PCSK9

from Wikipedia, the free encyclopedia
Proprotein convertase subtilisin / kexin type 9
Proprotein convertase subtilisin / kexin type 9
PDB  2p4e

Existing structural data : 4nmx , 4k8r , 3sqo , 3p5b , 3p5c , 3m0c , 2xtj , 3h42 , 3gcw , 3gcx , 2w2n , 2w2m , 2w2p , 2w2o , 2w2q , 3bps , 2qtw , 2pmw , 2p4e

Properties of human protein
Mass / length primary structure 692 amino acids
Identifier
Gene name PCSK9
External IDs
Enzyme classification
EC, category 3.4.21.-
Orthologue
human House mouse
Entrez 255738 100102
Ensemble ENSG00000169174 ENSMUSG00000044254
UniProt Q8NBP7 Q80W65
Refseq (mRNA) NM_174936 NM_153565
Refseq (protein) NP_777596 NP_705793
Gene locus Chr 1: 55.04 - 55.06 Mb Chr 4: 106.44 - 106.46 Mb
PubMed search 255738 100102

The proprotein convertase subtilisin / kexin type 9 ( English proprotein convertase subtilisin / kexin type 9 , abbreviated as: PCSK9 ; neural apoptosis-regulated convertase-1 , NARC-1 ) is a serine protease that is involved in lipid metabolism .

Biological importance

Proprotein activate inactive precursor forms of proteins ( proproteins ) by removing a prosegment and so the active protein (z. B. hormone or receptor ) release. So far, nine proprotein convertases have been characterized, including PCSK9. PCSK9 is of clinical importance as it reduces the number of LDL receptors on the cell membrane of the liver cells and consequently increases the concentration of LDL cholesterol in the blood.

Mutations in the PCSK9 gene are the third leading cause of hypercholesterolemia in patients with homozygous autosomal dominant hypercholesterolemia (ADH). The development of PCSK9 inhibitors is one approach to reducing LDL cholesterol.

Regulation in the cholesterol metabolism

PCSK9 is mainly located in the liver. The inactive PCSK9 undergoes autocatalytic cleavage in the endoplasmic reticulum before it is secreted from the liver cells into the bloodstream . However, the split off prosegment remains attached to the active protein at its catalytic center. This could explain why no other catalytic activity of PCSK9 apart from this self-cleavage is known.

The effects of the PCSK9 on the LDL receptor and the LDL cholesterol level are independent of its catalytic function, but take place through binding to the LDL receptor and its increased breakdown . Of therapeutic interest is the PCSK9 effect on the breakdown of the LDL receptors, which remove LDL cholesterol from the bloodstream. Circulating LDL cholesterol is broken down primarily via the LDL receptor in the liver. LDL receptors bind the circulating LDL cholesterol and are channeled into the cell together by endocytosis . As the pH value in the endosomes drops, the LDL cholesterol and the LDL receptor separate. While the LDL cholesterol continues to break down in the liver cell, the receptors are again transported to the cell surface in order to take up LDL cholesterol again.

PCSK9 regulates the LDL cholesterol level by binding the LDL receptor and being taken up with it by the liver cells. PCSK9-bound LDL receptors are broken down in this case and are not transported to the cell surface again and are therefore no longer available for LDL binding. This increases the LDL cholesterol level in the plasma.

Pathological dysregulation leads to hypercholesterolemia.

Genetic bases

Familial hypercholesterolemia is an autosomal dominant disease characterized by elevated plasma LDL levels, xanthomas, and early coronary artery disease . So far, mutations in three genes have been discovered as causes, all three of which influence the function of the LDL receptor: mutations of the LDL receptor gene, the apoB100 gene and the PCSK9 gene.

In 2003, mutations of a newly identified gene, the PCSK9 gene on chromosome 1, were discovered in two French families with familial hypercholesterolemia. These were found to be gain-of-function mutations . Since then, numerous other mutations in the PCSK9 gene have been identified, including loss-of-function mutations in patients with low LDL cholesterol levels and a low risk of CHD. Gain-of-function mutations are rare mutations and are the third most common cause of homozygous ADH, far behind LDL receptor and apoB mutations. In the meantime, however, well over 100 gene variants of PCSK9 have been identified, which could be responsible for a large proportion of severe hypercholesterolemia.

