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PCSK9

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Template:PBB Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is an enzyme that in humans is encoded by the PCSK9 gene.[1] Similar genes (orthologs) are found across many species.

Many enzymes, including PCSK9, are inactive when they are first synthesized, because they have a section of peptide chains that blocks their activity; proprotein convertases remove that section to activate the enzyme.

PCSK9 has medical significance because it acts in cholesterol homeostasis. Drugs that can block PCSK9, thus lowering low-density lipoprotein cholesterol (LDL-C), began Phase III clinical trials in 2012 to assess their safety and efficacy in humans, and to determine if they can improve outcomes in heart disease.[2][3]

PCSK9 was initially known as NARC-1.[4]

Function

This gene encodes a proprotein convertase belonging to the proteinase K subfamily of the secretory subtilase family. The encoded protein is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum. The protein may function as a proprotein convertase.

This protein plays a major regulatory role in cholesterol homeostasis. PCSK9 binds to the epidermal growth factor-like repeat A (EGF-A) domain of the low-density lipoprotein receptor (LDLR), inducing LDLR degradation. Reduced LDLR levels result in decreased metabolism of LDL-C, which could lead to hypercholesterolemia.[5]

PCSK9 may also have a role in the differentiation of cortical neurons.[1]

Clinical significance

Variants of PCSK9 can reduce or increase circulating cholesterol.

LDL-C is removed from the blood when it binds to an LDLR on the surface of liver cells, and is taken inside the cells. When PCSK9 binds to an LDLR, the receptor is destroyed along with the LDL particle. But if PCSK9 does not bind, the receptor can return to the surface of the cell and remove more cholesterol.[2]

Other variants are associated with a rare autosomal dominant familial hypercholesterolemia (HCHOLA3).[6][7][8] The mutations increase its protease activity, reducing LDLR levels and preventing the uptake of cholesterol into the cells.[7]

As a drug target

Drugs can inhibit PCSK9, leading to lowered circulating cholesterol. Since LDL is considered a risk factor for cardiovascular disease like heart attacks, it is plausible that these drugs may also reduce the risk of such diseases. Clinical studies, including phase III clinical trials, are now underway to describe the effect of PCSK9 inhibition on cardiovascular disease, and the safety and efficacy profile of the drugs.[9][10][11][12] Among those inhibitors under development in December 2013 were the antibodies alirocumab, evolocumab, 1D05-IgG2 (Merck), RG-7652 and LY3015014, as well as the RNAi therapeutic ALN-PCS02.[13]

Monoclonal antibodies

A number of monoclonal antibodies that bind to PCSK9 near the catalytic domain that interact with the LDLR and hence inhibit the function of PCSK9 are in clinical trials as of 2014. These include evolocumab (Amgen), bococizumab (Pfizer), and alirocumab (Aventis/Regeneron).[14]

Preliminary studies have been released for each and phase 3 trials are underway. In September 2014 results were announced that alirocumab cut roughly in half the number of heart attacks and strokes. The result is not conclusive, because the analysis was done retrospectively. The drugs could reach the market next year.[15]

A possible side effect of the monoclonal antibody might be irritation at the injection site. Before the infusions, participants received oral corticosteroids, histamine receptor blockers, and acetaminophen to reduce the risk of infusion-related reactions, which by themselves will cause several side effects.[citation needed]

Peptide mimics

Peptides that mimick the EGFA domain of the LDLR that binds to PCSK9 have been developed to inhibit PCSK9.[16]

Gene silencing

The PCSK9 antisense oligonucleotide increases expression of the LDLR and decreases circulating total cholesterol levels in mice.[17] A locked nucleic acid reduced PCSK9 mRNA levels in mice.[18][19]

Initial clinical trials showed positive results of ALN-PCS, which acts by means of RNA interference.[20][21]

Naturally Occuring Inhibitors

The plant alkaloid berberine inhibits the transcription of the PCSK9 gene. [22] Annexin A2, an endogenous protein, is a natural inhibitor of PCSK9 activity. [23]


