Micrograph of Melanin pigment (light refracting granular material—center of image) in a pigmentedmelanoma.Micrograph of the epidermis, with melanin labeled at left.
There are five basic types of melanin:eumelanin,pheomelanin,neuromelanin,allomelanin andpyomelanin.[2] Melanin is produced through a multistage chemical process known asmelanogenesis, where theoxidation of theamino acidtyrosine is followed bypolymerization. Pheomelanin is acysteinated form containing polybenzothiazine portions that are largely responsible for thered oryellow tint given to some skin or hair colors. Neuromelanin is found in the brain. Research has been undertaken to investigate its efficacy in treating neurodegenerative disorders such asParkinson's.[3] Allomelanin and pyomelanin are two types of nitrogen-free melanin.
Thephenotypic color variation observed in theepidermis andhair ofmammals is primarily determined by the levels of eumelanin and pheomelanin in the examined tissue. In an average human individual, eumelanin is more abundant in tissues requiringphotoprotection, such as the epidermis and theretinal pigment epithelium.[4] In healthy subjects, epidermal melanin is correlated with UV exposure, whileretinal melanin has been found to correlate with age, with levels diminishing 2.5-fold between the first and ninth decades of life,[5] which has been attributed tooxidative degradation mediated byreactive oxygen species generated vialipofuscin-dependent pathways.[6] In the absence ofalbinism orhyperpigmentation, the human epidermis contains approximately 74% eumelanin and 26% pheomelanin, largely irrespective of skin tone, with eumelanin content ranging between 71.8–78.9%, and pheomelanin varying between 21.1–28.2%.[7] Total melanin content in the epidermis ranges from around 0 μg/mg inalbino epidermal tissue[8] to >10 μg/mg in darker tissue.[7]
In the human skin, melanogenesis is initiated by exposure toUV radiation, causing the skin to darken. Eumelanin is an effective absorbent of light; the pigment is able to dissipate over 99.9% of absorbed UV radiation.[9] Because of this property, eumelanin is thought to protect skin cells from UVA and UVB radiation damage, reducing the risk of folate depletion and dermal degradation. Exposure to UV radiation is associated with increased risk ofmalignant melanoma, a cancer of melanocytes (melanin cells). Studies have shown a lower incidence for skin cancer in individuals with more concentrated melanin, i.e. darkerskin tone.[10]
Part of the structural formula of eumelanin. "(COOH)" can be COOH or H, or (more rarely) othersubstituents. The arrow denotes where the polymer continues.
Eumelanin (lit.'true melanin') has two forms linked to5,6-dihydroxyindole (DHI) and5,6-dihydroxyindole-2-carboxylic acid (DHICA). DHI-derived eumelanin is dark brown or black and insoluble, and DHICA -derived eumelanin which is lighter and soluble in alkali. Both eumelanins arise from the oxidation of tyrosine in specialized organelles calledmelanosomes. This reaction is catalyzed by the enzymetyrosinase. The initial product,dopaquinone can transform into either 5,6-dihydroxyindole (DHI) or 5,6-dihydroxyindole-2-carboxylic acid (DHICA). DHI and DHICA are oxidized and then polymerize to form the two eumelanins.[11]
In natural conditions, DHI and DHICA often co-polymerize, resulting in a range of eumelanin polymers. These polymers contribute to the variety of melanin components in human skin and hair, ranging from light yellow/red pheomelanin to light brown DHICA-enriched eumelanin and dark brown or black DHI-enriched eumelanin. These final polymers differ in solubility and color.[11]
Analysis of highly pigmented (Fitzpatrick type V and VI) skin finds that DHI-eumelanin comprises the largest portion, approximately 60–70%, followed by DHICA-eumelanin at 25–35%, and pheomelanin only 2–8%. Notably, while an enrichment of DHI-eumelanin occurs in duringsun tanning, it is accompanied by a decrease in DHICA-eumelanin and pheomelanin.[11] A small amount of black eumelanin in the absence of other pigments causes grey hair. A small amount of eumelanin in the absence of other pigments causes blond hair.[12] Eumelanin is present in the skin and hair, etc.
Part of the structural formula of pheomelanin. "(COOH)" can be COOH or H, or (more rarely) othersubstituents. The arrows denote where the polymer continues.
