Melanin
i/ˈmɛlənɪn/ (Greek:
μέλας - melas,
"black, dark") is a broad term for a group of natural pigments found in
most organisms (arachnids
are one of the few groups in which it has not been detected). Melanin is
produced by the oxidation of the amino acid
tyrosine,
followed by polymerization. The pigment is produced in a specialized group of
cells known as melanocytes.
There are three basic types of melanin: eumelanin, pheomelanin,
and neuromelanin.
The most common type is eumelanin, and is produced in 'black' and 'brown'
subtypes. Pheomelanin is a cysteine-containing red-brown polymer of benzothiazine
units largely responsible for red hair and freckles.
Neuromelanin is found in the brain, though its function remains obscure.
In the skin, melanogenesis occurs after exposure to UV
radiation, causing the skin to visibly tan. Melanin is an
effective absorber of light; the pigment is able to dissipate over 99.9% of
absorbed UV radiation.Because of this property, melanin is thought to protect
skin cells from UVB radiation damage, reducing the risk of cancer.
Furthermore, though exposure to UV radiation is associated with increased risk
of malignant melanoma, a cancer of the melanocytes,
studies have shown a lower incidence for skin cancer in individuals with more
concentrated melanin, i.e. darker skin tone. Nonetheless, the relationship
between skin pigmentation and photoprotection
is still being clarified.
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
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
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. 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. Pheomelanin is particularly concentrated in the
lips, nipples, glans of the penis, and vagina. In chemical terms, pheomelanin
differs from eumelanin in that its oligomer structure incorporates benzothiazine
and benzothiazole
units that are produced, 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 other
species. 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.
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). 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. 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
and harness this energy for growth.
The black feathers of birds owe their color to melanin; they
are less readily degraded by bacteria than white feathers, or those containing
other pigments such as carotenes. In a bird's eye, a specialized organ, rich in
blood vessels, the pecten oculi, is also extremely rich in melanin, which
has been considered to have role in absorption of light falling on optic disc
and using it to warm up the eye. This, in turn may stimulate release of
nutrients from pecten oculi to retina, via vitreous humor; it is plausible as
bird retina is devoid of its own blood vessels. In pigment epithelium of retina, presence of
high amounts of melanin granules may also minimize back-scatter of image light
on the retina.
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.
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:
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 KEGG database (see 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.In some African nations, the frequency of the disorder is even
higher, ranging from 1 in 2,000 to 1 in 5,000. 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.
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.
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". In humans, hypopigmentation and deafness occur
together in the rare Waardenburg's syndrome, predominantly
observed among the Hopi
in North
America. 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. Instead the absence of melanocytes
in the stria vascularis of the inner ear results in cochlear
impairment, 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.".Also see Nicolaus 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. Rasagiline,
an important monotherapy drug in Parkinson's disease, has melanin binding
properties, and melanoma tumor reducing properties.
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.
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 result 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 originated in Africa, 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 does not
appear to have undergone positive selection, while SLC24A5 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. 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. 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. 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. 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.
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