Treatment of hypercholesterolemia

Independent risk factors for coronary artery disease are increased LDL cholesterol and lipoprotein (a) as well as decreased HDL. The exposure time is crucial, so that genetic forms of hypercholesterolemia are particularly important for the development of atherosclerosis.

For milder forms of dyslipidemia, treatment takes the form of lifestyle changes. If the overall cardiovascular risk is increased and the LDL target value is not achieved through lifestyle measures, statin therapy is usually indicated. For patients at particularly high risk, an LDL cholesterol value of less than 70 mg / dl should be aimed for. In patients with proven atherosclerosis, the use of a statin is advisable, even if the initial LDL level is below 100 mg / dl. For many patients with familial hypercholesterolemia, these target values ​​remain difficult to achieve despite drug therapy.

Limits to statin effects

PCSK9 and LDL receptors are both mainly regulated by the intracellular cholesterol level: if this level falls, then gene expression of the LDL receptor and PCSK9 is induced. The mechanism of action of statins consists in the inhibition of a key enzyme ( HMG-CoA reductase , SREBP ) and leads to a lowering of intracellular cholesterol in the liver cells. They are therefore also known as HMG-CoA reductase inhibitors. The effect via the SREBP leads to a regulatory increase in the production (and secretion) of PCSK9, so statins increase the PCSK9 levels and thus attenuate their actual LDL lowering potential somewhat. This can explain why statins can hardly lower LDL cholesterol by more than 50%. A combination of statins with PCSK9 inhibitors is expected to have an additive effect.

PCSK9 as the target structure

PCSK9 inhibitors bind to the circulating PCSK9 and prevent them from binding to the LDL receptors. This increases the breakdown of LDL cholesterol via the LDL receptors. The PCSK9 inhibitors are a particularly active area of ​​research. The discovery of the PCSK9 gene and its mutations is an example of genetics-driven therapy development. The development of anti-PCSK9 monoclonal antibodies is the most advanced.

  • Alirocumab , also a monoclonal antibody developed by Sanofi and Regeneron Pharmaceuticals , has been approved as a praluent in the USA since July 2015 and Europe-wide since September 2015. The indications are largely identical to those of evolocumab.
  • Bococizumab (RN 316, Pfizer ) was investigated in phase II studies. In November 2016, Pfizer announced that further development had been discontinued.

Among the other approaches for PCSK9 inhibitors ( small molecules , peptide mimetics , gene silencing ) is the siRNA Inclisiran (formerly also PCSK9si and / or ALN-PCSsc). The substance comes from research by Alnylam Pharmaceuticals and is being developed together with The Medicines Company .