Pheomelanins (or phaeomelanins, from Greek φαιόςphaios, "grey") impart a range of yellowish to reddish colors.[13] Pheomelanins are particularly concentrated in the lips, nipples, glans of the penis, and vagina.[14] When a small amount of eumelanin in hair (which would otherwise cause blond hair) is mixed with pheomelanin, the result is orange hair, which is typically called"red" or "ginger" hair. Pheomelanin is also present in the skin, and redheads consequently often have a more pinkish hue to their skin as well. Exposure of the skin to ultraviolet light increases pheomelanin content, as it does for eumelanin; but rather than absorbing light, pheomelanin within the hair and skin reflect yellow to red light, which may increase damage from UV radiation exposure.[15]
Pheomelanin production is highly dependent oncysteine availability, which is transported into the melanosome, reacting with dopaquinone to form cys-dopa. Cys-dopa then undergoes several transformations before forming pheomelanin.[11] In chemical terms, pheomelanins differ from eumelanins in that the oligomer structure incorporatesbenzothiazine andbenzothiazole units that are produced,[16] instead of DHI andDHICA, when the amino acidL-cysteine is present.
Pheomelanins, unlike euemanins, are rare in lower organisms[17] with claims they are an "evolutionary innovation in the tetrapod lineage"[18] but recent research finds them also in some fish.[19]
Neuromelanin (NM) is an insoluble polymer pigment produced in specific populations ofcatecholaminergic neurons in the brain. Humans have the largest amount of NM, which is present in lesser amounts in other primates, and totally absent in many other species.[20] The biological function remains unknown, although human NM has been shown to efficiently bindtransition metals such as iron, as well as other potentially toxic molecules. Therefore, it may play crucial roles inapoptosis and the relatedParkinson's disease.[21]
Up until the 1960s, melanin was classified into eumelanin and pheomelanin. However, in 1955, a melanin associated with nerve cells was discovered, neuromelanin. In 1972 a water-soluble form, pyomelanin was discovered. In 1976, allomelanin, the fifth form of the melanins was found in nature.[2]
SEM micrograph ofAspergillus niger (strain: melanoliber) conodiophore possessing a large number of small conidospores (colorized). These spores release peptidomelanin into the surrounding medium during germination.The biochemical composition of peptidomelanin
Peptidomelanin is another water-soluble form of melanin.[22] It was found to be secreted into the surrounding medium by germinatingAspergillus niger (strain: melanoliber) spores. Peptidomelanin is formed as a copolymer between L-DOPA eumelanin and shortpeptides that form a 'corona', that are responsible for the substance's solubility. The peptide chains are linked to the L-DOPA core polymer via peptide bonds. This lead to a proposed biosynthetic process involving the hydroxylation of tyrosinylated peptides formed via proteases during sporogenesis, which are then incorporated autoxidatively into a growing L-DOPA core polymer.
It is possible to enrich melanin withselenium instead ofsulphur. This selenium analogue of pheomelanin has been successfully synthesized through chemical and biosynthetic routes using selenocystine as a feedstock.[23] Due to selenium's higher atomic number, the obtained selenomelanin can be expected to provide better protection against ionising radiation as compared to the other known forms of melanin. This protection has been demonstrated with radiation experiments on human cells and bacteria, opening up the possibility of applications in space travel.[24]
Trichochromes (formerly called trichosiderins) are pigments produced from the samemetabolic pathway as the eumelanins and pheomelanins, but unlike those molecules they have low molecular weight. They occur in some red human hair.[25]
The melanin in the skin is produced bymelanocytes, which are found in thebasal layer of theepidermis. Although, in general, human beings possess a similar concentration of melanocytes in their skin, the melanocytes in some individuals and ethnic groups produce variable amounts of melanin. The ratio of eumelanin (74%) and pheomelanin (26%) in the epidermis is constant regardless of the degree of pigmentation.[26] Some humans have very little or no melanin synthesis in their bodies, a condition known asalbinism.[27]
Because melanin is an aggregate of smaller component molecules, there are many different types of melanin with different 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.[28]
Melanins have very diverse roles and functions in various organisms. A form of melanin makes up the ink used by manycephalopods (seecephalopod ink) as a defense mechanism against predators. Melanins also protect microorganisms, such as bacteria and fungi, against stresses that involve cell damage such asUV radiation from the sun andreactive oxygen species. Melanin also protects against damage from high temperatures, chemical stresses (such asheavy metals andoxidizing agents), and biochemical threats (such as host defenses against invading microbes).[29] Therefore, in many pathogenic microbes (for example, inCryptococcus neoformans, a fungus) melanins appear to play important roles invirulence andpathogenicity by protecting the microbe againstimmune responses of itshost. 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.[30] Some types of fungi, calledradiotrophic fungi, appear to be able to use melanin as aphotosynthetic pigment that enables them to capturegamma rays[31] and harness this energy for growth.[32]
