Pro-opiomelanocortin (POMC) is a precursor
polypeptide
Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty ...
with 241
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
residues. POMC is
synthesized in
corticotrophs of the
anterior pituitary
The anterior pituitary (also called the adenohypophysis or pars anterior) is a major Organ (anatomy), organ of the endocrine system. The anterior pituitary is the glandular, Anatomical terms of location#Usage in human anatomy, anterior lobe that t ...
from the 267-amino-acid-long
polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the removal of a 26-amino-acid-long
signal peptide
A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16–30 amino acids long) present at the ...
sequence during
translation
Translation is the communication of the semantics, meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The English la ...
. POMC is part of the
central melanocortin system.
Function
POMC is cut (cleaved) to give rise to multiple
peptide
Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...
hormones. Each of these peptides is packaged in large dense-core
vesicles that are released from the cells by
exocytosis
Exocytosis is a term for the active transport process that transports large molecules from cell to the extracellular area. Hormones, proteins and neurotransmitters are examples of large molecules that can be transported out of the cell. Exocytosis ...
in response to appropriate stimulation:
*
α-MSH produced by neurons in the
ventromedial nucleus
The ventromedial nucleus of the hypothalamus (VMN, VMH or ventromedial hypothalamus) is a nucleus of the hypothalamus. In 2007, Kurrasch ''et al''. found that the ventromedial hypothalamus is a distinct morphological nucleus involved in termina ...
has important roles in the regulation of
appetite
Appetite is the desire to eat food items, usually due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to reg ...
(POMC neuron stimulation results in
satiety
Satiety ( /səˈtaɪ.ə.ti/ ''sə-TYE-ə-tee'') is a state or condition of fullness gratified beyond the point of satisfaction, the opposite of hunger. Following satiation (meal termination), satiety is a feeling of fullness lasting until the next ...
.
) and
sexual behavior
Human sexual activity, human sexual practice or human sexual behaviour is the manner in which humans experience and express their sexuality. People engage in a variety of sexual acts, ranging from activities done alone (e.g., masturbation) t ...
, while α-MSH secreted from the
intermediate lobe
The pars intermedia is one of the three parts of the anterior pituitary. It is a section of tissue sometimes called a middle or intermediate lobe, between the pars distalis, and the posterior pituitary. It is a small region that is largely with ...
of the
pituitary
The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus control much of th ...
regulates the movement of
melanin
Melanin (; ) is a family of biomolecules organized as oligomers or polymers, which among other functions provide the pigments of many organisms. Melanin pigments are produced in a specialized group of cells known as melanocytes.
There are ...
produced from melanocytes in skin.
*
ACTH
Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...
is a
peptide hormone
Peptide hormones are hormones composed of peptide molecules. These hormones influence the endocrine system of animals, including humans. Most hormones are classified as either amino-acid-based hormones (amines, peptides, or proteins) or steroid h ...
that regulates the secretion of mainly
glucocorticoids
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebra ...
from the cells of the
zona fasciculata
The ''zona fasciculata'' (sometimes, fascicular or fasciculate zone) constitutes the middle and also the widest zone of the adrenal cortex, sitting directly beneath the ''zona glomerulosa''. Constituent cells are organized into bundles or "fasc ...
of the
adrenal cortex
The adrenal cortex is the outer region and also the largest part of the adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. I ...
.
ACTH
Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...
can also regulate secretion of gonadocorticoids from the cells of the
zona reticularis
The zona reticularis (sometimes, reticulate zone) is the innermost layer of the adrenal cortex, lying deep to the zona fasciculata and superficial to the adrenal medulla. The cells are arranged cords that project in different directions giving a n ...
since they also express ACTH receptors.
*
β-Endorphin and
nkephalin">etnkephalin are endogenous
opioid peptides
Opioid peptides or opiate peptides are peptides that bind to opioid receptors in the brain; opiates and opioids mimic the effect of these peptides. Such peptides may be produced by the body itself, for example endorphins. The effects of these p ...
with widespread actions in the brain.
Synthesis
The ''POMC'' gene is located on chromosome 2p23.3. The ''POMC'' gene is expressed in both the anterior and intermediate lobes of the pituitary gland. This gene encodes a 285-amino acid polypeptide hormone precursor that undergoes extensive, tissue-specific, post-translational processing via cleavage by
subtilisin
Subtilisin is a protease (a protein-digesting enzyme) initially obtained from ''Bacillus subtilis''.
Subtilisins belong to subtilases, a group of serine proteases that – like all serine proteases – initiate the nucleophilic attack on the ...
-like enzymes known as
prohormone convertases. The encoded protein is synthesized mainly in
corticotroph cells of the anterior
pituitary
The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus control much of th ...
