiconductors. The melanin organic electronic device is now in the Smithsonian Institution's National Museum of American History's "Smithsonian Chips",^[31] collection of historic solid-state electronic devices.

Although synthetic melanin (commonly referred to as BSM, or "black synthetic matter") is made up of 3-6 oligomeric units linked together — the so-called "protomolecule" — there is no evidence that naturally occurring biopolymer (BCM, for "black cell matter") mimics this structure. However, since there is no reason to believe that natural melanin does not belong to the category of the polyarenes and polycationic polyenes, like pyrrol black and acetylene black, it is necessary to review all the chemical and biological analytic data gathered to date in the study of natural melanins (eumelanins, pheomelanins, allomelanins)."^[32]

Evidence exists in support of a highly cross-linked heteropolymer bound covalently to matrix scaffolding melanoproteins.^[33] It has been proposed that the ability of melanin to act as an antioxidant is directly proportional to its degree of polymerization or molecular weight.^[34] Suboptimal conditions for the effective polymerization of melanin monomers may lead to formation of lower-molecular-weight, pro-oxidant melanin that has been implicated in the causation and progression of macular degeneration and melanoma.^[35] Signaling pathways that upregulate melanization in the retinal pigment epithelium (RPE) also may be implicated in the downregulation of rod outer segment phagocytosis by the RPE. This phenomenon has been attributed in part to foveal sparing in macular degeneration.^[36]

Bias in human societies

The act of placing skin pigmentation within a rubric of racial classification and linked to social status or other human attributes is known as racialism. Many people and societies overlay racialism with racist perceptions and systems that arbitrarily assign to groups of people sharing a genetically transmitted pigmentation a status of inherent superiority or inferiority, privilege, or disadvantage based on skin color.

Apartheid-era South Africa is an example of a white supremacist society based on a system of stratification of power and privilege by skin color, as well as racial admixture. Similar examples can be found in Israel, Brazil's highly socially color-stratified society; and, in the U.S., segregation, institutional racism, and internal "color consciousness" on the part of members of some ethnicities.

See also

• Addison's disease
• Albino
• Carotene
• Griscelli syndrome A syndrome characterised by hypopigmentation.
• Human skin color
• List of human hair color genes
• Mc1r
• Melanin theory, a pseudoscientific theory that ascribes supernatural abilities to melanin
• Melanism
• Melanogenesis, the increased production of melanin
• Melanoma
• Melanotropin receptor
• Organic semiconductor
• Parkinson's disease
• Risks and benefits of sun exposure
• SLC24A5
• Vitamin D

References

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• "Link 4-Melanin 95-97," taken from R.A.Nicolaus,G.Scherillo La Melanina.Un riesame su struttura,proprietà e sistemi, Atti della Accademia Pontaniana, Vol.XLIV,265-287, Napoli 1995.[2]
• Dr. Mohammed O. Peracha, Dean Elloit, and Enrique Garcia-Valenzuela, "Occular Manifestations of Albinism" (Abstract at emedicine.com, Sept. 13, 2005).

External links

• Absorption spectrum of melanin