Editing Proopiomelanocortin

{{Short description|Mammalian protein found in Homo sapiens}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox_gene}}
{{Infobox protein family
| Symbol = Op_neuropeptide
| Name = Opioids neuropeptide
| image =
| width =
| caption =
| Pfam = PF08035
| Pfam_clan = 
| InterPro = IPR013532
| SMART =
| PROSITE = PDOC00964
| MEROPS =
| SCOP =
| TCDB =
| OPM family =
| OPM protein =
| CAZy =
| CDD =
}}
'''Pro-opiomelanocortin''' ('''POMC''') is a precursor [[polypeptide]] with 241 [[amino acid]] residues. POMC is [[Protein biosynthesis|synthesized]] in [[Corticotropic cell|corticotrophs]] of the [[anterior pituitary]] from the 267-amino-acid-long [[Precursor polypeptide|polypeptide precursor]] '''pre-pro-opiomelanocortin''' ('''pre-POMC'''), by the removal of a 26-amino-acid-long [[signal peptide]] sequence during [[translation (biology)|translation]].<ref>{{cite web |title=pro-opiomelanocortin preproprotein [Homo sapiens] - Protein - NCBI |url=https://www.ncbi.nlm.nih.gov/protein/NP_000930.1 |website=www.ncbi.nlm.nih.gov |access-date=30 December 2020}}</ref> POMC is part of the [[central melanocortin system]].

== Function ==

POMC is cut (cleaved) to give rise to multiple [[peptide]] hormones. Each of these peptides is packaged in large dense-core [[vesicle (biology)|vesicles]] that are released from the cells by [[exocytosis]] in response to appropriate stimulation:{{cn|date=May 2022}}
* [[Melanocyte-stimulating hormone|α-MSH]] produced by neurons in the [[ventromedial nucleus]] has important roles in the regulation of [[appetite]] (POMC neuron stimulation results in [[Hunger (motivational state)|satiety]].<ref name="pmid23146889">{{cite journal | vauthors = Varela L, Horvath TL | title = Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis | journal = EMBO Reports | volume = 13 | issue = 12 | pages = 1079–86 | date = December 2012 | pmid = 23146889 | pmc = 3512417 | doi = 10.1038/embor.2012.174 }}</ref>) and [[Human sexual activity|sexual behavior]], while α-MSH secreted from the [[pars intermedia|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 mainly [[glucocorticoids]] from the cells of the [[zona fasciculata]] of the [[adrenal cortex]]. [[ACTH]] can also regulate secretion of gonadocorticoids from the cells of the [[zona reticularis]] since they also express ACTH receptors.
* [[β-endorphin|β-Endorphin]] and [[Met-enkephalin| [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 [[Proprotein convertase|prohormone convertases]]. The encoded protein is synthesized mainly in [[corticotrope|corticotroph]] cells of the anterior [[pituitary]], where four cleavage sites are used; [[adrenocorticotropic hormone|adrenocorticotrophin]] (ACTH), essential for normal [[steroidogenesis]] and the maintenance of normal adrenal weight, and [[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]] (CPE), [[peptidylglycine alpha-amidating monooxygenase|peptidyl α-amidating monooxygenase]] (PAM), [[N-acetyltransferase|''N''-acetyltransferase]] (N-AT), and [[PRCP|prolylcarboxypeptidase]] (PRCP).{{cn|date=May 2022}}

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 [[melanotropin]]s, [[lipotropin]]s, and [[endorphin]]s that are contained within the adrenocorticotrophin and β-lipotropin peptides.{{cn|date=May 2022}}

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]]<ref name="pmid11373681">{{cite journal | vauthors = Cowley MA, Smart JL, Rubinstein M, Cerdán MG, Diano S, Horvath TL, Cone RD, Low MJ | title = Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus | journal = Nature | volume = 411 | issue = 6836 | pages = 480–4 | date = May 2001 | pmid = 11373681 | doi = 10.1038/35078085 | hdl = 11336/71802 | bibcode = 2001Natur.411..480C | s2cid = 4342893 | url = http://ri.conicet.gov.ar/bitstream/11336/71802/2/CONICET_Digital_Nro.6e51769a-234d-4b91-8b96-f20dc5c5a133_A.pdf | hdl-access = free }}</ref>
* Smaller populations of neurons in the [[dorsomedial hypothalamus]] and [[brainstem]]
* [[Melanocytes]] in the skin{{cn|date=December 2023}}

