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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.^[5]) 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^[6]
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 [1])
ε-Melanocyte-Stimulating Hormone (ε-MSH, present in some teleosts ^[7])
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.^{[citation needed]} 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,^[8] adrenal insufficiency, and red hair pigmentation.^[9]

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.^[10]

Dogs

A deletion mutation common in Labrador Retriever and Flat-Coated Retriever dogs is associated with increased interest in food and subsequent obesity.^[11]

Drug target

Two humans with POMC deficiency have been treated with setmelanotide, a melanocortin-4 receptor agonist.^[12]

Interactions

Proopiomelanocortin has been shown to interact with melanocortin 4 receptor.^[13]^[14]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000115138 - Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000020660 - Ensembl, May 2017
^ "Human PubMed Reference:".
^ "Mouse PubMed Reference:".
^ Varela L, Horvath TL (2012). "Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis". EMBO Reports. 13 (12): 1079–1086. doi:10.1038/embor.2012.174. PMC 3512417 . PMID 23146889.
^ Cowley MA, Smart JL, Rubinstein M, Cerdán MG, Diano S, Horvath TL, Cone RD, Low MJ (May 2001). "Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus". Nature. 411 (6836): 480–4. doi:10.1038/35078085. PMID 11373681.
^ Harris RM, Dijkstra PD, Hofmann HA (January 2014). "Complex structural and regulatory evolution of the pro-opiomelanocortin gene family". General and Comparative Endocrinology. 195: 107–15. doi:10.1016/j.ygcen.2013.10.007. PMID 24188887.
^ Kuehnen P, Mischke M, Wiegand S, Sers C, Horsthemke B, Lau S, Keil T, Lee YA, Grueters A, Krude H (2012). "An Alu element-associated hypermethylation variant of the POMC gene is associated with childhood obesity". PLoS Genetics. 8 (3): e1002543. doi:10.1371/journal.pgen.1002543. PMC 3305357 . PMID 22438814.
^ "Entrez Gene: POMC proopiomelanocortin (adrenocorticotropin/ beta-lipotropin/ alpha-melanocyte stimulating hormone/ beta-melanocyte stimulating hormone/ beta-endorphin)".
^ Mohamed, F. E. B., Hamza, R. T., Amr, N. H., Youssef, A. M., Kamal, T. M., & Mahmoud, R. A. (2016). Study of obesity associated proopiomelanocortin gene polymorphism: Relation to metabolic profile and eating habits in a sample of obese Egyptian children and adolescents. Egyptian Journal of Medical Human Genetics.
^ Raffan E, Dennis RJ, O'Donovan CJ, Becker JM, Scott RA, Smith SP, Withers DJ, Wood CJ, Conci E, Clements DN, Summers KM, German AJ, Mellersh CS, Arendt ML, Iyemere VP, Withers E, Söder J, Wernersson S, Andersson G, Lindblad-Toh K, Yeo GS, O'Rahilly S (May 2016). "A Deletion in the Canine POMC Gene Is Associated with Weight and Appetite in Obesity-Prone Labrador Retriever Dogs". Cell Metabolism. 23 (5): 893–900. doi:10.1016/j.cmet.2016.04.012. PMC 4873617 . PMID 27157046.
^ Kühnen P, Clément K, Wiegand S, Blankenstein O, Gottesdiener K, Martini LL, Mai K, Blume-Peytavi U, Grüters A, Krude H (July 2016). "Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist". The New England Journal of Medicine. 375 (3): 240–6. doi:10.1056/NEJMoa1512693. PMID 27468060.
^ Yang YK, Fong TM, Dickinson CJ, Mao C, Li JY, Tota MR, Mosley R, Van Der Ploeg LH, Gantz I (December 2000). "Molecular determinants of ligand binding to the human melanocortin-4 receptor". Biochemistry. 39 (48): 14900–11. doi:10.1021/bi001684q. PMID 11101306.
^ Yang YK, Ollmann MM, Wilson BD, Dickinson C, Yamada T, Barsh GS, Gantz I (March 1997). "Effects of recombinant agouti-signaling protein on melanocortin action". Molecular Endocrinology. 11 (3): 274–80. doi:10.1210/me.11.3.274. PMID 9058374.

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).

UpToDate Contents

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1. 肥満への遺伝的影響と病態生理 genetic contribution and pathophysiology of obesity
2. ACTH、CRH、および他の視床下部／下垂体ペプチドの測定 measurement of acth crh and other hypothalamic and pituitary peptides
3. レプチンの生理学 physiology of leptin
4. 小児における中枢性副腎不全の原因および臨床症状 causes and clinical manifestations of central adrenal insufficiency in children
5. 正常な副腎皮質性第二次性徴 normal adrenarche

English Journal

Cortisol and ACTH levels in drug-naive adolescents with first-episode early onset schizophrenia.