, where four cleavage sites are used;
adrenocorticotrophin (ACTH), essential for normal
steroidogenesis
A steroid is an organic compound with four fused rings (designated A, B, C, and D) arranged in a specific molecular configuration.
Steroids have two principal biological functions: as important components of cell membranes that alter memb ...
and the maintenance of normal adrenal weight, and
β-lipotropin
Lipotropin is the name for two hormones produced by the cleavage of pro-opiomelanocortin (POMC). The anterior pituitary gland produces the pro-hormone POMC, which is then cleaved again to form adrenocorticotropin (ACTH) and β-lipotropin (β-L ...
are the major end-products. However, there are at least eight potential cleavage sites within the polypeptide precursor and, depending on tissue type and the available convertases, processing may yield as many as ten biologically active peptides involved in diverse cellular functions. Cleavage sites consist of the sequences Arg-Lys, Lys-Arg, or Lys-Lys. Enzymes responsible for processing of POMC peptides include
prohormone convertase 1 (PC1),
prohormone convertase 2 (PC2),
carboxypeptidase E
Carboxypeptidase E (CPE), also known as carboxypeptidase H (CPH) and enkephalin convertase, is an enzyme that in humans is encoded by the ''CPE'' gene. This enzyme catalyzes the release of C-terminal arginine or lysine residues from polypeptides.
...
(CPE),
peptidyl α-amidating monooxygenase (PAM),
''N''-acetyltransferase (N-AT), and
prolylcarboxypeptidase (PRCP).
The processing of POMC involves glycosylations, acetylations, and extensive proteolytic cleavage at sites shown to contain regions of basic protein sequences. However, the proteases that recognize these cleavage sites are tissue-specific. In some tissues, including the
hypothalamus
The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...
,
placenta
The placenta (: placentas or placentae) is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas, and waste exchange between ...
, and
epithelium
Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...
, all cleavage sites may be used, giving rise to peptides with roles in pain and energy
homeostasis
In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...
,
melanocyte
Melanocytes are melanin-producing neural-crest, neural crest-derived cell (biology), cells located in the bottom layer (the stratum basale) of the skin's epidermis (skin), epidermis, the middle layer of the eye (the uvea),
the inner ear,
vagina ...
stimulation, and immune modulation. These include several distinct
melanotropins,
lipotropin
Lipotropin is the name for two hormones produced by the cleavage of pro-opiomelanocortin (POMC). The anterior pituitary gland produces the pro-hormone POMC, which is then cleaved again to form adrenocorticotropin (ACTH) and β-lipotropin (β-L ...
s, and
endorphin
Endorphins (contracted from endogenous morphine) are peptides produced in the brain that block the perception of pain and increase feelings of wellbeing. They are produced and stored in the pituitary gland of the brain. Endorphins are endogeno ...
s that are contained within the adrenocorticotrophin and β-lipotropin peptides.
It is synthesized by:
*
Corticotrope
Corticotropic cells, (corticotropes or corticotrophs) are basophilic cells in the anterior pituitary that produce pro-opiomelanocortin (POMC) which undergoes cleavage to adrenocorticotropin (ACTH), β-lipotropin (β-LPH), and melanocyte-stimulat ...
cells of the
anterior pituitary
The anterior pituitary (also called the adenohypophysis or pars anterior) is a major Organ (anatomy), organ of the endocrine system. The anterior pituitary is the glandular, Anatomical terms of location#Usage in human anatomy, anterior lobe that t ...
gland
*
Melanotrope A melanotroph (or melanotrope) is a cell in the pituitary gland that generates melanocyte-stimulating hormone (α‐MSH) from its precursor pro-opiomelanocortin. Chronic stress can induce the secretion of α‐MSH in melanotrophs and lead to their s ...
cells of the
intermediate lobe
The pars intermedia is one of the three parts of the anterior pituitary. It is a section of tissue sometimes called a middle or intermediate lobe, between the pars distalis, and the posterior pituitary. It is a small region that is largely with ...
of the
pituitary
The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus control much of th ...
gland
* Neurons in the
arcuate nucleus
The arcuate nucleus of the hypothalamus (ARH), or ARC, is also known as the infundibular nucleus to distinguish it from the arcuate nucleus of the medulla oblongata in the brainstem. The arcuate nucleus is an aggregation of neurons in the medio ...
of the
hypothalamus
The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...
* Smaller populations of neurons in the
dorsomedial hypothalamus and
brainstem
The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is conti ...
