extrinsic component of external side of plasma membrane
endoplasmic reticulum
perinuclear region of cytoplasm
COPII-coated ER to Golgi transport vesicle
lysosome
PCSK9-LDLR complex
extracellular region
extracellular space
lysosomal membrane
endolysosome membrane
endoplasmic reticulum lumen
Biological process
lipoprotein metabolic process
neurogenesis
steroid metabolic process
kidney development
positive regulation of receptor internalization
lipid metabolism
negative regulation of low-density lipoprotein particle clearance
negative regulation of sodium ion transmembrane transporter activity
regulation of low-density lipoprotein particle receptor catabolic process
cellular response to starvation
regulation of neuron apoptotic process
protein processing
regulation of signaling receptor activity
cholesterol metabolic process
protein autoprocessing
proteolysis
positive regulation of neuron apoptotic process
positive regulation of low-density lipoprotein particle receptor catabolic process
low-density lipoprotein receptor particle metabolic process
neuron differentiation
cellular response to insulin stimulus
lysosomal transport
phospholipid metabolic process
liver development
cholesterol homeostasis
triglyceride metabolic process
negative regulation of receptor recycling
apoptotic process
negative regulation of low-density lipoprotein particle receptor binding
negative regulation of low-density lipoprotein receptor activity
negative regulation of receptor-mediated endocytosis involved in cholesterol transport
low-density lipoprotein particle receptor catabolic process
low-density lipoprotein particle clearance
post-translational protein modification
negative regulation of signaling receptor activity
Sources:Amigo / QuickGO
Orthologs
Species
Human
Mouse
Entrez
255738
100102
Ensembl
ENSG00000169174
ENSMUSG00000044254
UniProt
Q8NBP7
Q80W65
RefSeq (mRNA)
NM_174936
NM_153565
RefSeq (protein)
NP_777596
NP_705793
Location (UCSC)
Chr 1: 55.04 – 55.06 Mb
Chr 4: 106.3 – 106.32 Mb
PubMed search
[3]
[4]
Wikidata
View/Edit Human
View/Edit Mouse
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans on chromosome 1.[5] It is the 9th member of the proprotein convertase family of proteins that activate other proteins.[6] Similar genes (orthologs) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme.[7] The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.[8]
PCSK9 is ubiquitously expressed in many tissues and cell types.[9] PCSK9 binds to and degrades the receptor for low-density lipoprotein particles (LDL), which typically transport 3,000 to 6,000 fat molecules (including cholesterol) per particle, within extracellular fluid. The LDL receptor (LDLR), on liver and other cell membranes, binds and initiates ingestion of LDL-particles from extracellular fluid into cells and targets the complex to lysosomes for destruction. If PCSK9 is blocked, the LDL-LDLR complex separates during trafficking, with the LDL digested in the lysosome, but the LDLRs instead recycled back to the cell surface and so able to remove additional LDL-particles from the extracellular fluid.[10][11] Therefore, blocking PCSK9 can lower blood LDL-particle concentrations.[12][13]
PCSK9 has medical importance because it acts in lipoprotein homeostasis. Agents that block PCSK9 can lower LDL particle concentrations. The first two PCSK9 inhibitors, alirocumab and evolocumab, were approved as once every two week injections, by the U.S. Food and Drug Administration in 2015 for lowering LDL-particle concentrations when statins and other drugs were not sufficiently effective or poorly tolerated. The cost of these new medications, as of 2015[update], was $14,000 per year at full retail; judged of unclear cost effectiveness by some.[14] While these medications are prescribed by many physicians, the payment for prescriptions are often denied by insurance providers.[15][16][17] As a result, pharmaceutical manufacturers lowered the prices of these drugs.[18]
^ abcGRCh38: Ensembl release 89: ENSG00000169174 – Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000044254 – Ensembl, May 2017
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Cite error: The named reference Seidah_2003 was invoked but never defined (see the help page).
^Zhang L, Song K, Zhu M, Shi J, Zhang H, Xu L, Chen Y (August 2016). "Proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipid metabolism, atherosclerosis and ischemic stroke". International Journal of Neuroscience. 126 (8): 675–680. doi:10.3109/00207454.2015.1057636. PMID 26040332. S2CID 40377207.
^Lagace TA (October 2014). "PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells". Current Opinion in Lipidology. 25 (5): 387–393. doi:10.1097/MOL.0000000000000114. PMC 4166010. PMID 25110901.
^Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield M, Devlin JJ, et al. (June 2015). "Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials". The Lancet. 385 (9984): 2264–2271. doi:10.1016/S0140-6736(14)61730-X. PMC 4608367. PMID 25748612.
^"BioGPS - your Gene Portal System". biogps.org. Retrieved 19 August 2016.
^Weinreich M, Frishman WH (2014). "Antihyperlipidemic therapies targeting PCSK9". Cardiology in Review. 22 (3): 140–146. doi:10.1097/CRD.0000000000000014. PMID 24407047. S2CID 2201087.
^Gearing ME (18 May 2015). "A potential new weapon against heart disease: PCSK9 inhibitors". Science in the News (Blog post). Harvard University.
