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PMID: 17351764 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

The proprotein convertases are potential targets in the treatment of dyslipidemia.

Journal of molecular medicine (Berlin, Germany) ·Vol. 85 ·No. 7 ·2007-07-00 ·Pages 685-96

Seidah NG, Prat A

Abstract

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.

MeSH Terms
Dyslipidemias/drug therapy Humans Lipid Metabolism Proprotein Convertase 9 Proprotein Convertases/metabolism,physiology Serine Endopeptidases/physiology Serine Proteinase Inhibitors/therapeutic use
Chemicals
Serine Proteinase Inhibitors PCSK9 protein, human Proprotein Convertase 9 Proprotein Convertases Serine Endopeptidases
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Seidah Nabil G
Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, 110 Pine Ave West, Montreal, Quebec, H2W 1R7, Canada. [email protected]
Prat Annik
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Article Info
Journal
Journal of molecular medicine (Berlin, Germany)
Abbr.
J Mol Med (Berl)
ISSN
0946-2716
DOI
10.1007/s00109-007-0172-7
Email
[email protected]
Published
2007-07-00
Epub
2007-00-10
Pages
685-96
Language
English
Region
Germany
NLM ID
9504370
Subset
IM
External Links
PubMed source DOI: 10.1007/s00109-007-0172-7 View journal details
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