Proopiomelanocortin: Function & Diseases

Proopiomelanocortin (POMC) is a so-called prohormone from which over ten different active hormones can be formed. The prohormone is synthesized in the adenohypophysis, hypothalamus, and placenta and epithelia to express the corresponding hormones. Deficiency of POMC leads to severe hormonal imbalances in the organism.

What is proopiomelanocortin?

Proopiomelanocortin is a protein composed of 241 different amino acids. As a substance itself, it is ineffective in the organism because it is only a so-called prohormone. As a prohormone, however, it can be broken down into more than ten important active hormones via various intermediate steps. This occurs through the influence of convertases. The convertases, in turn, represent enzymes that catalyze the conversion steps of the prohormone into active compounds. These reactions are called limited proteolysis. Through complicated regulatory mechanisms in the body, only enough proopiomelanocortin is converted to produce a sufficient concentration of the respective active target hormones. POMC is encoded by a gene on chromosome segment 2p23.3. The individual active peptide hormones are post-translationally cleaved from the prohormone proopiomelanocortin. Altered assembly of these hormones is therefore mediated only by gene 2p23.3. Thus, a mutation on this gene has a major impact on hormonal processes in the human organism.

Function, effects, and roles

Among the ten active hormones secreted from proopiomelanocortin are such agents as adrenocorticotropin (ACTH), melanocyte-stimulating hormone, γ-lipotropin (γ-LPH), and β-endorphin. Furthermore, the hormone corticotropin like intermediate peptide (CLIP) is also produced. ACTH is produced under the influence of corticotropin releasing hormone (CRH) in the anterior pituitary. It is responsible for steroid synthesis and stimulates the adrenal glands to produce cortisone and mineral corticoids. It also stimulates the formation of sex hormones such as testosterone and the estrogens. It is always produced to a greater extent during stress, as it is also responsible for the formation of the stress hormone cortisone. Melanocyte stimulating hormones are produced in the hypothalamus and pituitary intermediate lobe and are responsible for the activation of melanocortin receptors. Thus, they regulate the formation of melanin in melanocytes. Furthermore, they regulate the fever response and are involved in the control of hunger sensation and sexual arousal. Hormones that stimulate melanocytes are in turn formed from an intermediate in the breakdown of proopiomelanocortin, β-lipotropin. β-Lipotropin itself has additional lipid mobilizing activity. In addition to the melanocyte stimulating hormones, γ-lipotropin and the endorphins are also formed from β-lipotropin. The endorphins possess analgesic effects and are responsible, among other things, for the feeling of hunger and the development of the feeling of happiness or euphoria through the activation of dopamine-dependent synapses. For this reason, the prohormone proopiomelanocortin plays a major role overall in the regulation of hunger and sexuality, pain sensation, physical energy balance, body weight, and melanocyte stimulation.

Formation, occurrence, properties, and optimal levels

Proopiomelanocortin is formed in the adenohypophysis, hypothalamus, epithelia, and placenta, as mentioned earlier. Also known as POMC, this prohormone is encoded by a gene on chromosome 2 at chromosomal segment 2p23.3. As a prohormone, it exists in an inactive form. By splitting into different active peptide hormones, different bodily functions can be fulfilled that seem to have nothing to do with each other. However, failure of this prohormone results in its extremely important function for the organism, since the active hormones split off from proopiomelanocortin are then also simultaneously absent or show functional disorders. However, POMC is not simultaneously converted into all subsequent peptide hormones. The individual reaction steps are coordinated via complicated regulatory mechanisms. For example, corticotropin releasing hormone (CRH) is responsible for the formation of ACTH from POMC in the adenohypophysis. It becomes active, for example, during stress related to illness, emotions, physical and psychological strain, or even depression.

Diseases and disorders

A deficiency of proopiomelanocortin has major effects on the organism. The entire downstream hormone balance is thrown into disarray as a result. Initially, the peptide hormones secreted from proopiomelanocortin are absent or have functional defects. A genetically altered prohormone cannot secrete fully functional peptide hormones. An extreme clinical picture associated with a deficiency of proopiomelanocortin is characterized by extreme obesity. This obesity has existed since birth. Furthermore, the patients’ hair is colored red. The clinical picture includes hypoglycemic cramps, cholestasis, and hyperbilirubinemia. Due to extreme hyperphagia (binge eating) resulting from dysregulation of the hunger center, weight regulation is not possible. Adrenocortical insufficiency also develops because glucocorticoids and mineral corticoids can no longer be adequately formed. Overall, the disease leads to death from liver failure if left untreated. However, this extreme clinical picture has been observed only rarely. So far, a total of ten cases have been described. The cause of this syndrome is the deficiency of POMC due to a mutation at gene 2p23.3. This genetic defect is inherited in an autosomal recessive manner. The rarity of this disorder is due to the fact that a complete absence of POMC or a severe defect leading to loss of function is incompatible with life. Therefore, only a few mutations in this gene result in viable offspring, which, however, exhibit severe health problems. Differentially, of course, several diseases must be excluded that result from subsequent regulatory errors in the hormonal system. Complete detection of the disease can only be achieved by genetic testing.