Proopiomelanocortin
Encyclopedia
Pro-opiomelanocortin is a precursor polypeptide with 241 amino acid
residues. POMC is synthesized from the 285-amino acid long polypeptide precursor, pre-pro-opiomelanocortin (pre-POMC), by the removal of a 44-amino acid long signal peptide sequence during translation.
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
-like enzymes known as prohormone convertases. The encoded protein is synthesized mainly in corticotroph
cells of the anterior pituitary where four cleavage sites are used; adrenocorticotrophin
(ACTH), essential for normal steroidogenesis and the maintenance of normal adrenal weight, and β-lipotropin
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
(CPE), peptidyl α-amidating monooxygenase
(PAM), N-acetyltrasferase
(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
, placenta
, and epithelium
, all cleavage sites may be used, giving rise to peptides with roles in pain and energy homeostasis
, melanocyte
stimulation, and immune modulation. These include several distinct melanotropins, lipotropin
s, and endorphin
s that are contained within the adrenocorticotrophin and β-lipotropin peptides.
Mutations in this gene have been associated with early onset obesity
, adrenal insufficiency
, and red hair
pigmentation. Alternatively spliced transcript variants encoding the same protein have been described.
Cleaved into the following 11 chains:
Although the N-terminal 5 amino acids of β-endorphin are identical to the sequence of [Met]enkephalin, it is not generally thought that β-endorphin is converted into [Met]enkephalin. Instead, [Met]enkephalin is produced from its own precursor, proenkephalin A.
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.
in response to appropriate stimulation.:
with Melanocortin 4 receptor
.
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues. POMC is synthesized from the 285-amino acid long polypeptide precursor, pre-pro-opiomelanocortin (pre-POMC), by the removal of a 44-amino acid long signal peptide sequence during translation.
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
Subtilisin is a non-specific protease initially obtained from Bacillus subtilis.Subtilisins belong to subtilases, a group of serine proteases that initiate the nucleophilic attack on the peptide bond through a serine residue at the active site. They are physically and chemically...
-like enzymes known as prohormone convertases. The encoded protein is synthesized mainly in corticotroph
Corticotrope
Corticotropes are basophilic cells in the anterior pituitary that produce adrenocorticotropic hormone, melanocyte-stimulating hormone and lipotropin. These cells respond to corticotropin releasing hormone and make up about 20% of the cells in the anterior pituitary....
cells of the anterior pituitary where four cleavage sites are used; adrenocorticotrophin
Adrenocorticotropic hormone
Adrenocorticotropic hormone , also known as 'corticotropin', 'Adrenocorticotrophic hormone', is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological...
(ACTH), essential for normal steroidogenesis and the maintenance of normal adrenal weight, and β-lipotropin
Lipotropin
Lipotropin is a hormone produced by the cleavage of pro-opiomelanocortin . The anterior pituitary gland produces the pro-hormone POMC, which undergoes cleavage to adrenocorticotropin and β-lipotropin .- β-Lipotropin :...
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
Carboxypeptidase E, also known as carboxypeptidase H and enkephalin convertase, is an enzyme that in humans is encoded by the CPE gene....
(CPE), peptidyl α-amidating monooxygenase
Peptidylglycine alpha-amidating monooxygenase
Peptidyl-glycine alpha-amidating monooxygenase is an enzyme that in humans is encoded by the PAM gene.-Interactions:Peptidylglycine alpha-amidating monooxygenase has been shown to interact with TSC2.-Further reading:...
(PAM), N-acetyltrasferase
N-Acetyltransferase
N-acetyltransferase is an enzyme that catalyzes the transfer of acetyl groups from acetyl-CoA to arylamines. They have wide specificity for aromatic amines, particularly serotonin, and can also catalyze acetyl transfer between arylamines without CoA. EC 2.3.1.5....
(N-AT), and prolylcarboxypeptidase
PRCP
Lysosomal Pro-X carboxypeptidase is an enzyme that in humans is encoded by the PRCP gene.-Further reading:...
(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
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
, placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
, and epithelium
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
, all cleavage sites may be used, giving rise to peptides with roles in pain and energy homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
, melanocyte
Melanocyte
-External links: - "Eye: fovea, RPE" - "Integument: pigmented skin"...
stimulation, and immune modulation. These include several distinct melanotropins, lipotropin
Lipotropin
Lipotropin is a hormone produced by the cleavage of pro-opiomelanocortin . The anterior pituitary gland produces the pro-hormone POMC, which undergoes cleavage to adrenocorticotropin and β-lipotropin .- β-Lipotropin :...
s, and endorphin
Endorphin
Endorphins are endogenous opioid peptides that function as neurotransmitters. They are produced by the pituitary gland and the hypothalamus in vertebrates during exercise, excitement, pain, consumption of spicy food, love and orgasm, and they resemble the opiates in their abilities to produce...
s that are contained within the adrenocorticotrophin and β-lipotropin peptides.
Mutations in this gene have been associated with early onset obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
, adrenal insufficiency
Adrenal insufficiency
Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones , primarily cortisol, but may also include impaired aldosterone production which regulates sodium, potassium and water retention...
