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{{cs1 config|name-list-style=vanc}} |
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{{mergefrom|PLAU|date=January 2010}} |
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{{Short description|Human protein}} |
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{{drugbox |
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{{Infobox_gene}} |
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{{Drugbox |
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| verifiedrevid = 398416026 |
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| verifiedrevid = 409091966 |
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| IUPAC_name = |
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| IUPAC_name = |
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<!-- Clinical data --> |
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| image = |
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| tradename = |
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| Caption = The protease domain from urokinase in complex with and ] |
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| Drugs.com = {{drugs.com|monograph|urokinase}} |
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| pregnancy_category = |
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| legal_status = |
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<!-- Pharmacokinetic data --> |
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| bioavailability = |
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<!-- Identifiers --> |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 9039-53-6 |
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| CAS_number = 9039-53-6 |
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| ATC_prefix = B01 |
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| ATC_prefix = B01 |
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| ATC_suffix = AD04 |
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| ATC_suffix = AD04 |
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| ATC_supplemental = |
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| ATC_supplemental = |
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| PubChem = |
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| PubChem = |
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| DrugBank_Ref = {{drugbankcite|changed|drugbank}} |
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| DrugBank = BTD00030 |
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| DrugBank = DB00013 |
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| KEGG_Ref = {{keggcite|changed|kegg}} |
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| UNII_Ref = {{fdacite|changed|FDA}} |
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| UNII = 83G67E21XI |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D03341 |
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| KEGG = D03341 |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL = 1201420 |
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| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} |
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| ChemSpiderID = none |
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<!-- Chemical data --> |
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| C=1376 | H=2145 | N=383 | O=406 | S=18 |
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| C=1376 | H=2145 | N=383 | O=406 | S=18 |
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| molecular_weight = 31126.5 g/mol |
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| bioavailability = |
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'''Urokinase''', also known as '''urokinase-type plasminogen activator''' ('''uPA'''), is a ] present in humans and other animals. The human urokinase protein was discovered, but not named, by McFarlane and Pilling in 1947.<ref name=discovery>{{cite journal | vauthors = Degryse B | title = The urokinase receptor system as strategic therapeutic target: challenges for the 21st century | journal = Current Pharmaceutical Design | volume = 17 | issue = 19 | pages = 1872–1873 | date = 1 June 2011 | pmid = 21711231 | doi = 10.2174/138161211796718161 }}</ref> Urokinase was originally isolated from human ], and it is also present in the ] and in the ] of many tissues. The primary physiological substrate of this enzyme is ], which is an inactive form (]) of the serine protease ]. Activation of plasmin triggers a proteolytic cascade that, depending on the physiological environment, participates in ] or extracellular matrix degradation. This cascade had been involved in vascular diseases and cancer progression.<ref>{{cite journal | vauthors = Tang L, Han X | title = The urokinase plasminogen activator system in breast cancer invasion and metastasis | journal = Biomedicine & Pharmacotherapy | volume = 67 | issue = 2 | pages = 179–182 | date = March 2013 | pmid = 23201006 | doi = 10.1016/j.biopha.2012.10.003 }}</ref> |
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{{protein |
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| Name = plasminogen activator, urokinase |
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| caption = PLAU |
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| image = |
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| width = |
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| HGNCid = 9052 |
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| Symbol = PLAU |