== Regulation by the photoperiod ==
The levels of proopiomelanocortin (''pomc'') are regulated indirectly in some animals by the [[Photoperiodic|photoperiod]]. It is referred to{{clarify|date=August 2021}} the hours of light during a day and it changes across the seasons. Its regulation depends on the pathway of [[thyroid hormones]] that is regulated directly by the [[Photoperiodism|photoperiod.]] An example are the [[Winter white dwarf hamster|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.<ref>{{cite journal | vauthors = Barrett P, Ebling FJ, Schuhler S, Wilson D, Ross AW, Warner A, Jethwa P, Boelen A, Visser TJ, Ozanne DM, Archer ZA, Mercer JG, Morgan PJ | title = Hypothalamic thyroid hormone catabolism acts as a gatekeeper for the seasonal control of body weight and reproduction | journal = Endocrinology | volume = 148 | issue = 8 | pages = 3608–17 | date = August 2007 | pmid = 17478556 | doi = 10.1210/en.2007-0316 | s2cid = 28088190 | doi-access =  }}</ref>

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.<ref>{{cite journal | vauthors = Bao R, Onishi KG, Tolla E, Ebling FJ, Lewis JE, Anderson RL, Barrett P, Prendergast BJ, Stevenson TJ | title = Genome sequencing and transcriptome analyses of the Siberian hamster hypothalamus identify mechanisms for seasonal energy balance | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 26 | pages = 13116–13121 | date = June 2019 | pmid = 31189592 | pmc = 6600942 | doi = 10.1073/pnas.1902896116 | bibcode = 2019PNAS..11613116B | doi-access = free }}</ref>

[[File:Thyroid hormones.png|center|thumb|470x470px|Regulation of proopiomelanocortin by the photoperiod and thyroid hormones]]

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 ==
{{POMC}}

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|''N''-Terminal Peptide of Proopiomelanocortin]] (NPP, or pro-γ-MSH)
* [[Melanocyte-stimulating hormone|α-Melanotropin]] (α-Melanocyte-Stimulating Hormone, or α-MSH)
* [[Melanocyte-stimulating hormone|β-Melanotropin]] (β-MSH)
* [[Melanocyte-stimulating hormone|γ-Melanotropin]] (γ-MSH)
* '''𝛿'''-Melanocyte-Stimulating Hormone ('''𝛿'''-MSH, present in sharks<ref>{{cite journal | vauthors = Dores RM, Cameron E, Lecaude S, Danielson PB | title = Presence of the delta-MSH sequence in a proopiomelanocortin cDNA cloned from the pituitary of the galeoid shark, Heterodontus portusjacksoni | journal = General and Comparative Endocrinology | volume = 133 | issue = 1 | pages = 71–9 | date = August 2003 | pmid = 12899848 | doi = 10.1016/S0016-6480(03)00151-5 }}</ref>)
* ε-Melanocyte-Stimulating Hormone (ε-MSH, present in some [[teleost]]s<ref>{{cite journal | vauthors = Harris RM, Dijkstra PD, Hofmann HA | title = Complex structural and regulatory evolution of the pro-opiomelanocortin gene family | journal = General and Comparative Endocrinology | volume = 195 | pages = 107–15 | date = January 2014 | pmid = 24188887 | doi = 10.1016/j.ygcen.2013.10.007 }}</ref>)
* [[Corticotropin]] (Adrenocorticotropic Hormone, or ACTH)
* [[Corticotropin-like intermediate peptide|Corticotropin-like Intermediate Peptide]] (CLIP)
* [[Lipotropin#β-Lipotropin|β-Lipotropin]] (β-LPH)
* [[Lipotropin|Gamma Lipotropin]] (γ-LPH)
* [[Beta-endorphin|β-Endorphin]]
* [[Met-Enkephalin|[Met]Enkephalin]]

Although the N-terminal 5 amino acids of [[β-endorphin]] are identical to the sequence of [[Met-enkephalin| [Met]enkephalin]],<ref>{{cite book | vauthors = Cullen JM, Cascella M | chapter = Physiology, Enkephalin|date=2022| chapter-url = http://www.ncbi.nlm.nih.gov/books/NBK557764/ | title = StatPearls|place=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=32491696|access-date=2022-01-12}}</ref> it is not generally thought that β-endorphin is converted into [Met]enkephalin.{{Citation needed|reason=reliable source needed for the whole sentence|date=December 2013}} Instead, [Met]enkephalin is produced from its own precursor, [[proenkephalin A]].