Structure

  • 2p4e: Crystal Structure of PCSK9
    2p4e: Crystal Structure of PCSK9
  • 2pmw: The Crystal Structure of Proprotein convertase subtilisin kexin type 9 (PCSK9)
    2pmw: The Crystal Structure of Proprotein convertase subtilisin kexin type 9 (PCSK9)

References

  1. ^ a b Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M (February 2003). "The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation". Proc. Natl. Acad. Sci. U.S.A. 100 (3): 928–33. doi:10.1073/pnas.0335507100. PMC 298703. PMID 12552133.
  2. ^ a b Pollack A (November 5, 2012). "New Drugs for Lipids Set Off Race". New York Times.
  3. ^ Kolata G (July 9, 2013). "Rare Mutation Ignites Race for Cholesterol Drug". New York Times.
  4. ^ Yingnan Zhang, Charles Eigenbrot, Lijuan Zhou, et al. (November 13, 2013). "Identification of a small peptide that inhibits PCSK9 binding to the low density lipoprotein receptor". The Journal of Biological Chemistry (289): 942–955. doi:10.1074/jbc.M113.514067. {{cite journal}}: Vancouver style error: name in name 1 (help)CS1 maint: unflagged free DOI (link)
  5. ^ *"The Evolving Role of PCSK9 Modulation in the Regulation of LDL-Cholesterol". Retrieved 13 May 2015.
  6. ^ "Entrez Gene: PCSK9 proprotein convertase subtilisin/kexin type 9".
  7. ^ a b Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C (June 2003). "Mutations in PCSK9 cause autosomal dominant hypercholesterolemia". Nat. Genet. 34 (2): 154–6. doi:10.1038/ng1161. PMID 12730697.
  8. ^ Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L, Prat A (August 2004). "Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia". Arterioscler. Thromb. Vasc. Biol. 24 (8): 1454–9. doi:10.1161/01.ATV.0000134621.14315.43. PMID 15178557.
  9. ^ Lopez D (2008). "Inhibition of PCSK9 as a novel strategy for the treatment of hypercholesterolemia". Drug News Perspect. 21 (6): 323–30. doi:10.1358/dnp.2008.21.6.1246795. PMID 18836590.
  10. ^ Steinberg D, Witztum JL (June 2009). "Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels". Proc. Natl. Acad. Sci. U.S.A. 106 (24): 9546–7. doi:10.1073/pnas.0904560106. PMC 2701045. PMID 19506257.
  11. ^ Mayer G, Poirier S, Seidah NG (November 2008). "Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels". J. Biol. Chem. 283 (46): 31791–801. doi:10.1074/jbc.M805971200. PMID 18799458.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  12. ^ "Bristol-Myers Squibb selects Isis drug targeting PCSK9 as development candidate for prevention and treatment of cardiovascular disease". Press Release. FierceBiotech. 2008-04-08. Retrieved 2010-09-18.
  13. ^ Sheridan C (2013). "Phase 3 data for PCSK9 inhibitor wows". Nat. Biotechnol. 31 (12): 1057–8. doi:10.1038/nbt1213-1057. PMID 24316621.
