Carboxypeptidase E

Carboxypeptidase E (CPE), also known as carboxypeptidase H (CPH) and  convertase, is an is_associated_with::enzyme that in humans is encoded by the CPE is_associated_with::gene This enzyme catalyzes the release of is_associated_with::C-terminal is_associated_with::arginine or is_associated_with::lysine residues from is_associated_with::polypeptides.

CPE is involved in the biosynthesis of most is_associated_with::neuropeptides and is_associated_with::peptide hormones. The production of neuropeptides and peptide hormones typically requires two sets of enzymes that cleave the peptide precursors, which are small proteins. First, is_associated_with::proprotein convertases cut the precursor at specific sites to generate intermediates containing C-terminal basic residues (lysine and/or arginine). These intermediates are then cleaved by CPE to remove the basic residues. For some peptides, additional processing steps, such as C-terminal amidation, are subsequently required to generate the bioactive peptide, although for many peptides the action of the proprotein convertases and CPE is sufficient to produce the bioactive peptide.

Tissue distribution
Carboxypeptidase E is found in brain and throughout the neuroendocrine system, including the endocrine pancreas, pituitary, and is_associated_with::adrenal gland is_associated_with::chromaffin cells. Within cells, carboxypeptidase E is present in the secretory granules along with its peptide substrates and products. Carboxypeptidase E is a is_associated_with::glycoprotein that exists in both membrane-associated and soluble forms. The membrane-binding is due to an is_associated_with::amphiphilic α-helix within the C-terminal region of the protein.

Species distribution
Carboxypeptidase E is found in all species of vertebrates that have been examined, and is also present in many other organisms that have been studied (nematode, sea slug). Carboxypeptidase E is not found in the fruit fly (Drosophila), and another enzyme (presumably carboxypeptidase D) fills in for carboxypeptidase E in this organism. In humans, CPE is encoded by the CPE is_associated_with::gene.

Function
Carboxypeptidase E functions in the production of nearly all neuropeptides and peptide hormones. The enzyme acts as an is_associated_with::exopeptidase to activate is_associated_with::neuropeptides. It does that by cleaving off basic C-terminal amino acids, producing the active form of the peptide. Products of carboxypeptidase E include is_associated_with::insulin, the is_associated_with::enkephalins, is_associated_with::vasopressin, is_associated_with::oxytocin, and most other neuroendocrine peptide hormones and neuropeptides.

It has been proposed that membrane-associated carboxypeptidase E acts as a sorting signal for regulated secretory proteins in the trans-Golgi network of the is_associated_with::pituitary and in secretory granules; regulated secretory proteins are mostly is_associated_with::hormones and is_associated_with::neuropeptides. However, this role for carboxypeptidase E remains controversial, and evidence shows that this enzyme is not necessary for the sorting of regulated secretory proteins.

Clinical significance
Mice with mutant carboxypeptidase E, Cpefat, display is_associated_with::endocrine disorders like is_associated_with::obesity and is_associated_with::infertility. In some strains of mice, the fat mutation also causes is_associated_with::hyperproinsulinemia in adult male mice, but this is not found in all strains of mice. The obesity and infertility in the Cpefat mice develop with age; young mice (<8 weeks of age) are fertile and have normal body weight. Peptide processing in Cpefat mice is impaired, with a large accumulation of peptides with C-terminal lysine and/or arginine extensions. Levels of the mature forms of peptides are generally reduced in these mice, but not completely eliminated. It is thought that a related enzyme (carboxypeptidase D) also contributes to neuropeptide processing and gives rise to the mature peptides in the Cpefat mice.

In obesity, high levels of circulating free fatty acids have been reported to cause a decrease in the amount of carboxypeptidase E protein in pancreatic beta-cells, leading to beta-cell dysfunction (hyperproinsulinemia) and increased beta-cell apoptosis (via an increase in ER-stress). However, because CPE is not a rate-limiting enzyme for the production of most neuropeptides and peptide hormones, it is not clear how relatively modest decreases in CPE activity can cause physiological effects.