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| AltSymbols = |
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| EntrezGene = 5328 |
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| OMIM = 191840 |
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| RefSeq = NM_002658 |
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| UniProt = P00749 |
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| PDB = |
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| ECnumber = 3.4.21.31 |
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| Chromosome = 10 |
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| Arm = q |
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| Band = 24 |
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| LocusSupplementaryData = |
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}} |
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'''Urokinase''' (trade name '''Abbokinase'''), also called urokinase-type plasminogen activator (uPA), is a ] ({{EC number|3.4.21.73}}). Urokinase was originally isolated from human ], but is present in several physiological locations, such as blood stream and the ]. The primary physiological substrate is ], which is an inactive ] form of the serine protease ]. Activation of plasmin triggers a proteolysis cascade that, depending on the physiological environment, participates in ] or ] degradation. This links urokinase to vascular diseases and cancer. |
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Urokinase is encoded in humans by the ''PLAU'' gene, which stands for "plasminogen activator, urokinase".<ref name="pmid2415429">{{cite journal | vauthors = Nagai M, Hiramatsu R, Kanéda T, Hayasuke N, Arimura H, Nishida M, Suyama T | title = Molecular cloning of cDNA coding for human preprourokinase | journal = Gene | volume = 36 | issue = 1–2 | pages = 183–188 | date = Dec 1985 | pmid = 2415429 | doi = 10.1016/0378-1119(85)90084-8 }}</ref> The same symbol represents the gene in other animal species. |
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== Molecular characteristics == |
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Urokinase is a 411-] ], consisting of three ]: the serine protease domain, the ], and the ]. Urokinase is synthesized as a zymogen form (prourokinase or single-chain urokinase), and is activated by proteolytic cleavage between L158 and I159. The two resulting chains are kept together by a ] bond. |
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== Function == |
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The ''PLAU'' gene encodes a serine protease ({{EC number|3.4.21.73}}) involved in degradation of the extracellular matrix and possibly tumor cell migration and proliferation. A specific polymorphism in this gene may be associated with late-onset Alzheimer disease and also with decreased affinity for fibrin-binding. The protein encoded by this gene converts plasminogen to plasmin by specific cleavage of an Arg-Val bond in plasminogen. This gene's proprotein is cleaved at a Lys-Ile bond by plasmin to form a two-chain derivative in which a single disulfide bond connects the amino-terminal A-chain to the catalytically active, carboxy-terminal B-chain. This two-chain derivative is also called HMW-uPA (high molecular weight uPA). HMW-uPA can be further processed into LMW-uPA (low molecular weight uPA) by cleavage of chain A into a short chain A (A1) and an amino-terminal fragment. LMW-uPA is proteolytically active but does not bind to the uPA receptor.<ref>{{cite web | title = Entrez Gene: PLAU plasminogen activator, urokinase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5328}}</ref> |
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== Structure == |
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Urokinase is a 411-] ], consisting of three ]: the serine protease domain (consisting of residues 159–411), the ] (consisting of residues 50-131), and the ] (consisting of residues 1-49). The kringle domain and the serine protease domain are connected by an interdomain linker or connecting peptide (consisting of residues 132–158). Urokinase is synthesized as a zymogen form (prourokinase or single-chain urokinase), and is activated by proteolytic cleavage between Lys158 and Ile159. The two resulting chains are kept together by a ] bond between Cys148 and Cys279.<ref>{{cite journal | vauthors = Vincenza Carriero M, Franco P, Vocca I, Alfano D, Longanesi-Cattani I, Bifulco K, Mancini A, Caputi M, Stoppelli MP | display-authors = 6 | title = Structure, function and antagonists of urokinase-type plasminogen activator | journal = Frontiers in Bioscience | volume = 14 | issue = 10 | pages = 3782–3794 | date = January 2009 | pmid = 19273310 | doi = 10.2741/3488 | doi-access = free }}</ref> |
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In comparison to the mammalian system, ] (Danio rerio) contains two ] of urokinase which have been characterised as zfuPA-a and zfuPA-b. zfuPA-a differs from the mammalian uPA by lacking an ] encoding for the ] (urokinase receptor) binding domain; while the zfuPA-b lacks two cysteines of the epidermal growth factor-like domain. zfuPA-b also has no binding activity in fish ] or fish cell lines. The uPAR binding in mammalian system is essential for the activity of urokinase and uPAR as it also functions as an adhesion receptor due to its affinity to ], ] and other proteases like ]. The lack of the uPAR binding region in zebrafish uPA, suggests that zebrafish uPA functions without uPAR binding.<ref name = "Bager_2012">{{cite journal | vauthors = Bager R, Kristensen TK, Jensen JK, Szczur A, Christensen A, Andersen LM, Johansen JS, Larsen N, Baatrup E, Huang M, Ploug M, Andreasen PA | display-authors = 6 | title = Urokinase-type plasminogen activator-like proteases in teleosts lack genuine receptor-binding epidermal growth factor-like domains | journal = The Journal of Biological Chemistry | volume = 287 | issue = 33 | pages = 27526–27536 | date = August 2012 | pmid = 22733817 | pmc = 3431643 | doi = 10.1074/jbc.M112.369207 | doi-access = free }}</ref> |
