|, POC, proopiomelanocortin, OBAIRH, LPH, CLIP, ACTH, NPP, MSH|
Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior 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. POMC is part of the central melanocortin system.
POMC is cut (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 ventromedial 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 movement of melanin produced from melanocytes in skin.
- 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.
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
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)
- 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)
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.
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.
Proopiomelanocortin has been shown to interact with melanocortin 4 receptor. The endogenous agonists of melanocortin 4 receptor include α-MSH, β-MSH, γ-MSH, and ACTH. The fact that these are all cleavage products of POMC should suggest likely mechanisms of this interaction.
- GRCh38: Ensembl release 89: ENSG00000115138 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000020660 - Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- Varela L, Horvath TL (December 2012). "Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis". EMBO Reports. 13 (12): 1079–86. 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" (PDF). Nature. 411 (6836): 480–4. Bibcode:2001Natur.411..480C. doi:10.1038/35078085. hdl:11336/71802. PMID 11373681.
- Dores, Robert M.; Cameron, Erin; Lecaude, Stephanie; Danielson, Phillip B. (2003). "Presence of the δ-MSH sequence in a proopiomelanocortin cDNA cloned from the pituitary of the galeoid shark, Heterodontus portusjacksoni". General and Comparative Endocrinology. 133 (1): 71–79. doi:10.1016/S0016-6480(03)00151-5. PMID 12899848.
- 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.
- "POMC proopiomelanocortin". Entrez Gene.
- 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.
- Billes SK, Sinnayah P, Cowley MA (June 2014). "Naltrexone/bupropion for obesity: an investigational combination pharmacotherapy for weight loss". Pharmacological Research. 84: 1–11. doi:10.1016/j.phrs.2014.04.004. PMID 24754973.
- 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.
- 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.