The production of [[melanocyte-stimulating hormone|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]],<ref name="pmid22438814">{{cite journal | vauthors = Kuehnen P, Mischke M, Wiegand S, Sers C, Horsthemke B, Lau S, Keil T, Lee YA, Grueters A, Krude H | title = An Alu element-associated hypermethylation variant of the POMC gene is associated with childhood obesity | journal = PLOS Genetics | volume = 8 | issue = 3 | pages = e1002543 | year = 2012 | pmid = 22438814 | pmc = 3305357 | doi = 10.1371/journal.pgen.1002543 | doi-access = free }}</ref> [[adrenal insufficiency]], and [[red hair]] [[pigmentation]].<ref>{{cite web | work = Entrez Gene | title = POMC proopiomelanocortin | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5443}}</ref>

A study concluded that a [[Genetic polymorphism|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.<ref>{{cite journal | vauthors = Mohamed FE, Hamza RT, Amr NH, Youssef AM, Kamal TM, Mahmoud RA | date = 2017 | title = Study of obesity associated proopiomelanocortin gene polymorphism: Relation to metabolic profile and eating habits in a sample of obese Egyptian children and adolescents. | journal = Egyptian Journal of Medical Human Genetics | volume = 18 | issue = 1 | pages = 67–73 | doi = 10.1016/j.ejmhg.2016.02.009 | doi-access = free }}</ref>

[[Sepsis|Septic]] patients have increased circulating plasma concentrations of POMC.<ref>{{cite journal | vauthors = Téblick A, Vander Perre S, Pauwels L, Derde S, Van Oudenhove T, Langouche L, Van den Berghe G | title = The role of pro-opiomelanocortin in the ACTH-cortisol dissociation of sepsis | journal = Critical Care | volume = 25 | issue = 1 | pages = 65 | date = February 2021 | pmid = 33593393 | pmc = 7885358 | doi = 10.1186/s13054-021-03475-y | doi-access = free }}</ref> The clinical significance is currently under investigation. Further augmenting systemic glucocorticoid availability via infusion of [[hydrocortisone]] in [[Sepsis|septic]] mice resulted in a suppression of [[ACTH]], an endproduct of POMC, but not in a suppression of POMC.<ref>{{cite journal | vauthors = Téblick A, De Bruyn L, Van Oudenhove T, Vander Perre S, Pauwels L, Derde S, Langouche L, Van den Berghe G | title = Impact of Hydrocortisone and of CRH Infusion on the Hypothalamus-Pituitary-Adrenocortical Axis of Septic Male Mice | journal = Endocrinology | volume = 163 | issue = 1 | date = January 2022 | pages = bqab222 | pmid = 34698826  | pmc = 8599906 | doi=10.1210/endocr/bqab222 }}</ref>

== Dogs ==

A deletion mutation common in [[Labrador Retriever]] and [[Flat-coated Retriever]] dogs is associated with increased interest in food and subsequent obesity.<ref>{{cite journal | vauthors = 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 | title = A Deletion in the Canine POMC Gene Is Associated with Weight and Appetite in Obesity-Prone Labrador Retriever Dogs | journal = Cell Metabolism | volume = 23 | issue = 5 | pages = 893–900 | date = May 2016 | pmid = 27157046 | pmc = 4873617 | doi = 10.1016/j.cmet.2016.04.012 }}</ref>

== Drug target ==

POMC is used as a target for a medication used to treat obesity in humans. The combination of [[Naltrexone/bupropion|bupropion and naltrexone]] acts via hypothalamic POMC neurons to decrease appetite.<ref>{{cite journal | vauthors = Billes SK, Sinnayah P, Cowley MA | title = Naltrexone/bupropion for obesity: an investigational combination pharmacotherapy for weight loss | journal = Pharmacological Research | volume = 84 | pages = 1–11 | date = June 2014 | pmid = 24754973 | doi = 10.1016/j.phrs.2014.04.004 | doi-access = free }}</ref>

Two humans with POMC deficiency have been treated with [[setmelanotide]], a melanocortin-4 receptor agonist.<ref>{{cite journal | vauthors = Kühnen P, Clément K, Wiegand S, Blankenstein O, Gottesdiener K, Martini LL, Mai K, Blume-Peytavi U, Grüters A, Krude H | title = Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist | journal = The New England Journal of Medicine | volume = 375 | issue = 3 | pages = 240–6 | date = July 2016 | pmid = 27468060 | doi = 10.1056/NEJMoa1512693 | doi-access =free  }}</ref>