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== Interaction partners == |
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== Interaction partners == |
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The most important inhibitors of urokinase are the ]s ] (PAI-1) and ] (PAI-2), which inhibit the protease activity irreversibly. In the extracellular matrix, urokinase is tethered to the ] by its interaction to the ]. |
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The most important inhibitors of urokinase are the ]s ] (PAI-1) and ] (PAI-2), which inhibit the protease activity irreversibly. In the extracellular matrix, urokinase is tethered to the ] by its interaction to the ]. |
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uPa also interacts with ].<ref name=pmid2752144>{{cite journal | vauthors = Geiger M, Huber K, Wojta J, Stingl L, Espana F, Griffin JH, Binder BR | title = Complex formation between urokinase and plasma protein C inhibitor in vitro and in vivo | journal = Blood | volume = 74 | issue = 2 | pages = 722–728 | date = August 1989 | pmid = 2752144 | doi = 10.1182/blood.V74.2.722.722 | doi-access = free }}</ref><ref name=pmid2551064>{{cite journal | vauthors = España F, Berrettini M, Griffin JH | title = Purification and characterization of plasma protein C inhibitor | journal = Thrombosis Research | volume = 55 | issue = 3 | pages = 369–384 | date = August 1989 | pmid = 2551064 | doi = 10.1016/0049-3848(89)90069-8 }}</ref> |
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zfuPA-a and zfuPA-b are poor activators of human ], while human uPA is a poor activator of ] plasminogen. With the primary difference between the zebrafish uPA and human uPA being in the ]<ref name = "Bager_2012" /> |
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== Urokinase and cancer == |
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== Urokinase and cancer == |
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Elevated ] levels of urokinase and several other components of the ] are found to be correlated with ] ]. It is believed that the tissue degradation following plasminogen activation facilitates tissue invasion and, thus, contributes to ]. This makes urokinase an attractive ], and, so, ]s have been sought to be used as anticancer agents. However, incompatibilities between the human and ] systems hamper clinical evaluation of these agents. Through its interaction with the ], urokinase affects several other aspects of cancer biology such as cells adhesion, migration, and cellular ] pathways. |
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Elevated ] levels of urokinase and several other components of the ] are found to be correlated with ] ]. It is believed that the tissue degradation following plasminogen activation facilitates tissue invasion and, thus, contributes to ].<ref name="pmid30419600">{{cite journal | vauthors = Madunić J | title = The Urokinase Plasminogen Activator System in Human Cancers: An Overview of Its Prognostic and Predictive Role | journal = Thrombosis and Haemostasis | volume = 118 | issue = 12 | pages = 2020–2036 | date = December 2018 | pmid = 30419600 | doi = 10.1055/s-0038-1675399 | doi-access = free }}</ref> Urokinase-type plasminogen activator (uPA) is more commonly associated with cancer progression than ] (tPA).<ref name="pmid29484286">{{cite journal | vauthors = Mahmood N, Mihalcioiu C, Rabbani SA | title = Multifaceted Role of the Urokinase-Type Plasminogen Activator (uPA) and Its Receptor (uPAR): Diagnostic, Prognostic, and Therapeutic Applications | journal = Frontiers in Oncology | volume = 8 | pages = 24 | date = 2018 | pmid = 29484286 | pmc = 5816037 | doi = 10.3389/fonc.2018.00024 | doi-access = free }}</ref> This makes uPA an attractive ], and, so, ]s have been sought to be used as anticancer agents.<ref name="pmid10738907">{{cite journal | vauthors = Jankun J, Skrzypczak-Jankun E | title = Molecular basis of specific inhibition of urokinase plasminogen activator by amiloride | journal = Cancer Biochemistry Biophysics | volume = 17 | issue = 1–2 | pages = 109–123 | date = July 1999 | pmid = 10738907 }}</ref><ref name="pmid21544803">{{cite journal | vauthors = Matthews H, Ranson M, Kelso MJ | title = Anti-tumour/metastasis effects of the potassium-sparing diuretic amiloride: an orally active anti-cancer drug waiting for its call-of-duty? | journal = International Journal of Cancer | volume = 129 | issue = 9 | pages = 2051–2061 | date = November 2011 | pmid = 21544803 | doi = 10.1002/ijc.26156 | s2cid = 205943879 | doi-access = }}</ref> However, incompatibilities between the human and ] systems hamper clinical evaluation of these agents. Moreover, urokinase is used by normal cells for tissue remodeling and vessel growth, which necessitates distinguishing cancer-associated urokinase features for specific targeting.<ref name="pmid30419600" /> |
