proprotein convertase subtilisin/kexin type 9

Target id: 2388

Nomenclature: proprotein convertase subtilisin/kexin type 9

Family: S8: Subtilisin

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for proprotein convertase subtilisin/kexin type 9 in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 692 1p34.1-p32 PCSK9 proprotein convertase subtilisin/kexin type 9
Mouse - 694 4 C7 Pcsk9 proprotein convertase subtilisin/kexin type 9
Rat - 691 5q34 Pcsk9 proprotein convertase subtilisin/kexin type 9
Previous and Unofficial Names
FH3 | Narc1 | neural apoptosis-regulated convertase 1 | proprotein convertase 9 | proprotein convertase PC9
Database Links
Specialist databases
MEROPS S08.039 (Hs)
Other databases
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 3.4.21.-

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Reference
bococizumab Hs Inhibition 10.0 pKd 6
pKd 10.0 (Kd 1x10-10 M) [6]
Description: Affinity for hPCSK9 measured using proprietary BIACore® technology.
evolocumab Hs Inhibition 9.7 pKd 5
pKd 9.7 (Kd 1.9x10-10 M) [5]
Description: Dissociation equilibrium constant for wild-type hPCSK9, measured using proprietary BIACore® technology.
alirocumab Hs Inhibition 9.4 pKd 11
pKd 9.4 (Kd 3.77x10-10 M) [11]
Physiological Functions
PCSK9 may be an inflammatory mediator in the pathogenesis of atherosclerosis.
Species:  Mouse
Tissue:  Atherosclerotic vascular lesions and macrophages.
References:  12
Clinically-Relevant Mutations and Pathophysiology
Disease:  Hypercholesterolemia; autosomal dominant, 3
Synonyms: Familial hypercholesterolemia [Disease Ontology: DOID:13810]
Disease Ontology: DOID:13810
OMIM: 603776
References:  2,4
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human S127R 625T>A 1
Missense Human F216L 890T>C 1
Missense Human D374Y Patients carrying this gain of function mutation exhibit lower plasma concentrations of PCSK9 4
Biologically Significant Variants
Type:  Naturally occurring SNP
Species:  Human
Description:  Nucleotide change 625T->A causes a Ser to Arg substitution
Amino acid change:  S127R
Amino acids:  692
SNP accession: 
Validation:  1000 Genomes, HapMap, Cited, Frequency, Multiple observations
References:  2
Type:  Naturally occurring SNPs
Species:  Human
Description:  Nucleotide change 890T->C causes a Phe to Leu substitution
Amino acid change:  F216L
Amino acids:  692
SNP accession: 
Validation:  1000 Genomes, HapMap, Cited, Frequency, Multiple observations
References:  2
Biologically Significant Variant Comments
Healthy individuals carrying the PCSK9 R46L variant exhibit lower plasma concentrations of PCSK9 [4].
General Comments
Mature PCSK9 protein is secreted from hepatocytes. The enzyme acts to reduce the levels of LDL receptors by binding to local LDL receptor-cholesterol complexes, inducing their endocytic internalisation and degradaition [3,7,10,13]. This function of PCSK9 helps to modulate LDL metabolism. Inhibition of PCSK9 results in increased numbers of LDL receptors on hepatocyte membranes [8] which promotes LDL clearance. PCSK9 is being actively pursued as a mechanistic target for the development of novel agents to treat hypercholesterolemia, especially for patients who do not respond to or don't tolerate statin treatment. The focus to date has been on the development of anti-PCSK9 monoclonal antibodies, and two such therapeutics are in Phase III development: evolocumab and alirocumab. Preliminary clinical study results for these antibodies are reviewed by Navarese et al (2015) [9].

References

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1. Abifadel M, Elbitar S, El Khoury P, Ghaleb Y, Chémaly M, Moussalli ML, Rabès JP, Varret M, Boileau C. (2014) Living the PCSK9 Adventure: from the Identification of a New Gene in Familial Hypercholesterolemia Towards a Potential New Class of Anticholesterol Drugs. Curr Atheroscler Rep16 (9): 439. [PMID:25052769]

2. Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D et al.. (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet.34 (2): 154-6. [PMID:12730697]

3. DeVay RM, Shelton DL, Liang H. (2013) Characterization of proprotein convertase subtilisin/kexin type 9 (PCSK9) trafficking reveals a novel lysosomal targeting mechanism via amyloid precursor-like protein 2 (APLP2). J. Biol. Chem.288 (15): 10805-18. [PMID:23430252]

4. Humphries SE, Neely RD, Whittall RA, Troutt JS, Konrad RJ, Scartezini M, Li KW, Cooper JA, Acharya J, Neil A. (2009) Healthy individuals carrying the PCSK9 p.R46L variant and familial hypercholesterolemia patients carrying PCSK9 p.D374Y exhibit lower plasma concentrations of PCSK9. Clin. Chem.55 (12): 2153-61. [PMID:19797716]

5. Jackson SM, Shan B, Shen W, King CT. Antigen binding proteins to proprotein convertase subtilisin kexin type 9 (PCSK9). Patent number: US8030457. Assignee: Amgen, Inc.. Priority date: 23/08/2007. Publication date: 04/10/2011.

6. Liang H et al. Isolated antibody which specifically binds to PCSK9. Patent number: US8080243. Assignee: Rinat Neuroscience Corp., Pfizer Inc.. Priority date: 12/09/2008. Publication date: 20/12/2011.

7. Mbikay M, Mayne J, Chrétien M. (2013) Proprotein convertases subtilisin/kexin type 9, an enzyme turned escort protein: hepatic and extra hepatic functions. J Diabetes5 (4): 391-405. [PMID:23714205]

8. McNutt MC, Kwon HJ, Chen C, Chen JR, Horton JD, Lagace TA. (2009) Antagonism of secreted PCSK9 increases low density lipoprotein receptor expression in HepG2 cells. J. Biol. Chem.284 (16): 10561-70. [PMID:19224862]

9. Navarese EP, Kolodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, Brockmeyer M, Kandzari DE, Kubica JM, D'Agostino Sr RB et al.. (2015) Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis. Ann. Intern. Med.,  [Epub ahead of print]. [PMID:25915661]

10. Qian YW, Schmidt RJ, Zhang Y, Chu S, Lin A, Wang H, Wang X, Beyer TP, Bensch WR, Li W et al.. (2007) Secreted PCSK9 downregulates low density lipoprotein receptor through receptor-mediated endocytosis. J. Lipid Res.48 (7): 1488-98. [PMID:17449864]

11. Sleeman MW, Martin JH, Huang TT, MacDonald D. High affinity human antibodies to PCSK9. Patent number: US8062640. Assignee: Regeneron Pharmaceuticals, Inc.. Priority date: 15/12/2008. Publication date: 22/11/2011.

12. Tang ZH, Peng J, Ren Z, Yang J, Li TT, Li TH, Wang Z, Wei DH, Liu LS, Zheng XL et al.. (2017) New role of PCSK9 in atherosclerotic inflammation promotion involving the TLR4/NF-κB pathway. Atherosclerosis262: 113-122 [Epub ahead of print]. [PMID:28535426]

13. Wang Y, Huang Y, Hobbs HH, Cohen JC. (2012) Molecular characterization of proprotein convertase subtilisin/kexin type 9-mediated degradation of the LDLR. J. Lipid Res.53 (9): 1932-43. [PMID:22764087]

How to cite this page

S8: Subtilisin: proprotein convertase subtilisin/kexin type 9. Last modified on 24/05/2017. Accessed on 22/10/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2388.