PCSK9
Synonyms
FHCL3, EC 3.4.21, EC 3.4.21.111, Neural apoptosis-regulated convertase 1, Proprotein convertase 9, NARC1, PSEC0052, PCSK9, NARC-1, EC:3.4.21.-, Proprotein Convertase Subtilisin/Kexin Type 9, Subtilisin/Kexin-Like Protease PC9, PC9, Convertase Subtilisin/Kexin Type 9 Preproprotein, Hypercholesterolemia, Autosomal Dominant 3, EC 3.4.21.-, HCHOLA3, LDLCQ1, FH3, Neural Apoptosis Regulated Convertase 1
Description
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans on chromosome 1. It plays a crucial role in regulating plasma cholesterol homeostasis. It binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. It acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway and may prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. It can induce ubiquitination of LDLR leading to its subsequent degradation and inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. It is involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. It inhibits epithelial Na+ channel (ENaC)-mediated Na+ absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation and regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.
KO Status
F1 (+/-)
Drug Information
Launched drugs: 2
Drugs in clinical trials: 16
Latest Research Phase: Approved
Drug Name
Code
Phase
Company
Indications
Clinical Trials
Inclisiran sodium
ALN-60212, PCSK9si, ALN-PCSsc, KJX839, KJX-839
Approved
Alnylam Pharmaceuticals Inc
Plaque, Atherosclerotic, Homozygous familial hypercholesterolemia, Atherosclerosis, Diabetes Mellitus, Type 2, Hypercholesterolemia, Kidney Diseases, Hypolipoproteinemias, Dyslipidemias, Diabetes Mellitus, Hyperlipoproteinemia Type II, Hyperlipidemias
Alirocumab
316P, REGN-727, SAR-236553
Approved
Sanofi, Regeneron Pharmaceuticals Inc
Homozygous familial hypercholesterolemia, Atherosclerosis, Hypercholesterolemia, Acute Coronary Syndrome, Dyslipidemias, Hyperlipoproteinemia Type II
Evolocumab
AMG-145
Approved
Amgen Inc, Astellas Pharma Inc
Homozygous familial hypercholesterolemia, Myocardial Infarction, Diabetes Mellitus, Type 2, Atherosclerosis, Hypercholesterolemia, Coronary Artery Disease, Stroke, Coronary Disease, Dyslipidemias, Cardiovascular Diseases, Diabetes Mellitus, Hyperlipidemias, Hyperlipoproteinemia Type II
JS-002
JS-002
Phase 3 Clinical
Shanghai Junshi Biosciences Co Ltd
Hypertriglyceridemia, Atherosclerosis, Hypercholesterolemia, Hyperlipidemia, Familial Combined, Hyperlipidemias
Lerodalcibep
LIB-003
Phase 3 Clinical
Lib Therapeutics
Hypercholesterolemia, Stroke, Cardiovascular Diseases, Hyperlipoproteinemia Type II
IBI-306
IBI-306
Phase 3 Clinical
Innovent Biologics(Suzhou) Co Ltd
Homozygous familial hypercholesterolemia, Hypercholesterolemia
CiVi-007
CiVi-007, LNA-PCSK -9, LNA-PCSK9-GalNac
Phase 2 Clinical
F. Hoffmann-La Roche Ltd
Hypercholesterolemia
AK-102
AK-102
Phase 2 Clinical
Zhongshan Akeso Biopharma Co Ltd, Yabao Us Pharmaceutical Co Ltd
Homozygous familial hypercholesterolemia, Hypercholesterolemia, Hyperlipidemias, Hyperlipoproteinemia Type II
CVI-LM001
C-8304, CVI-LM001
Phase 2 Clinical
Xiwei'Ai Medicine Technology (Shanghai) Co Ltd
Hypercholesterolemia, Hyperlipidemias
SHR-1209
SHR-1209
Phase 2 Clinical
Jiangsu Hengrui Medicine Co Ltd
Hypercholesterolemia, Hyperlipidemias, Hyperlipoproteinemia Type II
References
Title
Authors
Source
The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation
Seidah N.G., Benjannet S., Wickham L., Marcinkiewicz J., Jasmin S.B., Stifani S., Basak A., Prat A., Chretien M.,
Proc. Natl. Acad. Sci. U.S.A. 100:928-933(2003)
Functional characterization of Narc 1, a novel proteinase related to proteinase K
Naureckiene S., Ma L., Sreekumar K., Purandare U., Lo C.F., Huang Y., Chiang L.W., Grenier J.M., Ozenberger B.A., Jacobsen J.S., Kennedy J.D., DiStefano P.S., Wood A., Bingham B.,
Arch. Biochem. Biophys. 420:55-67(2003)
Global, in vivo, and site-specific phosphorylation dynamics in signaling networks
Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.,
Cell 127:635-648(2006)
The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications
Benjannet S., Rhainds D., Hamelin J., Nassoury N., Seidah N.G.,
J. Biol. Chem. 281:30561-30572(2006)
The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR
Nassoury N., Blasiole D.A., Tebon Oler A., Benjannet S., Hamelin J., Poupon V., McPherson P.S., Attie A.D., Prat A., Seidah N.G.,
Traffic 8:718-732(2007)
Self-association of human PCSK9 correlates with its LDLR-degrading activity
Fan D., Yancey P.G., Qiu S., Ding L., Weeber E.J., Linton M.F., Fazio S.,
Biochemistry 47:1631-1639(2008)
PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1
Jonas M.C., Costantini C., Puglielli L.,
EMBO Rep. 9:916-922(2008)
PCSK9 is phosphorylated by a Golgi casein kinase-like kinase ex vivo and circulates as a phosphoprotein in humans
Dewpura T., Raymond A., Hamelin J., Seidah N.G., Mbikay M., Chretien M., Mayne J.,
FEBS J. 275:3480-3493(2008)
The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2
Poirier S., Mayer G., Benjannet S., Bergeron E., Marcinkiewicz J., Nassoury N., Mayer H., Nimpf J., Prat A., Seidah N.G.,
J. Biol. Chem. 283:2363-2372(2008)
Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels
Mayer G., Poirier S., Seidah N.G.,
J. Biol. Chem. 283:31791-31801(2008)