Urokinase

Urokinase

Clinical data
AHFS/Drugs.com	monograph
Identifiers
CAS Number	9039-53-6 Y
ATC code	B01AD04 (WHO)
DrugBank	DB00013 N
UNII	83G67E21XI N
KEGG	D03341 Y
ChEMBL	CHEMBL1201420 N
Chemical data
Formula	C1376H2145N383O406S18
Molecular mass	31126.5 g/mol
NY (what is this?)  (verify)

plasminogen activator, urokinase
Identifiers
Symbol	PLAU
Entrez	5328
HUGO	9052
OMIM	191840
RefSeq	NM_002658
UniProt	P00749
Other data
EC number	3.4.21.31
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. 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.

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

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. 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. Mesupron appears to be safe when combined with chemotherapeutic drug Capecitabine for the progression-free survival in human breast cancer.

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 Kinlytic^TM, and competes with Alteplase^TM 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.