Prohormone convertase catalyzes the cleavage of unneeded components of proteohormones and neuropeptides. In most cases, it becomes active immediately after translation of the corresponding proteins. Diseases associated with prohormone convertase have been found very rarely.
What is prohormone convertase?
Prohormone convertase is a serine protease that converts just-formed proteins from their original form to their effective form by cleaving off certain protein components. Prohormone convertase is a serine protease that converts just-formed proteins from their original form to their effective form by cleavage of certain protein components. When prohormone convertase is mentioned, proprotein convertase 1 (PC1) is usually meant. It converts many proteohormones and neuropeptides from their proform into the active form in the course of the so-called posttranslational modification. An example of this is the catalytic reaction of proinsulin into insulin. In addition to proinsulin, proprotein convertase 1 participates in the modification of proopiomelanocortin, prorenin, prodynorphin, proenkephalin, oxytocin neurophysin, and prosomatostatin. These proteins are modified right after translation (protein biosynthesis) by cleavage of protein components into the actual effective protein. In the process, peptide bonds are cleaved. Since prohormone convertase is a serine protease, the catalytic center of this enzyme represents the so-called catalytic triad. The catalytic triad consists of the three amino acids aspartic acid, histidine and serine. Their amino acid residues are linked together by hydrogen bonding. This combination enables them to catalytically dissolve peptide bonds. Catalysis proceeds via covalent intermediates and is therefore referred to as covalent catalysis. Proprotein convertase 1 (PC1) consists of 643 amino acids. A calcium ion acts as a cofactor. Other prohormone convertases besides PC1 are PC2 and PC3.
Function and role
The function of prohormone convertase will first be illustrated using insulin as an example. During insulin synthesis, a preproinsulin consisting of a signal sequence, the B chain, a C peptide, and an A chain is formed during translation. The entire molecule is composed of 110 amino acids. After its transport into the endoplasmic reticulum, the signal sequence is cleaved to form proinsulin, with disulfide bridges forming between the A chain and the B chain. Proinsulin now contains 84 amino acids. The C chain is then cleaved off by special peptidases (prohormone convertase). The chains that remain are connected only by disulfide bridges. The A chain contains 21 amino acids and the B chain 30 amino acids. Insulin has now formed, which is stabilized in the form of a hexamer by a zinc ion. Another substrate for prohormone convertase is proopiomelanocortin. Proopiomelanocortin is secreted in the adenohypophysis, hypothalamus, placenta or epithelia and is the precursor molecule of several important peptide hormones. It can be cleaved by prohormone convertase into 10 different hormones in a tissue-specific manner. These include adrenocorticotropin (ACTH), melanocyte-stimulating hormones, corticotropin-like intermediate peptide (CLIP), gammalipotropin or betaendorphin. The hormones formed are synthesized post-translationally from the prohormone. The opioid peptides enkephalin and dynorphin are also formed by convertases from proenkephalin and prodyphomin. They act as natural analgesics. Another active ingredient is the hormone-like renin, which is produced by convertases from prorenin. Renin promotes the formation of vasopressin via various reactions. Vasopressin is an antidiuretic hormone. The hormone oxytocin, in turn, is always produced as oxytocin neurophysin. This is stored in the posterior lobe of the pituitary gland and is cleaved into oxytocin and neurophysin as needed with the help of catalysis with prohormone convertase. The causes for the formation of proforms of various proteohormones and neuropeptides are manifold. Mostly, it is because they are favorable storage and transport forms. However, they need to be modified for their effectiveness. Prohormones generally belong to the group of precursor proteins, which still contain proenzymes and precursor structural proteins. All precursor proteins contain additional sequences which influence the activity of the protein in such a way that it becomes inactive.This happens due to the influence of these sequences on the conformation of the tertiary structure. When the additional sequences are cleaved off, a sudden conformational change occurs within the molecule. In the process, the entire molecule is reactivated.
Diseases and disorders
Diseases associated with prohormone convertase are very rare. They usually occur in genetic defects. Why the disorders are so rare is not known. It is possible that most of the gene mutations are then so severe that compatibility with life is not possible. However, a few cases are known in which a mutation has been found on the PCSK1 gene. The disorders are associated with severe metabolic disturbances. Prohormone convertase I deficiency has been described in two patients alone. These are a 43-year-old woman and a little girl. In each case, extreme obesity developed in childhood in both patients. Severe hypoglycemia and elevated prohormone levels of some proteohormones were also noted. At the same time, both patients had intestinal absorption disorders accompanied by severe diarrhea. The woman also suffered from hypogonadotropic hypogonadism with absent menstruation. The various symptoms are the result of failure to produce effective hormones from the proforms of the proteohormones. Proinsulin is highly elevated with low insulin. It can be converted only with difficulty. However, proinsulin already lowers the sugar level in the blood. However, because the concentration is so high, hypoglycemia occurs. Other prohormones such as proglucagon or proopiomelanocortin are then also elevated. The permanent digestive disturbances are caused by the low somastatin level, because prosomastatin is no longer converted to somastatin. Thus, pepsin, gastrin, and pancreatic enzymes can no longer be inhibited.
