117:. Furin is a serine endoprotease which cleaves protein precursors carboxyterminal of basic residues in motifs such as Arg–X–X–Arg and Lys/Arg–Arg. Cleavage usually results in activation of the proprotein but can also inactivate or modify the activity. Therefore, it is not surprising that it plays a major role in many physiological processes and pathologies, including cancer. Some of its substrates are: proparathyroid hormone, transforming growth factor beta 1 precursor, proalbumin, pro-beta-secretase, membrane type-1 matrix metalloproteinase, beta subunit of pro-nerve growth factor and von Willebrand factor. A furin-like pro-protein convertase has been implicated in the processing of RGMc (also called
37:. Proprotein convertases have medical significance, because they are involved in many important biological processes, such as cholesterol synthesis. Compounds called proprotein convertase inhibitors can block their action, and block the target proteins from becoming active. Many proprotein convertases, especially furin and PACE4, are involved in pathological processes such as viral infection, inflammation, hypercholesterolemia, and cancer, and have been postulated as therapeutic targets for some of these diseases.
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and commonly referred to as PC1/3) and PC2 are the primary enzymes involved in the processing of the bioactive peptides precursors at paired basic residues. PC1/3 and PC2 do not directly produce most neuropeptides and peptide hormones, but instead generate intermediates that contain C-terminal extensions of lysine and/or arginine residues; these are subsequently removed by
121:). Both the Ganz and Rotwein groups demonstrated that furin-like proprotein convertases (PPC) are responsible for conversion of 50 kDa HJV to a 40 kDa protein with a truncated COOH-terminus, at a conserved polybasic RNRR site. This suggests a potential mechanism to generate the soluble forms of HJV/hemojuvelin (s-hemojuvelin) found in the blood of rodents and humans.
33:(PPCs) are a family of proteins that activate other proteins. Many proteins are inactive when they are first synthesized, because they contain chains of amino acids that block their activity. Proprotein convertases remove those chains and activate the protein. The prototypical proprotein convertase is
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The two proprotein convertases that specialize in the processing of the precursors of peptide hormones and neuropeptides are also known in the field as "prohormone convertases". Both "prohormone convertase" and "proprotein convertase" are interchangeably abbreviated as "PC". PC1 (also known as PC3
191:
To date there are 9 PCSKs with varying functions and tissue distributions. Often, due to similar times of discovery from different groups the same PCSKs have acquired multiple names. In an attempt to alleviate confusion, there is a trend towards using the PCSK prefix with the appropriate number
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Current scientific evidence indicates that both up- and down-regulation of the expression of proprotein convertases are part of the multiple changes occurring in gynecological tumors. PCs activate crucial substrates implicated in the progression of gynecological cancers, including adhesion
183:-related catalytic domain, a specificity pocket that requires the amino acid amino terminal to the scissile bond to be arginine for rapid acylation, and a P-domain carboxy-terminal to the subtilisin domain, which is required for biosynthesis.
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Therapeutic
Potential of Furin Inhibition: An Evaluation Using a Conditional Furin Knockout Mouse Model, by Jeroen Declercq and Prof. Dr. J.W.M. Creemers, Morgan & Claypool Publishers, 2012, DOI:10.4199/C00068ED1V01Y201211PAC004
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molecules, metalloproteinases, and viral proteins. Experimental evidences suggest that careful targeting of PCs in gynecological cancer may represent a feasible strategy to deter tumor progression. Variants of
81:. Robert Fuller, working with Thorner, identified the partial sequence of the Kex2-homologous Furin gene in 1989. In 1990 human Kex2-homologous genes were cloned by the Steiner group,
61:( βMSH). This was the chemical evidence, at the level of primary protein sequence that peptide hormones could be found within larger protein molecules. The identity of the responsible
587:
Proprotein
Convertases in Gynecological Cancers, by A.J. Klein-Szanto, 2012, Morgan & Claypool Publishers, DOI:10.4199/C00068ED1V01Y201211PAC004
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Seidah NG, Chrétien M (November 1999). "Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides".
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Chrétien M, Li CH (July 1967). "Isolation, purification, and characterization of gamma-lipotropic hormone from sheep pituitary glands".
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plays a role in the activation of several different virus proteins, and inhibitors of furin have been explored as antiviral agents.