See also

literature

Web links

Individual evidence

  1. ↑ G. Lambert, B. Sjouke, B. Choque, JJ Kastelein, GK Hovingh: The PCSK9 decade. In: Journal of lipid research. Volume 53, number 12, December 2012, ISSN  0022-2275 , pp. 2515-2524, doi: 10.1194 / jlr.R026658 , PMID 22811413 , PMC 3494258 (free full text).
  2. ^ FR Maxfield, G. van Meer: Cholesterol, the central lipid of mammalian cells. In: Current opinion in cell biology. Volume 22, number 4, August 2010, ISSN  1879-0410 , pp. 422-429, doi: 10.1016 / j.ceb.2010.05.004 , PMID 20627678 , PMC 2910236 (free full text).
  3. ↑ NG Seidah, MS Sadr, M. Chrétien, M. Mbikay: The multifaceted proprotein convertases: their unique, redundant, complementary, and opposite functions. In: The Journal of biological chemistry. Volume 288, Number 30, July 2013, ISSN  1083-351X , pp. 21473-21481, doi: 10.1074 / jbc.R113.481549 , PMID 23775089 , PMC 3724608 (free full text).
  4. ↑ F. Petrides, K. Shearston, M. Chatelais, F. Guilbaud, O. Meilhac, G. Lambert: The promises of PCSK9 inhibition. In: Current opinion in lipidology. Volume 24, Number 4, August 2013, ISSN  1473-6535 , pp. 307-312, doi: 10.1097 / MOL.0b013e328361f62d , PMID 23817198 .
  5. ↑ M. Abifadel, M. Varret, JP Rabès, D. Allard, K. Ouguerram, M. Devillers, C. Cruaud, S. Benjannet, L. Wickham, D. Erlich, A. Derré, L. Villéger, M. Farnier, I. Beucler, E. Bruckert, J. Chambaz, B. Chanu, JM Lecerf, G. Luc, P. Moulin, J. Weissenbach, A. Prat, M. Krempf, C. Junien, NG Seidah, C. Boileau: Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. In: Nature genetics. Volume 34, Number 2, June 2003, ISSN  1061-4036 , pp. 154-156, doi: 10.1038 / ng1161 , PMID 12730697 .
  6. ↑ Jonathan C. Cohen , Eric Boerwinkle, Thomas H. Mosley, Helen H. Hobbs : Sequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease . In: New England Journal of Medicine . tape 354 , no. 12 , 2006, p. 1264-1272 , doi : 10.1056 / NEJMoa054013 , PMID 16554528 .
  7. ↑ Jonathan C. Cohen, Helen H. Hobbs: Simple Genetics for a Complex Disease . In: Science . tape 340 , no. 6133 , October 5, 2013, p. 689-690 , doi : 10.1126 / science.1239101 , PMID 23661745 .
  8. ^ Repatha on the website of the European Medicines Agency
  9. ↑ European Commission Approves Amgen's New Cholesterol-Lowering Medication Repatha ™ (evolocumab), The First PCSK9 Inhibitor To Be Approved In The World, For Treatment Of High Cholesterol , Amgen PM July 21, 2015, accessed July 22, 2015
  10. ↑ FDA approves Praluent to treat certain patients with high cholesterol , FDA PM July 24, 2015, accessed February 14, 2016
  11. ↑ Sanofi and Regeneron announce the approval of Praluent® (alirocumab) for the therapy of hypercholesterolemia in the European Union ( Memento of the original from January 16, 2016 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. , PM from Sanofi Germany on September 29, 2015 @1@ 2Template: Webachiv / IABot / www.sanofi.de
  12. ↑ [( http://www.ema.europa.eu/ema/index.jsp ? Curl = pages / medicines / human / medicines / 003766 / smops / Positive / human_smop_000828.jsp & mid = WC0b01ac058001d127 & source = homeMedSearch & category = human)] accessed on February 14, 2016
  13. ↑ Bococizumab (RN316) Significantly Reduced LDL Cholesterol In Statin-Treated Adults With High Cholesterol In A Phase 2b Study , Pfizer PM March 27, 2014, accessed April 1, 2014
  14. ↑ http://www.pfizer.com/news/press-release/press-release-detail/pfizer_discontinues_global_development_of_bococizumab_its_investigational_pcsk9_inhibitor
  15. ↑ Alnylam development pipeline , WebSite Alnylam, accessed on May 24, 2017
  16. ↑ The Medicines Company and Alnylam Announce Presentation of New Pre-Clinical Data on PCSK9 at Arteriosclerosis, Thrombosis and Vascular Biology 2014 Scientific Sessions , PM The Medicines Company from 1 May 2014, accessed on May 3, 2014
  17. ↑ The Medicines Company and Alnylam Pharmaceuticals Announce Agreement with FDA on Phase III Clinical Program for Inclisiran ( Memento of the original dated June 26, 2017 in the Internet Archive ) Info: The archive link has been inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. , PM Alnylam, April 26, 2017, accessed May 24, 2017 @1@ 2Template: Webachiv / IABot / investors.alnylam.com
  18. ↑ The Medicines Company and Alnylam Pharmaceuticals Announce Agreement with FDA on Phase III Clinical Program for Inclisiran , PM The Medicines Company, April 26, 2017, accessed May 24, 2017