The darkerfeathers of birds owe their color to melanin and are less readily degraded by bacteria than unpigmented ones or those containingcarotenoid pigments.[35] Feathers that contain melanin are also 39% more resistant to abrasion than those that do not because melanin granules help fill the space between thekeratin strands that form feathers.[36][37] Pheomelanin synthesis in birds implies the consumption of cysteine, a semi‐essential amino acid that is necessary for the synthesis of the antioxidant glutathione (GSH) but that may be toxic if in excess in the diet. Indeed, many carnivorous birds, which have a high protein content in their diet, exhibit pheomelanin‐based coloration.[38]
Melanin is also important inmammalian pigmentation.[39] The coat pattern of mammals is determined by theagouti gene which regulates the distribution of melanin.[40][41] The mechanisms of the gene have been extensively studied in mice to provide an insight into the diversity of mammalian coat patterns.[42]
Melanin inarthropods has been observed to be deposited in layers thus producing aBragg reflector of alternating refractive index. When the scale of this pattern matches the wavelength of visible light,structural coloration arises: giving a number of species aniridescent color.[43][44]
Arachnids are one of the few groups in which melanin has not been easily detected, though researchers found data suggesting spiders do in fact produce melanin.[45]
Some moth species, including thewood tiger moth, convert resources to melanin to enhance their thermoregulation. As the wood tiger moth has populations over a large range of latitudes, it has been observed that more northern populations showed higher rates of melanization. In both yellow and white male phenotypes of the wood tiger moth, individuals with more melanin had a heightened ability to trap heat but an increased predation rate due to a weaker and less effectiveaposematic signal.[46]
Melanin may protectDrosophila flies andmice against DNA damage from non-UV radiation.[47]
Melanin produced by plants are sometimes referred to as 'catechol melanins' as they can yieldcatechol on alkali fusion. It is commonly seen in theenzymatic browning of fruits such as bananas. Chestnut shell melanin can be used as an antioxidant and coloring agent.[48] Biosynthesis involves the oxidation ofindole-5,6-quinone by the tyrosinase typepolyphenol oxidase fromtyrosine andcatecholamines leading to the formation of catechol melanin. Despite this many plants contain compounds which inhibit the production of melanins.[49]
It is now understood that melanins do not have a single structure or stoichiometry.[citation needed] Nonetheless, chemical databases such as PubChem include structural and empirical formulae; typically3,8-Dimethyl-2,7-dihydrobenzo[1,2,3-cd:4,5,6-c′d′]diindole-4,5,9,10-tetrone. This can be thought of as a single monomer that accounts for the measured elemental composition and some properties of melanin, but is unlikely to be found in nature.[50] Solano[50] claims that this misleading trend stems from a report of an empirical formula in 1948,[51] but provides no other historical detail.
Melanin is brown, non-refractile, and finely granular with individual granules having a diameter of less than 800 nanometers. This differentiates melanin from commonblood 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 ofpotassium permanganate is an effective melanin bleach.[53]
There are approximately nine types ofoculocutaneous 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 and white Europeans. People with OCA2 usually have fair skin, but are often not as pale as OCA1. They (OCA2 or OCA1? see comments in History) have pale blonde to golden, strawberry blonde, or even brown hair, and most commonly blue eyes. 98.7–100% of modern Europeans are carriers of the derived alleleSLC24A5, a known cause of nonsyndromic oculocutaneous albinism. It is an autosomal recessive disorder characterized by acongenital 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.[54] In some African nations, the frequency of the disorder is even higher, ranging from 1 in 2,000 to 1 in 5,000.[55] Another form of Albinism, the "yellow oculocutaneous albinism", appears to be more prevalent among theAmish, 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.[55]
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 2,700 most prevalent among people of Puerto Rican origin, are associated with mortality beyond melanoma-related deaths.
The connection between albinism anddeafness is well known, though poorly understood. In his 1859 treatiseOn the Origin of Species,Charles Darwin observed that "cats which are entirely white and have blue eyes are generally deaf".[56] In humans, hypopigmentation and deafness occur together in the rareWaardenburg's syndrome, predominantly observed among theHopi in North America.[57] The incidence of albinism in Hopi Indians has been estimated as approximately 1 in 200 individuals. Similar patterns of albinism and deafness have been found in other mammals, including dogs and rodents. However, a lack of melaninper 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.[58] Instead, the absence ofmelanocytes in the stria vascularis of the inner ear results incochlear impairment,[59] though the reasons for this are not fully understood.