  14. ^ Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK (December 2012). "The PCSK9 decade". J. Lipid Res. 53 (12): 2515–24. doi:10.1194/jlr.R026658. PMC 3494258. PMID 22811413.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  15. ^ Reuters (September 1, 2014). "Cholesterol Drug Halves Heart Attack and Stroke in Early Test". New York Times. Retrieved September 1, 2014. {{cite news}}: |last= has generic name (help)
  16. ^ Shan L, Pang L, Zhang R, Murgolo NJ, Lan H, Hedrick JA (October 2008). "PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide". Biochem. Biophys. Res. Commun. 375 (1): 69–73. doi:10.1016/j.bbrc.2008.07.106. PMID 18675252.
  17. ^ Graham MJ, Lemonidis KM, Whipple CP, Subramaniam A, Monia BP, Crooke ST, Crooke RM (April 2007). "Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice". J. Lipid Res. 48 (4): 763–7. doi:10.1194/jlr.C600025-JLR200. PMID 17242417.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  18. ^ Gupta N, Fisker N, Asselin MC, Lindholm M, Rosenbohm C, Ørum H, Elmén J, Seidah NG, Straarup EM (2010). Deb S (ed.). "A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo". PLoS ONE. 5 (5): e10682. doi:10.1371/journal.pone.0010682. PMC 2871785. PMID 20498851.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  19. ^ Lindholm MW, Elmén J, Fisker N, Hansen HF, Persson R, Møller MR, Rosenbohm C, Ørum H, Straarup EM, Koch T (February 2012). "PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates". Mol. Ther. 20 (2): 376–81. doi:10.1038/mt.2011.260. PMC 3277239. PMID 22108858.
  20. ^ "Alnylam Reports Positive Preliminary Clinical Results for ALN-PCS, an RNAi Therapeutic Targeting PCSK9 for the Treatment of Severe Hypercholesterolemia". Press Release. BusinessWire. 2011-01-04. Retrieved 2011-01-04.
  21. ^ Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A, Butler D, Charisse K, Dorkin R, Fan Y, Gamba-Vitalo C, Hadwiger P, Jayaraman M, John M, Jayaprakash KN, Maier M, Nechev L, Rajeev KG, Read T, Röhl I, Soutschek J, Tan P, Wong J, Wang G, Zimmermann T, de Fougerolles A, Vornlocher HP, Langer R, Anderson DG, Manoharan M, Koteliansky V, Horton JD, Fitzgerald K (August 2008). "Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates". Proc. Natl. Acad. Sci. U.S.A. 105 (33): 11915–20. doi:10.1073/pnas.0805434105. PMC 2575310. PMID 18695239.
  22. ^ Li H, Dong B, Park SW, Lee HS, Chen W, Liu J (August 2009). "HNF1α plays a critical role in PCSK9 gene transcription and regulation by a natural hypocholesterolemic compound berberine". The Journal of Biological Chemistry. 284 (42): 28885–95. doi:10.1074/jbc.M109.052407. PMC 2781434. PMID 19687008.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  23. ^ Seidah NG, Poirier S, Denis M, Parker R. "Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation". PLoS One. 2012;7(7):e41865. doi:10.371/journal.pone.0041865. PMID 22848640. {{cite journal}}: Check |doi= value (help)