, and red hair
Red hair
Red hair occurs on approximately 1–2% of the human population. It occurs more frequently in people of northern or western European ancestry, and less frequently in other populations...
pigmentation. Alternatively spliced transcript variants encoding the same protein have been described.
Production
It is synthesized by:- CorticotropeCorticotropeCorticotropes are basophilic cells in the anterior pituitary that produce adrenocorticotropic hormone, melanocyte-stimulating hormone and lipotropin. These cells respond to corticotropin releasing hormone and make up about 20% of the cells in the anterior pituitary....
cells of the anterior pituitaryAnterior pituitaryA major organ of the endocrine system, the anterior pituitary, also called the adenohypophysis, is the glandular, anterior lobe of the pituitary gland...
gland - Melanotrope cells of the intermediate lobe of the pituitary gland
- About 3000 neurons in the arcuate nucleusArcuate nucleusThe arcuate nucleus is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence...
of the hypothalamusHypothalamusThe Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions... - Smaller populations of neurons in the dorsomedial hypothalamus and brainstem
- Melanocytes in the skin
Derivatives
The large molecule of POMC is the source of several important biologically active substances. POMC can be cleaved enzymatically into the following peptides:Cleaved into the following 11 chains:
- N-Terminal Peptide of ProopiomelanocortinN-Terminal peptide of proopiomelanocortinThe N-terminal peptide/fragment of proopiomelanocortin , also known as pro-γ-MSH, is a naturally-occurring, endogenous metabolite of the polypeptide proopiomelanocortin ....
(NPP, or pro-γ-MSH) - γ-MelanotropinMelanocyte-stimulating hormoneThe melanocyte-stimulating hormones are a class of peptide hormones that are produced by cells in the intermediate lobe of the pituitary gland...
(γ-MSH) - Corticotropin (Adrenocorticotropic Hormone, or ACTH)
- α-MelanotropinMelanocyte-stimulating hormoneThe melanocyte-stimulating hormones are a class of peptide hormones that are produced by cells in the intermediate lobe of the pituitary gland...
(α-Melanocyte-Stimulating Hormone, or α-MSH) - Corticotropin-like Intermediate PeptideCorticotropin-like intermediate peptideCorticotropin-like intermediate [lobe] peptide , also known as adrenocorticotropic hormone fragment 18-39 , is a naturally-occurring, endogenous neuropeptide with a docosapeptide structure and the amino acid sequence...
(CLIP) - β-Lipotropin (β-LPH)
- Lipotropin GammaLipotropinLipotropin is a hormone produced by the cleavage of pro-opiomelanocortin . The anterior pituitary gland produces the pro-hormone POMC, which undergoes cleavage to adrenocorticotropin and β-lipotropin .- β-Lipotropin :...
(γ-LPH) - β-MelanotropinMelanocyte-stimulating hormoneThe melanocyte-stimulating hormones are a class of peptide hormones that are produced by cells in the intermediate lobe of the pituitary gland...
(β-MSH) - β-EndorphinEndorphinEndorphins are endogenous opioid peptides that function as neurotransmitters. They are produced by the pituitary gland and the hypothalamus in vertebrates during exercise, excitement, pain, consumption of spicy food, love and orgasm, and they resemble the opiates in their abilities to produce...
- [Met]EnkephalinMet-enkephalin[Met]enkephalin, sometimes referred to as opioid growth factor , is a naturally-occurring, endogenous opioid peptide that has opioid effects of a relatively short duration. It is one of the two forms of enkephalin, the other being [leu]enkephalin...
Although the N-terminal 5 amino acids of β-endorphin are identical to the sequence of [Met]enkephalin, it is not generally thought that β-endorphin is converted into [Met]enkephalin. Instead, [Met]enkephalin is produced from its own precursor, proenkephalin A.
The production of β-MSH
Melanocyte-stimulating hormone
The melanocyte-stimulating hormones are a class of peptide hormones that are produced by cells in the intermediate lobe of the pituitary gland...
occurs in humans but not in mice or rats due to the absence of the enzymatic processing site in the rodent POMC.
Function
Each of these peptides is packaged in large dense-core vesicles that are released from the cells by exocytosisExocytosis
Exocytosis , also known as 'The peni-cytosis', is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...
in response to appropriate stimulation.:
- α-MSH produced by neurons in the arcuate nucleus has important roles in the regulation of appetiteAppetiteThe appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...
and sexual behavior, while α-MSH secreted from the intermediate lobe of the pituitary regulates the production of melaninMelaninMelanin is a pigment that is ubiquitous in nature, being found in most organisms . 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...
. - ACTH is a peptide hormone that regulates the secretion of glucocorticoids from the adrenal cortexAdrenal cortexSituated along the perimeter of the adrenal gland, the adrenal cortex mediates the stress response through the production of mineralocorticoids and glucocorticoids, including aldosterone and cortisol respectively. It is also a secondary site of androgen synthesis.-Layers:Notably, the reticularis in...
. - β-endorphin and [Met]enkephalin are endogenous opioid peptides with widespread actions in the brain.
Interactions
Proopiomelanocortin has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Melanocortin 4 receptor
Melanocortin 4 receptor
Melanocortin receptor 4 is a protein that in humans is encoded by the MC4R gene. It encodes the MC4 protein, a G-protein coupled receptor that binds α-melanocyte stimulating hormone...
.