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uPA breakdown of the ] is crucial for initiating the ] which is associated with cancer growth.<ref name="pmid29484286" /> |
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uPA ] is elevated in breast cancer tissue, which correlates with poor prognosis in breast cancer patients.<ref name="pmid29484286" /> For this reason, uPA can be used as a diagnostic biomarker in breast cancer.<ref name="pmid29484286" /> |
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Through its interaction with the ], urokinase affects several other aspects of cancer biology such as cell adhesion, migration, and cellular ] pathways. |
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As of December 7, 2012, Mesupron (]), a small molecule serine protease inhibitor developed by the WILEX pharmaceutical company, has completed phase II trials.<ref name="urlGemcitabine With or Without WX-671 in Treating Patients With Locally Advanced Pancreatic Cancer That Cannot Be Removed By Surgery - Full Text View - ClinicalTrials.gov">{{cite web | url = http://www.clinicaltrials.gov/ct2/show/NCT00499265 | title = Gemcitabine With or Without WX-671 in Treating Patients With Locally Advanced Pancreatic Cancer That Cannot Be Removed By Surgery | date = 28 March 2012 | publisher = ClinicalTrials.gov }}</ref> Mesupron appears to be safe when combined with chemotherapeutic drug ] for the progression-free survival in human breast cancer.<ref name="urlFox Chase Cancer Center : New Small Molecule Inhibitor Could be a Safe and First-Line Treatment for Metastatic Breast Cancer">{{cite web | url = http://www.fccc.edu/information/news/press-releases/2012/2012-12-07-SABC-Goldstein-WILEX.html | title = Fox Chase Cancer Center : New Small Molecule Inhibitor Could be a Safe and First-Line Treatment for Metastatic Breast Cancer | work = Press Release | publisher =Temple University Health System }}</ref> |
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== Clinical applications == |
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== Clinical applications == |
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Urokinase is used clinically as a ] agent in the treatment of severe or massive ], ], ], and occluded ] or ] cannulas. It is also administered intrapleurally to improve the drainage of complicated pleural effusions and empyemas. Urokinase is presently marketed as , and competes with ] as a thrombolytic drug in infarctation. |
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Urokinase is effective for the restoration of flow to intravenous catheters blocked by clotted blood or fibrin (catheter clearance). Catheters are used extensively to administer treatments to patients for such purposes as dialysis, nutrition, antibiotic treatment and cancer treatment. Approximately 25% of catheters become blocked, meaning that affected patients cannot receive treatment until the catheter has been cleared or replaced. Urokinase is also used clinically as a ] agent in the treatment of severe or massive ], peripheral arterial occlusive disease, ], acute ] (AMI, heart attack), and occluded ] cannulas (catheter clearance). It is also administered intrapleurally to improve the drainage of complicated pleural effusions and empyemas. Urokinase is marketed as Kinlytic (formerly Abbokinase) and competes with ] (e.g., alteplase) as a thrombolytic drug. |
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All plasminogen activators (urokinase, tPA) catalyze the production of plasmin, which in turn leads to the breakdown of the fibrin mesh structure in blood clots. While there are commonalities in the mode of action for urokinase and tPA, urokinase has some advantages for treatment of peripheral clots (Pulmonary Embolism, Deep Vein Thrombosis, Peripheral arterial occlusive disease). |
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Unlike tPA, which is activated by binding to the fibrin within clots, urokinase is not sequestered by fibrin and therefore does not specifically attack hemostatic clots. This makes urokinase less likely to break down such hemostatic clots that are essential for ongoing blood vessel repair throughout the body. Dissolution of these “good” clots can lead to serious adverse events through hemorrhagic bleeding. Years of clinical study have confirmed the safety advantage of using urokinase.<ref>{{cite journal | vauthors = Ouriel K, Gray B, Clair DG, Olin J | title = Complications associated with the use of urokinase and recombinant tissue plasminogen activator for catheter-directed peripheral arterial and venous thrombolysis | journal = Journal of Vascular and Interventional Radiology | volume = 11 | issue = 3 | pages = 295–298 | date = March 2000 | pmid = 10735422 | doi = 10.1016/S1051-0443(07)61420-1 }}</ref><ref>{{cite journal | vauthors = Cinà CS, Goh RH, Chan J, Kenny B, Evans G, Rawlinson J, Gill G | title = Intraarterial catheter-directed thrombolysis: urokinase versus tissue plasminogen activator | journal = Annals of Vascular Surgery | volume = 13 | issue = 6 | pages = 571–575 | date = November 1999 | pmid = 10541608 | doi = 10.1007/s100169900300 | s2cid = 470599 }}</ref> Consequently, urokinase has been preferentially used in ] and peripheral arterial occlusive disease where it is administered directly to the site of the clot while tPA is preferred in AMI where peripheral bleeding is a secondary consideration. |
