The family of the secretory
proprotein convertases (PCs) comprises seven
basic amino acid (aa)-specific
subtilisin-like
serine proteinases known as PC1/3, PC2,
furin, PC4,
PC5/6, PACE4 and PC7, and two other PCs, SKI-1 (
subtilisin-kexin
isozyme-1)/S1P (site-1 protease) and PCSK9 (
proprotein convertase subtilisin kexin 9) that cleave at nonbasic residues. Except for the testicular PC4, all the other convertases are expressed in brain and peripheral organs and play a critical role in various functions including the production of diverse
neuropeptides as well as
growth factors and receptors, the regulation of cellular adhesion/migration,
cholesterol and
fatty acid homeostasis, and growth/differentiation of progenitor cells. Some of these convertases process
proteins that are implicated in pathologies, including
cancer malignancies, tissue regeneration, and
viral infections. The implication of some of these convertases in
sterol/lipid metabolism has only recently been appreciated. SKI-1/S1P activates the synthesis of
cholesterol and
fatty acids as well as the
LDL receptor (LDLR), whereas PCSK9 inactivates the LDLR. Moreover,
furin,
PC5 and/or, PACE4 inactivates endothelial and
lipoprotein lipases. Humans and mice exhibiting either a gain or loss of function of PCSK9 through specific point mutations or knockouts develop
hypercholesterolemia and hypocholesterolemia phenotypes, respectively. A PCSK9 inhibitor in combination with
statins offers a most promising therapeutic target to treat cardiovascular disorders including
dyslipidemias. Specific inhibitors/modulators of the other PCs should find novel therapeutic applications in the control of PC-regulated pathologies.