Proprotein convertase 1

Proprotein convertase 1, also known as prohormone convertase, prohormone convertase 3, or neuroendocrine convertase 1 and often abbreviated as PC1/3 is an is_associated_with::enzyme that in humans is encoded by the PCSK1 is_associated_with::gene. PCSK1 and PCSK2 differentially cleave is_associated_with::proopiomelanocortin and they act together to process is_associated_with::proinsulin and is_associated_with::proglucagon in pancreatic islets.

Function
PC1/3 is an enzyme that performs the proteolytic cleavage of prois_associated_with::hormones to their intermediate (or sometimes completely cleaved) forms. It is present only in neurois_associated_with::endocrine cells such as is_associated_with::brain, is_associated_with::pituitary and is_associated_with::adrenal, and most often cleaves after a pair of basic residues within prohormones but can occasionally cleave after a single arginine. It binds to a protein known as proSAAS, which also represents its endogenous inhibitor. PC1 is synthesized as a 99 kDa proform quickly converted to an 87 kDa major active form, which itself is nearly completely cleaved to a 66 kDa active form within neuroendocrine cells.

Proprotein convertase 1 is the enzyme largely responsible for the first step in the biosynthesis of is_associated_with::insulin. Following the action of proprotein convertase 1, a carboxypeptidase is required to remove the basic residues from the processing intermediate and generate the bioactive form of insulin. Another prohormone convertase, is_associated_with::proprotein convertase 2 plays a more minor role in the first step of insulin biosynthesis, but a greater role in the first step of is_associated_with::glucagon biosynthesis. The knockout of proprotein convertase 1 is not lethal in mice or humans, most likely due to the presence of the second convertase, although mice lacking proprotein convertase 1 activity show a number of defects including slow growth.

Proprotein convertase 1 is a calcium (Ca2+) activated serine endoprotease (meaning that a serine residue is part of the active site that hydrolyzes the peptide bond within the substrate). It is related to the bacterial enzyme known as is_associated_with::subtilisin. There are nine subtilisin homologs in mammals; in addition to proprotein convertase 1 and 2, other members of this enzyme family include is_associated_with::furin, PACE4, PC4, PC5/6, PC7/8, is_associated_with::PCSK9, and SKI1/S1P.

Clinical significance
Variants in the PCSK1 gene may be associated with is_associated_with::obesity.