^Joseph L, Robinson JG (2015). "Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibition and the Future of Lipid Lowering Therapy". Progress in Cardiovascular Diseases. 58 (1): 19–31. doi:10.1016/j.pcad.2015.04.004. PMID 25936907.
^Hlatky MA, Kazi DS (November 2017). "PCSK9 Inhibitors: Economics and Policy". Journal of the American College of Cardiology. 70 (21): 2677–2687. doi:10.1016/j.jacc.2017.10.001. PMID 29169476.
^Kolata G (2 October 2018). "These Cholesterol-Reducers May Save Lives. So Why Aren't Heart Patients Getting Them?". The New York Times. Retrieved 21 May 2023.
^Baum SJ, Toth PP, Underberg JA, Jellinger P, Ross J, Wilemon K (April 2017). "PCSK9 inhibitor access barriers-issues and recommendations: Improving the access process for patients, clinicians and payers". Clinical Cardiology. 40 (4): 243–254. doi:10.1002/clc.22713. PMC 5412679. PMID 28328015.
^Navar AM, Taylor B, Mulder H, Fievitz E, Monda KL, Fievitz A, et al. (November 2017). "Association of Prior Authorization and Out-of-pocket Costs With Patient Access to PCSK9 Inhibitor Therapy". JAMA Cardiology (Original Investigation). 2 (11): 1217–1225. doi:10.1001/jamacardio.2017.3451. PMC 5963012. PMID 28973087.
Weinstock CP (4 October 2017). "Insurers are slow to approve pricey new cholesterol drugs". Health & Pharma. Reuters.
^Liu A (11 February 2019). "PCSK9 price-cut matchup is on, as Regeneron and Sanofi slash Praluent list tag 60%". Fierce Pharma. Questex. Retrieved 2019-05-18.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans on chromosome 1. It is the 9th member of the proprotein...
antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is a protein that targets LDL receptors for degradation; its inhibition...
proprotein convertase, specifically, inhibiting translation of the protein PCSK9. Inclisiran was approved for use in the European Union in December 2020...
antibody that belongs to a novel class of anti-cholesterol drugs, known as PCSK9 inhibitors, and it was the first such agent to receive FDA approval. The...
gain-of-function mutations in PCSK9, the molecular "scissor" of LDL receptors, resulting in less LDLR available. PCSK9 mutations cause less than 5% of...
metabolism disorders. In familial hypercholesterolemia, a mutation in the LDLR, PCSK9, or APOB is usually the reason for this and these mutations result in high...
is being evaluated for the treatment of hypercholesterolaemia. It is a PCSK9 inhibitor. "Recommended International Nonproprietary Names: List 90" (PDF)...
coronary artery disease. The following genes have an association with MI: PCSK9, SORT1, MIA3, WDR12, MRAS, PHACTR1, LPA, TCF21, MTHFDSL, ZC3HC1, CDKN2A...
for Daiichi. In September 2020, AstraZeneca acquired the preclinical oral PCSK9 inhibitor program from Dogma Therapeutics. On 27 December 2020, AstraZeneca...
cholesterol up to 72% more than its competitors. The new drug would target the PCSK9 gene. In July 2015, the company announced a new global collaboration with...
bacterial and viral proteins. In 2003, he discovered PCSK9 and showed that point mutations in the PCSK9 gene cause dominant familial hypercholesterolemia...
hypercholesterolemia. Inherited high cholesterol can also include genetic mutations in the PCSK9 gene and the gene for apolipoprotein B. Elevated cholesterol levels are...
2019). "Novartis Buys The Medicines Company: A $9.7 Billion Gamble on a PCSK9 Cholesterol Drug". BioSpace. Urbandale, Iowa. Archived from the original...
in a race with Amgen and Pfizer to win approval for a drug that inhibits PCSK9, a protein that slows the clearance of low-density lipoprotein (LDL) cholesterol...
Medicine. She and Jonathan C. Cohen found that people with hypomorphic PCSK9 mutations had lower LDL-cholesterol levels and were almost immune to heart...
2021. Musunuru, Kiran; et al. (May 2021). "In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates". Nature. 593 (7859): 429–434. Bibcode:2021Natur...
may represent a feasible strategy to deter tumor progression. Variants of PCSK9 can reduce or increase circulating cholesterol. Furin plays a role in the...
Clausen V (January 2017). "A Highly Durable RNAi Therapeutic Inhibitor of PCSK9". New England Journal of Medicine. 376 (1): 41–51. doi:10.1056/NEJMoa1609243...
autosomal dominant familial hypercholesterolemia (HCHOLA3) variant of the PCSK9 gene, or the LDL receptor gene. Familial hypercholesterolemia affects about...
development code RN316) is a drug that was in development by Pfizer targeting PCSK9 to reduce LDL cholesterol. Pfizer withdrew the drug from development in...
has led to the development of a new class of cholesterol-lowering drugs, PCSK9 antibodies, for patients who do not tolerate or respond adequately to statins)...
trafficking soluble (i.e. non-membrane-bound) proteins, namely lipoproteins and PCSK9. It recognizes cargo proteins via a three-amino-acid sequence near the N-termini...
Global Information