Şimşek Ş1, Gençoğlan S2, Yüksel T1, Aktaş H1.
Asia-Pacific psychiatry : official journal of the Pacific Rim College of Psychiatrists.Asia Pac Psychiatry.2017 Mar;9(1). doi: 10.1111/appy.12264. Epub 2016 Nov 2.
The aim of this study was to investigate serum levels of cortisol and adrenocorticotropic hormone in adolescents with first-episode early onset schizophrenia. A total of 23 adolescent patients, who did not receive prior therapy and who were diagnosed with psychosis according to DSM-IV, were included
PMID 27804260

Proopiomelanocortin, glucocorticoid, and CRH receptor expression in human ACTH-secreting pituitary adenomas.

Cassarino MF1, Sesta A1, Pagliardini L1, Losa M2, Lasio G3, Cavagnini F1, Pecori Giraldi F4,5.
Endocrine.Endocrine.2017 Mar;55(3):853-860. doi: 10.1007/s12020-016-0990-x. Epub 2016 May 24.
ACTH-secreting pituitary tumors are by definition partially autonomous, i.e., secrete ACTH independent of physiological control. However, only few, small-sized studies on proopiomelanocortin (POMC) and its regulation by corticotropin-releasing hormone (CRH) or glucocorticoids are available. Objectiv
PMID 27220856

B Lymphocytes Express Pomc mRNA, Processing Enzymes and β-Endorphin in Painful Inflammation.

Maddila SC1, Busch-Dienstfertig M1, Stein C2.
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology.J Neuroimmune Pharmacol.2017 Mar;12(1):180-186. doi: 10.1007/s11481-016-9715-4. Epub 2016 Nov 11.
Immune cell-derived beta-endorphin (END) and other opioid peptides elicit potent and clinically relevant inhibition of pain (analgesia) in inflamed tissue by activation of peripheral opioid receptors. Pro-opiomelanocortin (POMC) is the polypeptide precursor of END and is processed by prohormone conv
PMID 27837406

Japanese Journal

肥満を合併する高血圧 (第1土曜特集いま臨床医が知っておくべき高血圧のすべて) -- (病態に応じた治療法)

医学のあゆみ 260(5), 387-390, 2017-02-04
NAID 40021082842

Evaluation of the Effects and Mechanism of L-Citrulline on Anti-obesity by Appetite Suppression in Obese/Diabetic KK-Ay Mice and High-Fat Diet Fed SD Rats

Ｂｉｏｌｏｇｉｃａｌ　＆　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｂｕｌｌｅｔｉｎ 40(4), 524-530, 2017
NAID 130005530068

Hypothalamic control of glucose and lipid metabolism in skeletal muscle

The Journal of Physical Fitness and Sports Medicine 6(2), 75-87, 2017
NAID 130005464538

Related Pictures

Frontiers | Observations on the Evolution of the Melanocortin Receptor Gene Family 130・メラノトロピン、ペプチドホルモン Melanin production through novel processing of proopiomelanocortin in the Pro-Opiomelanocortin; POMC; Pro-Opiocortin Research | Neuropeptide Lab Melanocortin peptides (shaded boxes) derived from POMC. ACTH: | Download Scientific

★リンクテーブル★

リンク元	「プロオピオメラノコルチン」

「プロオピオメラノコルチン」

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

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

POMC
Identifiers
Aliases	POMC, ACTH, CLIP, LPH, MSH, NPP, POC, proopiomelanocortin
External IDs	OMIM: 176830 MGI: 97742 HomoloGene: 723 GeneCards: POMC
Gene location (Human)
Chr.	Chromosome 2 (human)
End	25,168,903 bp
Gene location (Mouse)
Chr.	Chromosome 12 (mouse)
End	3,960,642 bp
RNA expression pattern
	More reference expression data
Gene ontology
Molecular function	• type 3 melanocortin receptor binding; • hormone activity; • type 1 melanocortin receptor binding; • receptor binding; • G-protein coupled receptor binding; • type 4 melanocortin receptor binding; • neuropeptide hormone activity;
Cellular component	• cytoplasm; • peroxisome; • extracellular region; • peroxisomal matrix; • secretory granule lumen; • extracellular space; • secretory granule;
Biological process	• glucose homeostasis; • cellular pigmentation; • cell-cell signaling; • generation of precursor metabolites and energy; • regulation of glycogen metabolic process; • regulation of blood pressure; • peptide hormone processing; • negative regulation of tumor necrosis factor production; • regulation of appetite; • signal transduction; • positive regulation of transcription from RNA polymerase II promoter; • neuropeptide signaling pathway; • positive regulation of neutrophil mediated killing of fungus; • regulation of corticosterone secretion; • regulation of receptor activity; • G-protein coupled receptor signaling pathway;
	Sources:Amigo / QuickGO
Orthologs
	5443
	18976
	ENSG00000115138
	ENSMUSG00000020660
	P01189
	P01193
	NM_000939; NM_001035256; NM_001319204; NM_001319205
	NM_008895; NM_001278581; NM_001278582; NM_001278583; NM_001278584
	NP_000930; NP_001030333; NP_001306133; NP_001306134
	NP_001265510; NP_001265511; NP_001265512; NP_001265513; NP_032921
	Wikidata
View/Edit Human	View/Edit Mouse