*
Melanocytes
Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea),
the inner ear,
vaginal epithelium, meninges,
bones,
and hea ...
in the skin
Regulation by the photoperiod
The levels of proopiomelanocortin (''pomc'') are regulated indirectly in some animals by the
photoperiod
Photoperiod is the change of day length around the seasons. The rotation of the earth around its axis produces 24 hour changes in light (day) and dark (night) cycles on earth. The length of the light and dark in each phase varies across the season ...
. It is referred to the hours of light during a day and it changes across the seasons. Its regulation depends on the pathway of
thyroid hormones
File:Thyroid_system.svg, upright=1.5, The thyroid system of the thyroid hormones T3 and T4
rect 376 268 820 433 Thyroid-stimulating hormone
rect 411 200 849 266 Thyrotropin-releasing hormone
rect 297 168 502 200 Hypothalamus
rect 66 216 386 ...
that is regulated directly by the
photoperiod. An example are the
siberian hamsters who experience physiological seasonal changes dependent on the photoperiod. During spring in this species, when there is more than 13 hours of light per day, iodothyronine deiodinase 2 (DIO2) promotes the conversion of the prohormone thyroxine (T4) to the active hormone triiodothyronine (T3) through the removal of an iodine atom on the outer ring. It allows T3 to bind to the thyroid hormone receptor (TR), which then binds to thyroid hormone response elements (TREs) in the DNA sequence. The ''pomc'' proximal promoter sequence contains two thyroid-receptor 1b (Thrb) half-sites: TCC-TGG-TGA and TCA-CCT-GGA indicating that T3 may be capable of directly regulating ''pomc'' transcription. For this reason during spring and early summer, the level of pomc increases due to the increased level of T3.
However, during autumn and winter, when there is less than 13 hours of light per day, iodothyronine desiodinase 3 removes an iodine atom which converts thyroxine to the inactive reverse triiodothyronine (rT3), or which converts the active triiodothyronine to diiodothyronine (T2). Consequently, there is less T3 and it blocks the transcription of ''pomc'', which reduces its levels during these seasons.

Influences of photoperiods on relevant similar biological endocrine changes that demonstrate modifications of thyroid hormone regulation in humans have yet to be adequately documented.
Derivatives
The large molecule of POMC is the source of several important biologically active substances . POMC can be cleaved enzymatically into the following
peptides
Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Dalton (unit), Da or more are called proteins. Chains of fewer t ...
:
*
''N''-Terminal Peptide of Proopiomelanocortin (NPP, or pro-γ-MSH)
*
α-Melanotropin (α-Melanocyte-Stimulating Hormone, or α-MSH)
*
β-Melanotropin (β-MSH)
*
γ-Melanotropin (γ-MSH)
* 𝛿-Melanocyte-Stimulating Hormone (𝛿-MSH, present in sharks)
* ε-Melanocyte-Stimulating Hormone (ε-MSH, present in some
teleost
Teleostei (; Ancient Greek, Greek ''teleios'' "complete" + ''osteon'' "bone"), members of which are known as teleosts (), is, by far, the largest group of ray-finned fishes (class Actinopterygii), with 96% of all neontology, extant species of f ...
s)
*
Corticotropin
Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important c ...
(Adrenocorticotropic Hormone, or ACTH)
*
Corticotropin-like Intermediate Peptide
Corticotropin-like intermediate obepeptide (CLIP), also known as adrenocorticotropic hormone fragment 18-39 (ACTH(18-39)), is a naturally occurring, endogenous neuropeptide with a docosapeptide structure and the amino acid sequence Arg-Pro-Val-Ly ...
(CLIP)
*
β-Lipotropin
Lipotropin is the name for two hormones produced by the cleavage of pro-opiomelanocortin (POMC). The anterior pituitary gland produces the pro-hormone POMC, which is then cleaved again to form adrenocorticotropin (ACTH) and β-lipotropin (β-L ...
(β-LPH)
*
Gamma Lipotropin (γ-LPH)
*
β-Endorphin
*
nkephalin">etnkephalin
Although the N-terminal 5 amino acids of
β-endorphin are identical to the sequence of
nkephalin">etnkephalin, it is not generally thought that β-endorphin is converted into
etnkephalin. Instead,
etnkephalin is produced from its own precursor,
proenkephalin A
Proenkephalin (PENK), formerly known as proenkephalin A (since proenkephalin B was renamed prodynorphin), is an endogenous opioid polypeptide hormone which, via proteolyic bond cleavage, cleavage, produces the enkephalin peptides met-enkephalin, ...
.
The production of
β-MSH occurs in humans but not in mice or rats due to the absence of the enzymatic processing site in the rodent POMC.
Clinical significance
Mutations in this gene have been associated with early onset
obesity
Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...
