| Opioids neuropeptide | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | Op_neuropeptide | ||||||
| Pfam | PF08035 | ||||||
| InterPro | IPR013532 | ||||||
| PROSITE | PDOC00964 | ||||||
| |||||||
Pro-opiomelanocortin (POMC) is a precursorpolypeptide with 241amino acid residues. POMC issynthesized incorticotrophs of theanterior pituitary from the 267-amino-acid-longpolypeptide precursorpre-pro-opiomelanocortin (pre-POMC), by the removal of a 26-amino-acid-longsignal peptide sequence duringtranslation.[5] POMC is part of thecentral melanocortin system.
ThePOMC 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 bysubtilisin-like enzymes known asprohormone convertases.
ThePOMC gene is expressed in both the anterior and intermediate lobes of thepituitary gland. Its protein product is primarily synthesized bycorticotropic cells in theanterior pituitary, but it is also produced in several other tissues:
POMC is cut (cleaved) to give rise to multiplepeptide hormones. Each of these peptides is packaged in large dense-corevesicles that are released from the cells byexocytosis in response to appropriate stimulation:[citation needed]
ThePOMC gene encodes a 285-amino acid polypeptide precursor that undergoes extensive, tissue-specific post-translational processing. This processing is primarily mediated bysubtilisin-likeprohormone 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 normalsteroidogenesis and adrenal gland maintenance, andβ-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 includeprohormone convertase 1 (PC1),prohormone convertase 2 (PC2),carboxypeptidase E (CPE),peptidyl α-amidating monooxygenase (PAM),N-acetyltransferase (N-AT), andprolylcarboxypeptidase (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 thehypothalamus,placenta, andepithelium, all cleavage sites may be active, generating peptides involved inpain modulation, energyhomeostasis, immune responses, andmelanocyte stimulation. These peptides include multiplemelanotropins,lipotropins, andendorphins, many of which are derived from the larger ACTH and β-lipotropin peptides.[citation needed]
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 someteleost fish[11]Corticotropin (Adrenocorticotropic Hormone, or ACTH)Corticotropin-like Intermediate Peptide (CLIP)β-Lipotropin (β-LPH)Gamma Lipotropin (γ-LPH)β-Endorphin[Met]EnkephalinAlthough the first five amino acids ofβ-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 ofβ-MSH occurs in humans, but not in mice or rats, due to the absence of the necessary cleavage site in the rodent POMC sequence.
The levels of proopiomelanocortin (pomc) are regulated indirectly in some animals by thephotoperiod. 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 ofthyroid hormones that is regulated directly by thephotoperiod. An example are thesiberian 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. Thepomc 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 regulatingpomc 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 ofpomc, which reduces its levels during these seasons.[14]
Influences of photoperiods on relevant similar biological endocrine changes that demonstrate modifications of thyroid hormone regulation in humans have yet to be adequately documented.
Mutations in thePOMC gene have been associated with early-onsetobesity,[15]adrenal insufficiency, andred hairpigmentation.[16]
In cases of primary adrenal insufficiency, decreased cortisol production leads to compensatory overproduction of pituitaryACTH through feedback mechanisms. Because ACTH is co-produced with α-MSH and γ-MSH fromPOMC, this overproduction can result inhyperpigmentation.[17]
A specificgenetic polymorphism in thePOMC gene is associated with elevated fastinginsulin levels, but only inobese individuals. Themelanocortin 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 ofpolygenic obesity and help explain the connection between obesity andtype 2 diabetes.[18]
Increased circulating levels of POMC have also been observed in patients withsepsis.[19] While the clinical implications of this finding are still under investigation, animal studies have shown that infusion ofhydrocortisone in septic mice suppresses ACTH (a downstream product of POMC) without reducing POMC levels themselves.[20]
POMC is a pharmacological target for obesity treatment. The combination drugnaltrexone/bupropion acts on hypothalamic POMC neurons to reduce appetite and food intake.[21]
In rare cases of POMC deficiency, treatment withsetmelanotide, a selectivemelanocortin-4 receptor agonist, has been effective. Two individuals with confirmed POMC deficiency showed clinical improvement following this therapy.[22]
A deletion mutation common inLabrador Retriever andFlat-coated Retriever dogs is associated with increased interest in food and subsequent obesity.[23]
Proopiomelanocortin has been shown tointeract withmelanocortin 4 receptor.[24][25] The endogenous agonists of melanocortin 4 receptor includeα-MSH,β-MSH,γ-MSH, andACTH. The fact that these are all cleavage products of POMC should suggest likely mechanisms of this interaction.[citation needed]
This article incorporatespublic domain material fromReference Sequence collection.National Center for Biotechnology Information.
