POMC is cut 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:
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, 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, prohormone convertase 2, carboxypeptidase E, peptidyl α-amidating monooxygenase, N-acetyltransferase, and prolylcarboxypeptidase. 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:
The levels of proopiomelanocortin 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 of 13 hours of light per day, iodothyronine deiodinase 2 promotes the conversion of the prohormone thyroxine to the active hormone triiodothyronine through the removal of an iodine atom on the outer ring. It allows that T3 bind to the thyroid hormone receptor, which then bind to thyroid hormone response elements in the DNA sequence. The pomc proximal promoter sequence contains two thyroid-receptor 1b 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 starting summer, levels of pomc increases due to increase levels of T3. However, during autumn and winter, when there is less of 13 hours of light per day, iodothyronine desiodinase 3 removes an iodine atom which converts thyroxine to the inactive reverse triiodothyronine, or which converts the active triiodothyronine to diiodothyronine. Consequently, there is less T3 and it blocks the transcription of pomc, that reduces his levels during these seasons. . 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| enkephalin, it is not generally thought that β-endorphin is converted into enkephalin. Instead, 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.
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. Two humans with POMC deficiency have been treated with setmelanotide, a melanocortin-4 receptor agonist.
Interactions
Proopiomelanocortin has been shown to interact with melanocortin 4 receptor. 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.
