Proopiomelanocortin

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Identifiers
Aliases
External IDs	GeneCards: [1]
Orthologs
Species	Human	Mouse
Entrez	n/a	n/a
Ensembl	n/a	n/a
UniProt	n/a	n/a
RefSeq (mRNA)	n/a	n/a
RefSeq (protein)	n/a	n/a
Location (UCSC)	n/a	n/a
PubMed search	n/a	n/a
Wikidata
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Opioids neuropeptide
Identifiers
Symbol	Op_neuropeptide
Pfam	PF08035
InterPro	IPR013532
PROSITE	PDOC00964
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in the pituitary 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.

Function

POMC is cleaved to give rise to multiple peptide hormones. Each of these peptides is packaged in large dense-core vesicles that are released from the cells by exocytosis in response to appropriate stimulation:

• α-MSH produced by neurons in the arcuate nucleus has important roles in the regulation of appetite (POMC neuron stimulation results in satiety.) and sexual behavior , while α-MSH secreted from the intermediate lobe of the pituitary regulates the production of melanin.
• ACTH is a peptide hormone that regulates the secretion of glucocorticoids from the adrenal cortex.
• β-Endorphin and [Met]enkephalin are endogenous opioid peptides 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-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-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, 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, lipotropins, and endorphins that are contained within the adrenocorticotrophin and β-lipotropin peptides.

It is synthesized by:

• Corticotrope cells of the anterior pituitary gland
• Melanotrope cells of the intermediate lobe of the pituitary gland
• Neurons in the arcuate nucleus of the hypothalamus
• Smaller populations of neurons in the dorsomedial hypothalamus and brainstem
• Melanocytes in the skin

Derivatives

proopiomelanocortin derivatives
POMC
γ-MSH	ACTH		β-lipotropin
	α-MSH	CLIP	γ-lipotropin		β-endorphin
				β-MSH

The large molecule of POMC is the source of several important biologically active substances . POMC can be cleaved enzymatically into the following peptides:

• 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 [2])
• ε-Melanocyte-Stimulating Hormone (ε-MSH, present in some teleosts )
• Corticotropin (Adrenocorticotropic Hormone, or ACTH
• Corticotropin-like Intermediate Peptide (CLIP)
• β-Lipotropin (β-LPH)
• Gamma Lipotropin (γ-LPH)
• β-Endorphin
• [Met]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 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, adrenal insufficiency, and red hair pigmentation.

A study concluded that a polymorphism was associated with higher fasting insulin levels in the obese patients only. These findings support the hypothesis that the melanocortin 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 obesity, contributing to the link between type 2 diabetes and obesity.

Dogs

A deletion mutation common in Labrador Retriever and Flat-Coated Retriever dogs is associated with increased interest in food and subsequent obesity.

Drug target

Two humans with POMC deficiency have been treated with setmelanotide, a melanocortin-4 receptor agonist.

Interactions

Proopiomelanocortin has been shown to interact with melanocortin 4 receptor.

See also

• Afamelanotide
• Agouti-related peptide
• Melanocortin
• Melanotan II

Further reading

• Millington GW (May 2006). "Proopiomelanocortin (POMC): the cutaneous roles of its melanocortin products and receptors". Clinical and Experimental Dermatology. 31 (3): 407–12. doi:10.1111/j.1365-2230.2006.02128.x. PMID 16681590.
• Millington GW (September 2007). "The role of proopiomelanocortin (POMC) neurones in feeding behaviour". Nutrition & Metabolism. 4: 18. doi:10.1186/1743-7075-4-18. PMC 2018708. PMID 17764572.
• Bhardwaj RS, Luger TA (1994). "Proopiomelanocortin production by epidermal cells: evidence for an immune neuroendocrine network in the epidermis". Archives of Dermatological Research. 287 (1): 85–90. doi:10.1007/BF00370724. PMID 7726641.
• Raffin-Sanson ML, de Keyzer Y, Bertagna X (August 2003). "Proopiomelanocortin, a polypeptide precursor with multiple functions: from physiology to pathological conditions". European Journal of Endocrinology. 149 (2): 79–90. doi:10.1530/eje.0.1490079. PMID 12887283.
• Dores RM, Lecaude S (May 2005). "Trends in the evolution of the proopiomelanocortin gene". General and Comparative Endocrinology. 142 (1–2): 81–93. doi:10.1016/j.ygcen.2005.02.003. PMID 15862552.
• König S, Luger TA, Scholzen TE (October 2006). "Monitoring neuropeptide-specific proteases: processing of the proopiomelanocortin peptides adrenocorticotropin and alpha-melanocyte-stimulating hormone in the skin". Experimental Dermatology. 15 (10): 751–61. doi:10.1111/j.1600-0625.2006.00472.x. PMID 16984256.
• Farooqi S, O'Rahilly S (December 2006). "Genetics of obesity in humans". Endocrine Reviews. 27 (7): 710–18. doi:10.1210/er.2006-0040. PMID 17122358.

External links

• Pro-Opiomelanocortin at the US National Library of Medicine Medical Subject Headings (MeSH)

 This article incorporates public domain material from the National Center for Biotechnology Information website https://www.ncbi.nlm.nih.gov/RefSeq/ (Reference Sequence collection).