,
adrenal insufficiency
Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal glands—also referred to as the adrenal cortex—normally secrete glucocorticoids (primarily cortisol), mineraloco ...
, and
red hair
Red hair, also known as ginger hair, is a human hair color found in 2–6% of people of northern Europe, Northern or Northwestern European ancestry and lesser frequency in other populations. It is most common in individuals Zygosity#Homozy ...
pigmentation
A pigment is a powder used to add or alter color or change visual appearance. Pigments are completely or nearly insoluble and chemically unreactive in water or another medium; in contrast, dyes are colored substances which are soluble or go in ...
.
A study concluded that a
polymorphism was associated with higher fasting
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
levels in the
obese
Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classified as obese when ...
patients only. These findings support the hypothesis that the
melanocortin
The melanocortins are a family of neuropeptide hormones which are the ligands of the melanocortin receptors.Ericson, M.D., et al., ''Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016.'' Biochim Biophys Acta Mol B ...
pathway may modulate glucose metabolism in obese subjects indicating a possible gene-environment interaction. POMC variant may be involved in the natural history of
polygenic
A polygene is a member of a group of non- epistatic genes that interact additively to influence a phenotypic trait, thus contributing to multiple-gene inheritance (polygenic inheritance, multigenic inheritance, quantitative inheritance), a type ...
obesity, contributing to the link between type 2 diabetes and obesity.
Septic patients have increased circulating plasma concentrations of POMC. The clinical significance is currently under investigation. Further augmenting systemic glucocorticoid availability via infusion of
hydrocortisone
Hydrocortisone is the name for the hormone cortisol when supplied as a medication. It is a corticosteroid and works as an anti-inflammatory and by immune suppression. Uses include conditions such as adrenocortical insufficiency, adrenogenit ...
in
septic mice resulted in a suppression of
ACTH
Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...
, an endproduct of POMC, but not in a suppression of POMC.
Dogs
A deletion mutation common in
Labrador Retriever
The Labrador Retriever or simply Labrador or Lab is a British list of dog breeds, breed of water dog retriever gun dog. It was developed in the United Kingdom from St. John's water dogs imported from the Newfoundland Colony, colony of Newfoun ...
and
Flat-coated Retriever
The Flat-coated Retriever is a gun dog breed originating from England. It was developed as a retriever both on land and in the water.
Description
Appearance
The Flat-Coated Retriever breed standard calls for males to be tall at the withers, ...
dogs is associated with increased interest in food and subsequent obesity.
Drug target
POMC is used as a target for a medication used to treat obesity in humans. The combination of
bupropion and naltrexone acts via hypothalamic POMC neurons to decrease appetite.
Two humans with POMC deficiency have been treated with
setmelanotide
Setmelanotide, sold under the brand name Imcivree, is a medication used for the treatment of genetic obesity caused by a rare single-gene mutation.
The most common side effects include injection site reactions, skin hyperpigmentation (skin pat ...
, a melanocortin-4 receptor agonist.
Interactions
Proopiomelanocortin has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization advocating for the legal and human rights of children with intersex traits. The organization was founded in 2006 and fo ...
with
melanocortin 4 receptor
The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor involved in regulating energy homeostasis, appetite, and sexual function. It plays a key role in metabolic processes and is predisposes to certain forms of obesity in humans. MC4R ...
.
The endogenous agonists of melanocortin 4 receptor include
α-MSH,
β-MSH,
γ-MSH, and
ACTH
Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...
. The fact that these are all cleavage products of POMC should suggest likely mechanisms of this interaction.
See also
*
Afamelanotide
Afamelanotide, sold under the brand name Scenesse, is a medication used to prevent phototoxicity and to reduce pain from light exposure for people with erythropoietic protoporphyria. It is a melanocortin 1 receptor (MC1 receptor) agonist an ...
*
Agouti-related peptide
Agouti-related protein (AgRP), also called agouti-related peptide, is a neuropeptide produced in the brain by the AgRP/NPY neuron. It is synthesized in neuropeptide Y (NPY)-containing cell bodies located in the ventromedial part of the arcuate nu ...
*
Melanocortin
The melanocortins are a family of neuropeptide hormones which are the ligands of the melanocortin receptors.Ericson, M.D., et al., ''Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016.'' Biochim Biophys Acta Mol B ...
*
Melanotan II
Melanotan II is a synthetic analogue of the peptide hormone α-melanocyte-stimulating hormone (α-MSH) that stimulates melanogenesis to facilitate tanning. It may also increase sexual arousal.
It was developed as a successor to ''afamelanotid ...
References
Further reading
*
*
*
*
*
*
*
External links
*
*
{{Neuropeptides
Neuropeptides
Neuroendocrinology
Precursor proteins