Urokinase

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Urokinase
Clinical data
AHFS/Drugs.com monograph
Legal status ?
Identifiers
CAS number 9039-53-6 YesY
ATC code B01AD04
DrugBank DB00013
UNII 83G67E21XI N
KEGG D03341 YesY
ChEMBL CHEMBL1201420 N
Chemical data
Formula C1376H2145N383O406S18 
Mol. mass 31126.5 g/mol
 N (what is this?)  (verify)
plasminogen activator, urokinase
Identifiers
Symbol PLAU
Entrez 5328
HUGO 9052
OMIM 191840
RefSeq NM_002658
UniProt P00749
Other data
Locus Chr. 10 q24

Urokinase (trade name Abbokinase), also called urokinase-type plasminogen activator (uPA), is a serine protease (EC 3.4.21.73). It was discovered in 1947 by McFarlane.[1] Urokinase was originally isolated from human urine, but is present in several physiological locations, such as blood stream and the extracellular matrix. The primary physiological substrate is plasminogen, which is an inactive form (zymogen) of the serine protease plasmin. Activation of plasmin triggers a proteolysis cascade that, depending on the physiological environment, participates in thrombolysis or extracellular matrix degradation. This links urokinase to vascular diseases and cancer.

Molecular characteristics[edit]

Urokinase is a 411-residue protein, consisting of three domains: the serine protease domain, the kringle domain, and the growth factor domain. 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 disulfide bond.

Interaction partners[edit]

The most important inhibitors of urokinase are the serpins plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2), which inhibit the protease activity irreversibly. In the extracellular matrix, urokinase is tethered to the cell membrane by its interaction to the urokinase receptor.

Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition.

The molecular weight of (high molecular weight) urokinase is about 54000 Daltons. Only the Abbokinase = low molecular weight urokinase has a molecular weight of about 31000 Daltons.

Urokinase and cancer[edit]

Elevated expression levels of urokinase and several other components of the plasminogen activation system are found to be correlated with tumor malignancy. It is believed that the tissue degradation following plasminogen activation facilitates tissue invasion and, thus, contributes to metastasis. This makes urokinase an attractive drug target, and, so, inhibitors have been sought to be used as anticancer agents.[2][3] However, incompatibilities between the human and murine systems hamper clinical evaluation of these agents. Through its interaction with the urokinase receptor, urokinase affects several other aspects of cancer biology such as cells adhesion, migration, and cellular mitotic pathways.

As of December 7, 2012 Mesupron®, a small molecule serine protease inhibitor developed by the WILEX pharmaceutical company, has completed phase II trials.[4] Mesupron appears to be safe when combined with chemotherapeutic drug Capecitabine for the progression-free survival in human breast cancer.[5]

Clinical applications[edit]

Urokinase is used clinically as a thrombolytic agent in the treatment of severe or massive deep venous thrombosis, pulmonary embolism, myocardial infarction, and occluded intravenous or dialysis cannulas. It is also administered intrapleurally to improve the drainage of complicated pleural effusions and empyemas. Urokinase is presently marketed as KinlyticTM, and competes with AlteplaseTM as a thrombolytic drug in infarction. It is the most effective drug in myocardial infarction. In contrast to TPA tissue plasminogen activator it immediately removes the clot. Its injection is very costly.

References[edit]

  1. ^ Nursing grand rounds pdfs.journals.lww.com/.../Nursing_grand_rounds.8.pdf J Vitello-Cicciu - 1987
  2. ^ Jankun J, Skrzypczak-Jankun E (July 1999). "Molecular basis of specific inhibition of urokinase plasminogen activator by amiloride". Cancer Biochem. Biophys. 17 (1-2): 109–23. PMID 10738907. 
  3. ^ Matthews H, Ranson M, Kelso MJ (November 2011). "Anti-tumour/metastasis effects of the potassium-sparing diuretic amiloride: an orally active anti-cancer drug waiting for its call-of-duty?". Int. J. Cancer 129 (9): 2051–61. doi:10.1002/ijc.26156. PMID 21544803. 
  4. ^ "Gemcitabine With or Without WX-671 in Treating Patients With Locally Advanced Pancreatic Cancer That Cannot Be Removed By Surgery". ClinicalTrials.gov. 
  5. ^ "Fox Chase Cancer Center : New Small Molecule Inhibitor Could be a Safe and First-Line Treatment for Metastatic Breast Cancer". Press Release. Temple University Health System.