Further reading

  • Abifadel M, Rabès JP, Boileau C, Varret M (June 2007). "[After the LDL receptor and apolipoprotein B, autosomal dominant hypercholesterolemia reveals its third protagonist: PCSK9]". Ann. Endocrinol. (Paris) (in French). 68 (2–3): 138–46. doi:10.1016/j.ando.2007.02.002. PMID 17391637.
  • Allard D, Amsellem S, Abifadel M, Trillard M, Devillers M, Luc G, Krempf M, Reznik Y, Girardet JP, Fredenrich A, Junien C, Varret M, Boileau C, Benlian P, Rabès JP (November 2005). "Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia". Hum. Mutat. 26 (5): 497. doi:10.1002/humu.9383. PMID 16211558.
  • Benjannet S, Rhainds D, Essalmani R, Mayne J, Wickham L, Jin W, Asselin MC, Hamelin J, Varret M, Allard D, Trillard M, Abifadel M, Tebon A, Attie AD, Rader DJ, Boileau C, Brissette L, Chrétien M, Prat A, Seidah NG (November 2004). "NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol". J. Biol. Chem. 279 (47): 48865–75. doi:10.1074/jbc.M409699200. PMID 15358785.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH (February 2005). "Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9". Nat. Genet. 37 (2): 161–5. doi:10.1038/ng1509. PMID 15654334.
  • Lalanne F, Lambert G, Amar MJ, Chétiveaux M, Zaïr Y, Jarnoux AL, Ouguerram K, Friburg J, Seidah NG, Brewer HB, Krempf M, Costet P (June 2005). "Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells". J. Lipid Res. 46 (6): 1312–9. doi:10.1194/jlr.M400396-JLR200. PMID 15741654.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • Lambert G (June 2007). "Unravelling the functional significance of PCSK9". Curr. Opin. Lipidol. 18 (3): 304–9. doi:10.1097/MOL.0b013e3281338531. PMID 17495605.
  • Leren TP (May 2004). "Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia". Clin. Genet. 65 (5): 419–22. doi:10.1111/j.0009-9163.2004.0238.x. PMID 15099351.
  • Maxwell KN, Breslow JL (May 2004). "Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype". Proc. Natl. Acad. Sci. U.S.A. 101 (18): 7100–5. doi:10.1073/pnas.0402133101. PMC 406472. PMID 15118091.
  • Maxwell KN, Soccio RE, Duncan EM, Sehayek E, Breslow JL (November 2003). "Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice". J. Lipid Res. 44 (11): 2109–19. doi:10.1194/jlr.M300203-JLR200. PMID 12897189.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • Naoumova RP, Tosi I, Patel D, Neuwirth C, Horswell SD, Marais AD, van Heyningen C, Soutar AK (December 2005). "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response". Arterioscler. Thromb. Vasc. Biol. 25 (12): 2654–60. doi:10.1161/01.ATV.0000190668.94752.ab. PMID 16224054.
  • Naureckiene S, Ma L, Sreekumar K, Purandare U, Lo CF, Huang Y, Chiang LW, Grenier JM, Ozenberger BA, Jacobsen JS, Kennedy JD, DiStefano PS, Wood A, Bingham B (December 2003). "Functional characterization of Narc 1, a novel proteinase related to proteinase K". Arch. Biochem. Biophys. 420 (1): 55–67. doi:10.1016/j.abb.2003.09.011. PMID 14622975.
  • Ouguerram K, Chetiveaux M, Zair Y, Costet P, Abifadel M, Varret M, Boileau C, Magot T, Krempf M (August 2004). "Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9". Arterioscler. Thromb. Vasc. Biol. 24 (8): 1448–53. doi:10.1161/01.ATV.0000133684.77013.88. PMID 15166014.
  • Pisciotta L, Priore Oliva C, Cefalù AB, Noto D, Bellocchio A, Fresa R, Cantafora A, Patel D, Averna M, Tarugi P, Calandra S, Bertolini S (June 2006). "Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia". Atherosclerosis. 186 (2): 433–40. doi:10.1016/j.atherosclerosis.2005.08.015. PMID 16183066.
  • Shibata N, Ohnuma T, Higashi S, Higashi M, Usui C, Ohkubo T, Watanabe T, Kawashima R, Kitajima A, Ueki A, Nagao M, Arai H (December 2005). "No genetic association between PCSK9 polymorphisms and Alzheimer's disease and plasma cholesterol level in Japanese patients". Psychiatr. Genet. 15 (4): 239. doi:10.1097/00041444-200512000-00004. PMID 16314752.
  • Sun XM, Eden ER, Tosi I, Neuwirth CK, Wile D, Naoumova RP, Soutar AK (May 2005). "Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia". Hum. Mol. Genet. 14 (9): 1161–9. doi:10.1093/hmg/ddi128. PMID 15772090.
  • Timms KM, Wagner S, Samuels ME, Forbey K, Goldfine H, Jammulapati S, Skolnick MH, Hopkins PN, Hunt SC, Shattuck DM (March 2004). "A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree". Hum. Genet. 114 (4): 349–53. doi:10.1007/s00439-003-1071-9. PMID 14727179.
  • Varret M, Rabès JP, Saint-Jore B, Cenarro A, Marinoni JC, Civeira F, Devillers M, Krempf M, Coulon M, Thiart R, Kotze MJ, Schmidt H, Buzzi JC, Kostner GM, Bertolini S, Pocovi M, Rosa A, Farnier M, Martinez M, Junien C, Boileau C (May 1999). "A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32". Am. J. Hum. Genet. 64 (5): 1378–87. doi:10.1086/302370. PMC 1377874. PMID 10205269.
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