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
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
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.
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
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 cell 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
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 marketed as KinlyticTM, and competes with AlteplaseTM as a thrombolytic drug in infarction. However, urokinase is not very selective for clot-bound plasminogen, unlike tissue plasminogen activator (TPA) which preferentially interacts with clot-bound plasminogen. Because urokinase binds about equally to freely circulating plasminogen and clot-bound plasminogen, it causes significant fibrinogenolysis and clot fibrinolysis making its use less favorable than TPA.[6]
Bisobrin is a fibrinolytic agent (Antifibrinolytic), simple molecules that will accomplish the same end.
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