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A revolutionary method for the production of urokinase was patented by ] in 1976 (U.S. Patent No. 3,930,944). Nicol was believed to be the first African American woman to receive a molecular biology patent.<ref>{{Cite web|title=Evelyn Nicol 1930 - 2020 - Obituary|url=https://www.legacy.com/amp/obituaries/chicagotribune/196328986|access-date=2020-08-28|website=www.legacy.com|language=en}}</ref> |
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==Society and culture== |
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The presence of a ] enzyme in human urine was reported in 1947, without a name given for such an enzyme behind its effect.<ref name="pmid20241608">{{cite journal | vauthors = Macfarlane RG, Pilling J | title = Fibrinolytic activity of normal urine | journal = Nature | volume = 159 | issue = 4049 | pages = 779 | date = June 1947 | pmid = 20241608 | doi = 10.1038/159779a0 | s2cid = 4125748 | bibcode = 1947Natur.159Q.779M | doi-access = free }}</ref> In 1952 a purified form of the enzyme was extracted from human urine and named "urokinase" for "urinary kinase".<ref>Sobel GW, Mohler SR, Jones NW, Dowdy ABC, Guest MM. Urokinase: an activator of plasma profibrinolysin extracted from urine. Am J Physiol 1952; 171: 768-69.</ref> The full text for this article is lost, and the only citation points to the abstract of a list of papers read at a conference in the same journal.<ref>{{cite journal |journal=American Journal of Physiology. Legacy Content |date=30 November 1952 |volume=171 |issue=3 |pages=704–781 |doi=10.1152/ajplegacy.1952.171.3.704 |quote=Normal human and dog urine contains fibrinolysin (plasmin) and a potent activator of profibrinolysin (plasminogen). The activator, which we have designated urokinase, can be concentrated and partially purified by acetone or alcohol fractionation methods.|title=Abstracts of Papers Read }}</ref> A few other papers on the purification were published independently around the same time. By 1960, it was still unclear whether the activation of ] has anything to do with a protease, but a ] is thought to play a role regardless.<ref>{{cite journal | vauthors = Celander DR, Guest MM | title = The biochemistry and physiology of urokinase | journal = The American Journal of Cardiology | volume = 6 | issue = 2 | pages = 409–419 | date = August 1960 | pmid = 13808740 | doi = 10.1016/0002-9149(60)90333-7 }}</ref> |
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== References == |
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{{Reflist|2}} |
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== Further reading == |
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{{refbegin}} |
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* {{cite journal | vauthors = Ploug M, Gårdsvoll H, Jørgensen TJ, Lønborg Hansen L, Danø K | title = Structural analysis of the interaction between urokinase-type plasminogen activator and its receptor: a potential target for anti-invasive cancer therapy | journal = Biochemical Society Transactions | volume = 30 | issue = 2 | pages = 177–183 | date = April 2002 | pmid = 12023847 | doi = 10.1042/BST0300177 }} |
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* {{cite journal | vauthors = Alfano M, Sidenius N, Blasi F, Poli G | title = The role of urokinase-type plasminogen activator (uPA)/uPA receptor in HIV-1 infection | journal = Journal of Leukocyte Biology | volume = 74 | issue = 5 | pages = 750–756 | date = November 2003 | pmid = 12960238 | doi = 10.1189/jlb.0403176 | s2cid = 8526093 | doi-access = }} |
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* {{cite journal | vauthors = Harbeck N, Kates RE, Gauger K, Willems A, Kiechle M, Magdolen V, Schmitt M | title = Urokinase-type plasminogen activator (uPA) and its inhibitor PAI-I: novel tumor-derived factors with a high prognostic and predictive impact in breast cancer | journal = Thrombosis and Haemostasis | volume = 91 | issue = 3 | pages = 450–456 | date = March 2004 | pmid = 14983219 | doi = 10.1160/TH03-12-0798 | s2cid = 19904733 }} |
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* {{cite journal | vauthors = Gilabert-Estelles J, Ramon LA, España F, Gilabert J, Castello R, Estelles A | title = Expression of the fibrinolytic components in endometriosis | journal = Pathophysiology of Haemostasis and Thrombosis | volume = 35 | issue = 1–2 | pages = 136–140 | year = 2006 | pmid = 16855359 | doi = 10.1159/000093556 | s2cid = 29270171 }} |
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{{refend}} |
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== External links == |
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* {{PDBe-KB2|P00749|Human Urokinase-type plasminogen activator}} |
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* {{PDBe-KB2|P06869|Mouse Urokinase-type plasminogen activator}} |
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{{Coagulation}} |
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{{Coagulation}} |
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{{Serine endopeptidases}} |
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{{Antithrombotics}} |
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{{Antithrombotics}} |
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{{Serine endopeptidases}} |
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{{Enzymes}} |
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{{PDB Gallery|geneid=5328}} |
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{{Portal bar|Biology|border=no}} |
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