　　[★]

英: pro-opiomelanocortin proopiomelanocortin, POMC
同: プロコルチコトロピン・エンドルフィン procorticotropin-endorphin
関: pro-opiomelanocortin peptide family, POMC peptide family

参考

sequence

http://www.ncbi.nlm.nih.gov/protein/114319045?report=genbank&log$=protalign&blast_rank=1&RID=P0TED5HH01N

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000115138 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000020660 - Ensembl, May 2017

[3] "Human PubMed Reference:".

[4] "Mouse PubMed Reference:".

[pmid23146889-5] Varela L, Horvath TL (2012). "Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis". EMBO Reports. 13 (12): 1079–1086. doi:10.1038/embor.2012.174. PMC 3512417 . PMID 23146889.

[pmid11373681-6] Cowley MA, Smart JL, Rubinstein M, Cerdán MG, Diano S, Horvath TL, Cone RD, Low MJ (May 2001). "Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus". Nature. 411 (6836): 480–4. doi:10.1038/35078085. PMID 11373681.

[7] Harris RM, Dijkstra PD, Hofmann HA (January 2014). "Complex structural and regulatory evolution of the pro-opiomelanocortin gene family". General and Comparative Endocrinology. 195: 107–15. doi:10.1016/j.ygcen.2013.10.007. PMID 24188887.

[pmid22438814-8] Kuehnen P, Mischke M, Wiegand S, Sers C, Horsthemke B, Lau S, Keil T, Lee YA, Grueters A, Krude H (2012). "An Alu element-associated hypermethylation variant of the POMC gene is associated with childhood obesity". PLoS Genetics. 8 (3): e1002543. doi:10.1371/journal.pgen.1002543. PMC 3305357 . PMID 22438814.

[9] "Entrez Gene: POMC proopiomelanocortin (adrenocorticotropin/ beta-lipotropin/ alpha-melanocyte stimulating hormone/ beta-melanocyte stimulating hormone/ beta-endorphin)".

[10] Mohamed, F. E. B., Hamza, R. T., Amr, N. H., Youssef, A. M., Kamal, T. M., & Mahmoud, R. A. (2016). Study of obesity associated proopiomelanocortin gene polymorphism: Relation to metabolic profile and eating habits in a sample of obese Egyptian children and adolescents. Egyptian Journal of Medical Human Genetics.

[11] Raffan E, Dennis RJ, O'Donovan CJ, Becker JM, Scott RA, Smith SP, Withers DJ, Wood CJ, Conci E, Clements DN, Summers KM, German AJ, Mellersh CS, Arendt ML, Iyemere VP, Withers E, Söder J, Wernersson S, Andersson G, Lindblad-Toh K, Yeo GS, O'Rahilly S (May 2016). "A Deletion in the Canine POMC Gene Is Associated with Weight and Appetite in Obesity-Prone Labrador Retriever Dogs". Cell Metabolism. 23 (5): 893–900. doi:10.1016/j.cmet.2016.04.012. PMC 4873617 . PMID 27157046.

[12] Kühnen P, Clément K, Wiegand S, Blankenstein O, Gottesdiener K, Martini LL, Mai K, Blume-Peytavi U, Grüters A, Krude H (July 2016). "Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist". The New England Journal of Medicine. 375 (3): 240–6. doi:10.1056/NEJMoa1512693. PMID 27468060.

[pmid11101306-13] Yang YK, Fong TM, Dickinson CJ, Mao C, Li JY, Tota MR, Mosley R, Van Der Ploeg LH, Gantz I (December 2000). "Molecular determinants of ligand binding to the human melanocortin-4 receptor". Biochemistry. 39 (48): 14900–11. doi:10.1021/bi001684q. PMID 11101306.

[pmid9058374-14] Yang YK, Ollmann MM, Wilson BD, Dickinson C, Yamada T, Barsh GS, Gantz I (March 1997). "Effects of recombinant agouti-signaling protein on melanocortin action". Molecular Endocrinology. 11 (3): 274–80. doi:10.1210/me.11.3.274. PMID 9058374.

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proopiomelanocortin