Proopiomelanocortin

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.^[5] POMC is part of the central melanocortin system.

POMC
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2LWC, 5E33, 1PLW, 1PLX
Identifiers
Aliases	POMC, POC, proopiomelanocortin, OBAIRH, LPH, CLIP, ACTH, NPP, MSH
External IDs	OMIM: 176830; MGI: 97742; HomoloGene: 723; GeneCards: POMC; OMA:POMC - orthologs
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2p23.3 Start 25,160,853 bp[1] End 25,168,903 bp[1]
Gene location (Mouse) Chr. Chromosome 12 (mouse)[2] Band 12 A1.1|12 1.99 cM Start 4,004,951 bp[2] End 4,010,642 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in anterior pituitary right testis left testis gonad body of pancreas right adrenal cortex left adrenal gland apex of heart left adrenal cortex right auricle of heart Top expressed in pituitary gland arcuate nucleus median eminence pars distalis of adenohypophysis pars intermedia ventromedial nucleus suprachiasmatic nucleus trophoblast giant cell seminiferous tubule otic vesicle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function type 3 melanocortin receptor binding hormone activity type 1 melanocortin receptor binding signaling 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 negative regulation of tumor necrosis factor production regulation of appetite signal transduction positive regulation of transcription by RNA polymerase II neuropeptide signaling pathway positive regulation of neutrophil mediated killing of fungus regulation of corticosterone secretion regulation of signaling receptor activity G protein-coupled receptor signaling pathway cytokine-mediated signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5443 18976 Ensembl ENSG00000115138 ENSMUSG00000020660 UniProt P01189 P01193 RefSeq (mRNA) NM_000939 NM_001035256 NM_001319204 NM_001319205 NM_008895 NM_001278581 NM_001278582 NM_001278583 NM_001278584 RefSeq (protein) NP_000930 NP_001030333 NP_001306133 NP_001306134 NP_001265510 NP_001265511 NP_001265512 NP_001265513 NP_032921 Location (UCSC) Chr 2: 25.16 – 25.17 Mb Chr 12: 4 – 4.01 Mb PubMed search [3] [4]
Wikidata
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Opioids neuropeptide
Identifiers
Symbol	Op_neuropeptide
Pfam	PF08035
InterPro	IPR013532
PROSITE	PDOC00964
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Gene

The POMC gene is located on chromosome 2p23.3. 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.

Tissue distribution

The POMC gene is expressed in both the anterior and intermediate lobes of the pituitary gland. Its protein product is primarily synthesized by corticotropic cells in the anterior pituitary, but it is also produced in several other tissues:

• Corticotropic cells of the anterior pituitary gland
• Melanotropic cells of the intermediate lobe of the pituitary gland
• Neurons of the arcuate nucleus (infundibular nucleus) in the hypothalamus^[6][7]
• Smaller populations of neurons in the dorsomedial hypothalamus and brainstem
• Melanocytes in the skin.^[8]

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.^[9]) 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.

Post-translational modifications

The POMC gene encodes a 285-amino acid polypeptide precursor that undergoes extensive, tissue-specific post-translational processing. This processing is primarily mediated by subtilisin-like prohormone convertases, which cleave the precursor at specific basic amino acid sequences—typically Arg-Lys, Lys-Arg, or Lys-Lys.

In many tissues, four primary cleavage sites are utilized, resulting in the production of two major bioactive peptides: adrenocorticotrophin (ACTH), which is essential for normal steroidogenesis and adrenal gland maintenance, and β-lipotropin. However, the POMC precursor contains at least eight potential cleavage sites, and depending on the tissue type and the specific convertases expressed, it can be processed into up to ten biologically active peptides with diverse functions.

Key processing enzymes 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]}

In addition to proteolytic cleavage, POMC processing involves other post-translational modifications such as glycosylation and acetylation. The specific pattern of cleavage and modification is tissue-dependent. For example, in the hypothalamus, placenta, and epithelium, all cleavage sites may be active, generating peptides involved in pain modulation, energy homeostasis, immune responses, and melanocyte stimulation. These peptides include multiple melanotropins, lipotropins, and endorphins, many of which are derived from the larger ACTH and β-lipotropin peptides.^{[citation needed]}

Derivatives

proopiomelanocortin derivatives

POMC
γ-MSH	ACTH		β-lipotropin
	α-MSH	CLIP	γ-lipotropin		β-endorphin
				β-MSH

The large POMC precursor is the source of numerous biologically active peptides, which are produced through sequential enzymatic cleavage. These include:

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), found in sharks^[10] ε-Melanocyte-Stimulating Hormone (ε-MSH), present in some teleost fish^[11] Corticotropin (Adrenocorticotropic Hormone, or ACTH) Corticotropin-like Intermediate Peptide (CLIP) β-Lipotropin (β-LPH) Gamma Lipotropin (γ-LPH) β-Endorphin [Met]Enkephalin Although the first five amino acids of β-Endorphin are identical to [Met]enkephalin,^[12] β-Endorphin is not generally believed to be a precursor of [Met]enkephalin.^{[citation needed]} Instead, [Met]enkephalin is produced independently 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 necessary cleavage site in the rodent POMC sequence.

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.^[13]

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.^[14]

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.

Clinical significance

Mutations in the POMC gene have been associated with early-onset obesity,^[15] adrenal insufficiency, and red hair pigmentation.^[16]

In cases of primary adrenal insufficiency, decreased cortisol production leads to compensatory overproduction of pituitary ACTH through feedback mechanisms. Because ACTH is co-produced with α-MSH and γ-MSH from POMC, this overproduction can result in hyperpigmentation.^[17]

A specific genetic polymorphism in the POMC gene is associated with elevated fasting insulin levels, but only in obese individuals. The melanocortin signaling pathway may influence glucose metabolism in the context of obesity, indicating a possible gene–environment interaction. Thus, POMC variants may contribute to the development of polygenic obesity and help explain the connection between obesity and type 2 diabetes.^[18]

Increased circulating levels of POMC have also been observed in patients with sepsis.^[19] While the clinical implications of this finding are still under investigation, animal studies have shown that infusion of hydrocortisone in septic mice suppresses ACTH (a downstream product of POMC) without reducing POMC levels themselves.^[20]

Drug target

POMC is a pharmacological target for obesity treatment. The combination drug naltrexone/bupropion acts on hypothalamic POMC neurons to reduce appetite and food intake.^[21]

In rare cases of POMC deficiency, treatment with setmelanotide, a selective melanocortin-4 receptor agonist, has been effective. Two individuals with confirmed POMC deficiency showed clinical improvement following this therapy.^[22]

Dogs

A deletion mutation common in Labrador Retriever and Flat-coated Retriever dogs is associated with increased interest in food and subsequent obesity.^[23]

Interactions

Proopiomelanocortin has been shown to interact with melanocortin 4 receptor.^[24][25] 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]}

See also

• Afamelanotide
• Agouti-related peptide
• Melanocortin
• Melanotan II