58:
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600:"Structural and Enzymatic Characterization of a Purified Prohormone-Processing Enzyme: Secreted, Soluble Kex2 Protease"
345:
518:"Pro-protein convertases control the maturation and processing of the iron-regulatory protein, RGMc/hemojuvelin"
772:
469:"Soluble hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site"
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Steiner DF, Cunningham D, Spigelman L, Aten B (August 1967). "Insulin biosynthesis: evidence for a precursor".
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while examining the biosynthesis of insulin in 1967. At the same time, while conducting chemical sequencing of
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Andrew W. Artenstein; Steven M. Opal (December 29, 2011). "Proprotein
Convertases in Health and Disease".
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360:, by Daniel Bassi, Morgan & Claypool Publishers, 2012, DOI: doi:10.4199/C00060ED1V01Y201206PAC001
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57:(βLPH) with sheep pituitary glands Dr. Michel Chretien determined the sequence of another hormone,
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702:"Cutting back on pro-protein convertases: the latest approaches to pharmacological inhibition"
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and Robert Fuller in 1992. The Kex2 crystal structure was solved by a group led by
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The Role of
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Lin L, Nemeth E, Goodnough JB, Thapa DR, Gabayan V, Ganz T (2008).
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gene as responsible for processing of the alpha factor mating
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Kuninger D, Kuns-Hashimoto R, Nili M, Rotwein P (2008).
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348:, By ANDREW POLLACK, New York Times, November 5, 2012
171:. That of Furin was determined by a group led by
147:can reduce or increase circulating cholesterol.
159:Kex2 was first purified and characterized by
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179:. The key features of Kex2 and Furin are a
771:at the U.S. National Library of Medicine
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577:, DOI 10.4199/C00050ED1V01Y201112NPE001
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65:was not clear for decades. In 1984,
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113:One of the most well-known PPCs is
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346:New Drugs for Lipids Set Off Race
73:, identified the product of the
69:, working in the laboratory of
59:melanocyte-stimulating hormone
1:
754:Protein Activation and Cancer
700:Fugère M, Day R (June 2005).
671:10.1016/S0006-8993(99)01909-5
598:Brenner C, Fuller RS (1992).
49:conversion was discovered by
392:10.1126/science.157.3789.697
251:PC5, PC6 (new name: PC5/6)
211:PC1, PC3 (new name: PC1/3)
805:
718:10.1016/j.tips.2005.04.006
485:10.1016/j.bcmd.2007.06.023
281:Site 1 Protease, S1P, SKI
198:Current PCSK nomenclature
773:Medical Subject Headings
769:Proprotein+Convertases
125:Prohormone convertases
31:Proprotein convertases
18:Proprotein convertases
706:Trends Pharmacol. Sci
625:10.1073/pnas.89.3.922
604:Proc. Natl. Acad. Sci
535:10.1186/1471-2091-9-9
325:10.1056/NEJMra1106700
155:Biochemical structure
138:Clinical significance
55:β-lipotrophic hormone
473:Blood Cells Mol. Dis
167:, Robert Fuller and
101:and co-workers, and
616:1992PNAS...89..922B
384:1967Sci...157..697S
201:Other common names
87:Wim J.M. van de Ven
132:carboxypeptidase E
45:The phenomenon of
378:(3789): 697–700.
319:(26): 2507–2518.
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231:Furin, Pace, PC1
103:Kazuhisa Nakayama
51:Donald F. Steiner
16:(Redirected from
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67:David Julius
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173:Manual Than
119:hemojuvelin
99:Gary Thomas
298:References
181:subtilisin
47:prohormone
659:Brain Res
271:PC7, PC8
79:pheromone
783:Category
736:15925704
687:22831526
679:10701998
554:18384687
503:17869549
408:29382220
333:22204726
192:suffix.
789:Enzymes
727:7119077
644:1736307
612:Bibcode
545:2323002
494:2211380
443:6035976
400:4291105
380:Bibcode
372:Science
291:NARC-1
63:enzymes
41:History
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261:PACE4
683:S2CID
635:48357
528:: 9.
404:S2CID
287:PCSK9
277:PCSK8
267:PCSK7
257:PCSK6
247:PCSK5
237:PCSK4
227:PCSK3
217:PCSK2
207:PCSK1
149:Furin
145:PCSK9
115:furin
109:Furin
35:furin
732:PMID
675:PMID
640:PMID
571:ISBN
550:PMID
499:PMID
439:PMID
396:PMID
329:PMID
241:PC4
221:PC2
175:and
75:Kex2
722:PMC
714:doi
667:doi
663:848
630:PMC
620:doi
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