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Eumelanin

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Eumelanin

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


Melanin

It has been traditionally believed that skin pigmentation is the most important photon-protective factor, since melanin, besides functioning as a broadband UV absorbent, aids in the acquiescence of vitamin D from sunlight. Sunlight exposure to the epidermis produces melanin in billions of individuals, causing a tan effect on the skin. Some believe that melanin somehow blocks vitamin D absorption; evidence about this is not clear. More opportunity for valid scientific study may be required. Many epidemiological studies have shown a lower incidence for skin cancer in individuals with more concentrated melanin.[2]

For many dominant animals, melanin pigments are derivatives of the amino acid tyrosine. There are three basic types, namely eumelanin, pheomelanin, and neuromelanin. The most common biological type is eumelanin, which is a polymer, which in rudimentary form is a hydro-carbon. Pheomelanin is a cysteine-containing red-brown polymer of benzothiazine units largely responsible for red hair and freckles. Neuromelanin is present in the brain, but its function remains obscure. The production of melanin in human skin is called melanogenesis. This occurs by means of a process called "ultrafast internal conversion", which enables melanin to dissipate more than 99.9% of the absorbed UV radiation as heat[3] (see photoprotection). This prevents the UVB radiation damage that is responsible for the formation of malignant melanoma and other skin cancers.

Humans


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 pigment-bearing neurons within areas of the brainstem, such as the locus coeruleus and the substantia nigra. It also occurs in the zona reticularis of the adrenal gland.

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 synthesis 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

Eumelanin polymers have long been thought to comprise numerous cross-linked 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) polymers. The two types are recognized: black and brown. Black melanin is darker than brown. 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

Pheomelanin imparts a pink to red hue and, thus, is found in particularly large quantities in red hair.[4] Pheomelanin is particularly concentrated in the lips, nipples, glans of the penis, and vagina.[5] In chemical terms, pheomelanin differs from eumelanin in that its oligomer structure incorporates benzothiazine and benzothiazole units that are produced,[6] instead of DHI and DHICA, when the amino acid L-cysteine is present.

Neuromelanin

Neuromelanin (NM) is a dark polymer pigment produced in specific populations of catecholaminergic neurons in the brain. Humans have the most number of NM, while they are in lesser amount in other non-human primates, and totally absent in lower species.[7] However, the biological function remains unknown, although human NM has been shown to efficiently bind transition metals such as iron, as well as other potentially toxic molecules. Therefore, it may play crucial roles in apoptosis and the related Parkinson's disease.[8]

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).[9] 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.[10] 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[11] and harness its energy for growth.[12]

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.[13]

In some mice, melanin is used slightly differently. For instance, in Agouti mice, the hair appears brown because of alternation between black eumelanin production and a yellow variety of pheomelanin. The hairs are actually banded black and yellow, and the net effect is the brown color of most mice. Some genetic irregularities can produce either fully black or fully yellow mice.

Catechol melanins are plant melanins.

Biosynthetic pathways



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

TyrosineDOPAdopaquinone

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

Also, 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

Detailed metabolic pathways can be found in the External links).

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 nine 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.[14] In some African nations, the frequency of the disorder is even higher, ranging from 1 in 2,000 to 1 in 5,000.[15] 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.[15]

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.
[15]

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

The connection between albinism and deafness is well known, though poorly understood. 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".[16] In humans, hypopigmentation and deafness occur together in the rare Waardenburg's syndrome, predominantly observed among the Hopi in North America.[17] 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.[18] Instead the absence of melanocytes in the stria vascularis of the inner ear results in cochlear impairment,[19] though why this is, is not fully understood.

In Parkinson's disease, a disorder that affects neuromotor functioning, there is decreased neuromelanin in the substantia nigra and locus coeruleus as consequence of specific dropping out of dopaminergic and noradrenergic pigmented neurons. This results in diminished dopamine and norepinephrine 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.".[20] Also see Nicolaus[21] 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.[22] Rasagiline, an important monotherapy drug in Parkinson's disease, has melanin binding properties, and melanoma tumor reducing properties.[23]

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. This has been suggested to underlie the increased nicotine dependence and lower smoking cessation rates in darker pigmented individuals.[24]

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, autumn through spring.

The most recent scientific evidence indicates that all humans evolved in Africa,[25] 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[26] does not appear to have undergone positive selection, while SLC24A5[27] 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.[28] 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

Evidence exists in support of a highly cross-linked heteropolymer bound covalently to matrix scaffolding melanoproteins.[29] 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.[30] 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.[31] 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.[32]

See also

References

  • "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.[1]
  • 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
  • Tyrosine metabolism in KEGG
  • Melanogenesis in KEGG
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