Pro-opiomelanocortin (POMC)

August 29, 2022

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.
- ^{“pro-opiomelanocortin preproprotein [Homo sapiens] – Protein – NCBI”. www.ncbi.nlm.nih.gov. Retrieved 30 December 2020.}
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:^{[citation needed]}

α-MSH produced by neurons in the ventromedial nucleus has important roles in the regulation of appetite (POMC neuron stimulation results in satiety).
- ^{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.}
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 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 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).^{[citation needed]}

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.^{[citation needed]}

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
- ^{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. S2CID 4342893.}
Smaller populations of neurons in the dorsomedial hypothalamus and brainstem
Melanocytes in the skin

Regulation by the photoperiod

The levels of proopiomelanocortin (pomc) are regulated indirectly in some animals by the photoperiod. It is referred to^{[clarification needed]} 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.
- ^{Barrett P, Ebling FJ, Schuhler S, Wilson D, Ross AW, Warner A, et al. (August 2007). “Hypothalamic thyroid hormone catabolism acts as a gatekeeper for the seasonal control of body weight and reproduction”. Endocrinology. 148 (8): 3608–17. doi:10.1210/en.2007-0316. PMID 17478556.}

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.
- ^{Bao R, Onishi KG, Tolla E, Ebling FJ, Lewis JE, Anderson RL, et al. (June 2019). “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. doi:10.1073/pnas.1902896116. PMC 6600942. PMID 31189592.}

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

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)
- ^{Dores RM, Cameron E, Lecaude S, Danielson PB (August 2003). “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. doi:10.1016/S0016-6480(03)00151-5. PMID 12899848.}
ε-Melanocyte-Stimulating Hormone (ε-MSH, present in some teleosts)
- ^{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.}
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,
- ^{Cullen, Joshua M.; Cascella, Marco (2022), “Physiology, Enkephalin”, StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32491696, retrieved 2022-01-12}
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,
- ^{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.}
adrenal insufficiency, and red hair pigmentation.
- ^{“POMC proopiomelanocortin”. Entrez Gene}

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.
- ^{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. doi:10.1016/j.ejmhg.2016.02.009.}

Septic patients have increased circulating plasma concentrations of POMC.
- ^{Téblick A, Vander Perre S, Pauwels L, Derde S, Van Oudenhove T, Langouche L, Van den Berghe G (February 2021). “The role of pro-opiomelanocortin in the ACTH-cortisol dissociation of sepsis”. Critical Care. 25 (1): 65. doi:10.1186/s13054-021-03475-y. PMC 7885358. PMID 33593393.}
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.
- ^[17]

Dogs

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

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.
- ^{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.}

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

Interactions

Proopiomelanocortin has been shown to interact with melanocortin 4 receptor.
- ^{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/mend.11.3.9898. PMID 9058374.}
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.^{[citation needed]}

External links

Pro-Opiomelanocortin at the US National Library of Medicine Medical Subject Headings (MeSH)
Overview of all the structural information available in the PDB for UniProt: P01189 (Pro-opiomelanocortin) at the PDBe-KB.

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

Hormones

Peptides: neuropeptides

Categories:

From Wikipedia where the page was last updated June 13, 2022