== Interactions ==

Proopiomelanocortin has been shown to [[Protein-protein interaction|interact]] with [[melanocortin 4 receptor]].<ref name="pmid11101306">{{cite journal | vauthors = Yang YK, Fong TM, Dickinson CJ, Mao C, Li JY, Tota MR, Mosley R, Van Der Ploeg LH, Gantz I | title = Molecular determinants of ligand binding to the human melanocortin-4 receptor | journal = Biochemistry | volume = 39 | issue = 48 | pages = 14900–11 | date = December 2000 | pmid = 11101306 | doi = 10.1021/bi001684q }}</ref><ref name="pmid9058374">{{cite journal | vauthors = Yang YK, Ollmann MM, Wilson BD, Dickinson C, Yamada T, Barsh GS, Gantz I | title = Effects of recombinant agouti-signaling protein on melanocortin action | journal = Molecular Endocrinology | volume = 11 | issue = 3 | pages = 274–80 | date = March 1997 | pmid = 9058374 | doi = 10.1210/mend.11.3.9898 | doi-access = free }}</ref> The endogenous agonists of melanocortin 4 receptor include [[Α-Melanocyte-stimulating hormone|α-MSH]], [[Β-Melanocyte-stimulating hormone|β-MSH]], [[Γ-Melanocyte-stimulating hormone|γ-MSH]], and [[Adrenocorticotropic hormone|ACTH]]. The fact that these are all cleavage products of POMC should suggest likely mechanisms of this interaction.{{cn|date=May 2022}}

== See also ==
* [[Afamelanotide]]
* [[Agouti-related peptide]]
* [[Melanocortin]]
* [[Melanotan II]]

== References ==
{{Reflist|2}}

== Further reading ==
{{Refbegin|2}}
* {{cite journal | vauthors = Millington GW | title = Proopiomelanocortin (POMC): the cutaneous roles of its melanocortin products and receptors | journal = Clinical and Experimental Dermatology | volume = 31 | issue = 3 | pages = 407–12 | date = May 2006 | pmid = 16681590 | doi = 10.1111/j.1365-2230.2006.02128.x | s2cid = 25213876 }}
* {{cite journal | vauthors = Millington GW | title = The role of proopiomelanocortin (POMC) neurones in feeding behaviour | journal = Nutrition & Metabolism | volume = 4 | pages = 18 | date = September 2007 | pmid = 17764572 | pmc = 2018708 | doi = 10.1186/1743-7075-4-18 | doi-access = free }}
* {{cite journal | vauthors = Bhardwaj RS, Luger TA | title = Proopiomelanocortin production by epidermal cells: evidence for an immune neuroendocrine network in the epidermis | journal = Archives of Dermatological Research | volume = 287 | issue = 1 | pages = 85–90 | year = 1994 | pmid = 7726641 | doi = 10.1007/BF00370724 | s2cid = 33604397 }}
* {{cite journal | vauthors = Raffin-Sanson ML, de Keyzer Y, Bertagna X | title = Proopiomelanocortin, a polypeptide precursor with multiple functions: from physiology to pathological conditions | journal = European Journal of Endocrinology | volume = 149 | issue = 2 | pages = 79–90 | date = August 2003 | pmid = 12887283 | doi = 10.1530/eje.0.1490079 | doi-access = free }}
* {{cite journal | vauthors = Dores RM, Lecaude S | title = Trends in the evolution of the proopiomelanocortin gene | journal = General and Comparative Endocrinology | volume = 142 | issue = 1–2 | pages = 81–93 | date = May 2005 | pmid = 15862552 | doi = 10.1016/j.ygcen.2005.02.003 }}
* {{cite journal | vauthors = König S, Luger TA, Scholzen TE | title = Monitoring neuropeptide-specific proteases: processing of the proopiomelanocortin peptides adrenocorticotropin and alpha-melanocyte-stimulating hormone in the skin | journal = Experimental Dermatology | volume = 15 | issue = 10 | pages = 751–61 | date = October 2006 | pmid = 16984256 | doi = 10.1111/j.1600-0625.2006.00472.x | s2cid = 32034934 | doi-access = free }}
* {{cite journal | vauthors = Farooqi S, O'Rahilly S | title = Genetics of obesity in humans | journal = Endocrine Reviews | volume = 27 | issue = 7 | pages = 710–18 | date = December 2006 | pmid = 17122358 | doi = 10.1210/er.2006-0040 | doi-access = free }}
{{Refend}}

== External links ==
* {{MeshName|Pro-Opiomelanocortin}}
* {{PDBe-KB2|P01189|Pro-opiomelanocortin}}

{{NCBI RefSeq}}
{{Hormones}}
{{Neuropeptides}}

[[Category:Neuropeptides]]
[[Category:Neuroendocrinology]]
[[Category:Precursor proteins]]