proprotein convertase subtilisin/kexin type 9; neural apoptosis-regulated convertase 1; NARC-1; Proprotein convertase 9; PC9; subtilisin/kexin-like protease PC9 (PCSK9 NARC1 PSEC0052)
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Function
- protease with charge-relay system
- role in differentiation of cortical neurons
- may play a role in cholesterol homeostasis
- binds to LDL receptors, increasing the degradation of LDL receptors & reducing clearance of LDL cholesterol from the circulation[3]
- the soluble zymogen undergoes autocatalytic intramolecular processing in the endoplasmic reticulum, resulting in cleavage of its propeptide that remains associated with the secreted enzyme
- the precursor protein but not the mature protein may form multimers
Inhibition:
- inhibited by EGTA
Structure
Compartment
Alternative splicing
named isoforms=2
Expression
- highly expressed in liver
- expressed in neuroepithelioma, colon carcinoma, hepatic & pancreatic cell lines, & in Schwann cells
Pathology
- mutations associated with autosomal dominant hypercholesterolemia 3
Polymorphism
- variant Leu-23 ins polymorphism in PCSK9 may modify effect of LDLR mutation in familial hypercholesterolemia
- some PCSK9 variants decrease serum of LDL cholesterol[5]
Pharmacology
- PCSK9 inhibitors (monoclonal antibodies, i.e. alirocumab, evolocumab ..) increase recycling of LDL receptors & reduce LDL cholesterol levels[3]
Comparative biology
- CRISPR knock out of the PCSK9 gene in the livers of mice increases LDL receptors & reduces plasma LDL cholesterol without observable adverse effects[4]
More general terms
Additional terms
References
- ↑ UniProt http://www.uniprot.org/uniprot/Q8NBP7.html
- ↑ SeattleSNPs http://pga.gs.washington.edu/data/pcsk9/
- ↑ 3.0 3.1 3.2 Roth EM et al Atorvastatin with or without an Antibody to PCSK9 in Primary Hypercholesterolemia. N Engl J Med. Oct 31, 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23113833 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1201832
Giugliano RP et al Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study The Lancet, Early Online Publication, 6 November 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23141813 <Internet> http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61770-X/abstract
Koren MJ et al Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study The Lancet, Early Online Publication, 6 November 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23141812 <Internet> http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61771-1/abstract
Tonkin AM and Watts GF Into the future: diversifying lipid management The Lancet, Early Online Publication, 6 November 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23141810 <Internet> http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61888-1/fulltext - ↑ 4.0 4.1 Ding Q et al Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing. Circ Res 2014 Jun 10 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24916110 <Internet> http://circres.ahajournals.org/content/early/2014/06/10/CIRCRESAHA.115.304351
- ↑ 5.0 5.1 Ference BA, Robinson JG, Brook RD et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med 2016 Dec 1; 375:2144 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27959767 <Internet> http://www.nejm.org/doi/10.1056/NEJMoa1604304
Database
- Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=255738
- Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:255738
- OMIM: https://mirror.omim.org/entry/603776
- OMIM: https://mirror.omim.org/entry/607786
- UniProt: http://www.uniprot.org/uniprot/Q8NBP7.html