Proopiomelanocortin Explained

Symbol:Op_neuropeptide
Opioids neuropeptide
Pfam:PF08035
Interpro:IPR013532
Prosite:PDOC00964

Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the removal of a 26-amino-acid-long signal peptide sequence during translation.[1] 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 vesicles that are released from the cells by exocytosis in response to appropriate stimulation:

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:

Regulation by the photoperiod

The levels of proopiomelanocortin (pomc) are regulated indirectly in some animals by the photoperiod. It is referred to 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 photoperiod. An example are the 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.[4]

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.[5]

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

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

Although the N-terminal 5 amino acids of β-endorphin are identical to the sequence of [Met]enkephalin,[8] 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,[9] adrenal insufficiency, and red hair pigmentation.[10]

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.[11]

Septic patients have increased circulating plasma concentrations of POMC.[12] The clinical significance is currently under investigation. Further augmenting systemic glucocorticoid availability via infusion of hydrocortisone in septic mice resulted in a suppression of ACTH, an endproduct of POMC, but not in a suppression of POMC.[13]

Dogs

A deletion mutation common in Labrador Retriever and Flat-Coated Retriever dogs is associated with increased interest in food and subsequent obesity.[14]

Drug target

POMC is used as a target for a medication used to treat obesity in humans. The combination of bupropion and naltrexone acts via hypothalamic POMC neurons to decrease appetite.[15]

Two humans with POMC deficiency have been treated with setmelanotide, a melanocortin-4 receptor agonist.[16]

Interactions

Proopiomelanocortin has been shown to interact with melanocortin 4 receptor.[17] [18] 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.

See also

Further reading

Notes and References

  1. Web site: pro-opiomelanocortin preproprotein [Homo sapiens] - Protein - NCBI ]. www.ncbi.nlm.nih.gov . 30 December 2020.
  2. Varela L, Horvath TL . Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis . EMBO Reports . 13 . 12 . 1079–86 . December 2012 . 23146889 . 3512417 . 10.1038/embor.2012.174 .
  3. Cowley MA, Smart JL, Rubinstein M, Cerdán MG, Diano S, Horvath TL, Cone RD, Low MJ . Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus . Nature . 411 . 6836 . 480–4 . May 2001 . 11373681 . 10.1038/35078085 . 11336/71802 . 2001Natur.411..480C . 4342893 . free .
  4. 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 . Hypothalamic thyroid hormone catabolism acts as a gatekeeper for the seasonal control of body weight and reproduction . Endocrinology . 148 . 8 . 3608–17 . August 2007 . 17478556 . 10.1210/en.2007-0316 . 28088190 .
  5. Bao R, Onishi KG, Tolla E, Ebling FJ, Lewis JE, Anderson RL, Barrett P, Prendergast BJ, Stevenson TJ . Genome sequencing and transcriptome analyses of the Siberian hamster hypothalamus identify mechanisms for seasonal energy balance . Proceedings of the National Academy of Sciences of the United States of America . 116 . 26 . 13116–13121 . June 2019 . 31189592 . 6600942 . 10.1073/pnas.1902896116 . 2019PNAS..11613116B . free .
  6. Dores RM, Cameron E, Lecaude S, Danielson PB . Presence of the delta-MSH sequence in a proopiomelanocortin cDNA cloned from the pituitary of the galeoid shark, Heterodontus portusjacksoni . General and Comparative Endocrinology . 133 . 1 . 71–9 . August 2003 . 12899848 . 10.1016/S0016-6480(03)00151-5 .
  7. Harris RM, Dijkstra PD, Hofmann HA . Complex structural and regulatory evolution of the pro-opiomelanocortin gene family . General and Comparative Endocrinology . 195 . 107–15 . January 2014 . 24188887 . 10.1016/j.ygcen.2013.10.007 .
  8. Book: Cullen JM, Cascella M . Physiology, Enkephalin. 2022. http://www.ncbi.nlm.nih.gov/books/NBK557764/ . StatPearls. Treasure Island (FL). StatPearls Publishing. 32491696. 2022-01-12.
  9. Kuehnen P, Mischke M, Wiegand S, Sers C, Horsthemke B, Lau S, Keil T, Lee YA, Grueters A, Krude H . An Alu element-associated hypermethylation variant of the POMC gene is associated with childhood obesity . PLOS Genetics . 8 . 3 . e1002543 . 2012 . 22438814 . 3305357 . 10.1371/journal.pgen.1002543 . free .
  10. Web site: Entrez Gene . POMC proopiomelanocortin .
  11. Mohamed FE, Hamza RT, Amr NH, Youssef AM, Kamal TM, Mahmoud RA . 2017 . 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 . 18 . 1 . 67–73 . 10.1016/j.ejmhg.2016.02.009 . free .
  12. Téblick A, Vander Perre S, Pauwels L, Derde S, Van Oudenhove T, Langouche L, Van den Berghe G . The role of pro-opiomelanocortin in the ACTH-cortisol dissociation of sepsis . Critical Care . 25 . 1 . 65 . February 2021 . 33593393 . 7885358 . 10.1186/s13054-021-03475-y . free .
  13. Téblick A, De Bruyn L, Van Oudenhove T, Vander Perre S, Pauwels L, Derde S, Langouche L, Van den Berghe G . Impact of Hydrocortisone and of CRH Infusion on the Hypothalamus-Pituitary-Adrenocortical Axis of Septic Male Mice . Endocrinology . 163 . 1 . January 2022 . bqab222 . 34698826 . 8599906 . 10.1210/endocr/bqab222 .
  14. 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 . 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 . May 2016 . 27157046 . 4873617 . 10.1016/j.cmet.2016.04.012 .
  15. Billes SK, Sinnayah P, Cowley MA . Naltrexone/bupropion for obesity: an investigational combination pharmacotherapy for weight loss . Pharmacological Research . 84 . 1–11 . June 2014 . 24754973 . 10.1016/j.phrs.2014.04.004 . free .
  16. Kühnen P, Clément K, Wiegand S, Blankenstein O, Gottesdiener K, Martini LL, Mai K, Blume-Peytavi U, Grüters A, Krude H . Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist . The New England Journal of Medicine . 375 . 3 . 240–6 . July 2016 . 27468060 . 10.1056/NEJMoa1512693 . free .
  17. Yang YK, Fong TM, Dickinson CJ, Mao C, Li JY, Tota MR, Mosley R, Van Der Ploeg LH, Gantz I . Molecular determinants of ligand binding to the human melanocortin-4 receptor . Biochemistry . 39 . 48 . 14900–11 . December 2000 . 11101306 . 10.1021/bi001684q .
  18. Yang YK, Ollmann MM, Wilson BD, Dickinson C, Yamada T, Barsh GS, Gantz I . Effects of recombinant agouti-signaling protein on melanocortin action . Molecular Endocrinology . 11 . 3 . 274–80 . March 1997 . 9058374 . 10.1210/mend.11.3.9898 . free .

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