In Parkinson's disease, a disorder that affectsneuromotor functioning, there is decreased neuromelanin in the substantia nigra and locus coeruleus as a consequence of specific dropping out of dopaminergic and noradrenergic pigmented neurons. This results in diminisheddopamine andnorepinephrine 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."[60]
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 melanosomalmatrix proteins, changes inpH, or in local concentrations of metal ions. A decreased molecular weight or a decrease in the degree of polymerization ofocular melanin has been proposed to turn the normally anti-oxidant polymer into apro-oxidant. In its pro-oxidant state, melanin has been suggested to be involved in the causation and progression ofmacular degeneration andmelanoma.[61]Rasagiline, an important monotherapy drug in Parkinson's disease, has melanin binding properties, and melanoma tumor reducing properties.[62]
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 ofport-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 a similar manner, melanin can complicate laser treatment of other dermatological conditions in people with darker skin.
Freckles andmoles 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. This has been suggested to underlie the increasednicotine dependence and lowersmoking cessation rates in darker pigmented individuals.[63]
Melanocytes insert granules of melanin into specialized cellularvesicles calledmelanosomes. These are then transferred into thekeratinocyte cells of the humanepidermis. The melanosomes in each recipient cell accumulate atop thecell nucleus, where they protect the nuclearDNA from mutations caused by theionizing radiation of the sun'sultraviolet rays. In general, people whose ancestors lived for long periods in the regions of the globe near theequator 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 result inmelanomas in lighter-skinned people.[64]
Not all the effects of pigmentation are advantageous. Pigmentation increases the heat load in hot climates, and dark-skinned people absorb 30% more heat from sunlight than do very light-skinned people, although this factor may be offset by more profuse sweating. In cold climates dark skin entails more heat loss by radiation. Pigmentation also hinders synthesis ofvitamin D. Since pigmentation appears to be not entirely advantageous to life in the tropics, other hypotheses about its biological significance have been advanced; for example a secondary phenomenon induced by adaptation to parasites and tropical diseases.[65]
Early humans evolved dark skin color, as an adaptation to a loss of body hair that increased the effects of UV radiation. Before the development of hairlessness, early humans might have had light skin underneath their fur, similar to that found in otherprimates.[66]Anatomically modern humans evolved in Africa between 200,000 and 100,000 years ago,[67] and then populated the rest of the world through migration between 80,000 and 50,000 years ago, in some areasinterbreeding with certainarchaic human species (Neanderthals,Denisovans, and possibly others).[68] The first modern humans had darker skin as the indigenous people of Africa today. Following migration and settlement in Asia and Europe, the selective pressure dark UV-radiation protecting skin decreased where radiation from the sun was less intense. This resulted in the current range of human skin color. Of the two common gene variants known to be associated with pale human skin,Mc1r does not appear to have undergone positive selection,[69] whileSLC24A5 has undergone positive selection.[70]
As with peoples having migrated northward, those with light skin migrating toward the equator acclimatize to the much stronger solar radiation. Nature selects for less melanin when ultraviolet radiation is weak. Most people's skin darkens when exposed to UV light, giving them more protection when it is needed. This is the physiological purpose ofsun tanning. Dark-skinned people, who produce more skin-protecting eumelanin, have a greater protection againstsunburn and the development of melanoma, a potentially deadly form of skin cancer, as well as other health problems related to exposure to strongsolar radiation, including thephotodegradation of certainvitamins such asriboflavins,carotenoids,tocopherol, andfolate.[71]
Melanin in the eyes, in theiris andchoroid, helps protect fromultraviolet andhigh-frequency visible light; people with blue, green, and grey eyes are more at risk of sun-related eye problems. Furthermore, the ocular lens yellows with age, providing added protection. However, the lens also becomes more rigid with age, losing most of itsaccommodation—the ability to change shape to focus from far to near—a detriment due probably toprotein crosslinking caused by UV exposure.
Recent research suggests that melanin may serve a protective role other than photoprotection.[72] Melanin is able to effectivelychelate metal ions through its carboxylate and phenolic hydroxyl groups, often 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
Heavily pigmented melanoma cells have aYoung's modulus of about 4.93 kPa, compared to non-pigmented cells, with a value of 0.98 kPa.[77] Theelasticity of melanoma cells is crucial to metastasis and growth; non-pigmented tumors were larger than pigmented tumors, and spread far more easily. Pigmented and non-pigmented cells are both present in melanomatumors, so that they can both bedrug-resistant and metastatic.[77]
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