Urokinase

Source: Wikipedia, the free encyclopedia.
PLAU
Available structures
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000122861

ENSMUSG00000021822

UniProt

P00749

P06869

RefSeq (mRNA)

NM_001145031
NM_002658
NM_001319191

NM_008873

RefSeq (protein)

NP_001138503
NP_001306120
NP_002649

NP_032899

Location (UCSC)Chr 10: 73.91 – 73.92 MbChr 14: 20.89 – 20.89 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Urokinase
Clinical data
AHFS/Drugs.comMonograph
ATC code
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC1376H2145N383O406S18
Molar mass31126.65 g·mol−1
 ☒NcheckY (what is this?)  (verify)

Urokinase, also known as urokinase-type plasminogen activator (uPA), is a

plasminogen, which is an inactive form (zymogen) of the serine protease plasmin. Activation of plasmin triggers a proteolytic cascade that, depending on the physiological environment, participates in thrombolysis or extracellular matrix degradation. This cascade had been involved in vascular diseases and cancer progression.[6]

Urokinase is encoded in humans by the PLAU gene, which stands for "plasminogen activator, urokinase".[7] The same symbol represents the gene in other animal species.

Function

The PLAU gene encodes a serine protease (EC 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.[8]

Structure

Urokinase is a 411-residue protein, consisting of three domains: the serine protease domain (consisting of residues 159-411), the kringle domain (consisting of residues 50-131), and the EGF-like domain (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 disulfide bond between Cys148 and Cys279.[9]

In comparison to the mammalian system,

orthologs of urokinase which have been characterised as zfuPA-a and zfuPA-b. zfuPA-a differs from the mammalian uPA by lacking an exon sequence encoding for the uPAR (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 white blood cells 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 vitronectin, integrins and other proteases like PAI-1. The lack of the uPAR binding region in zebrafish uPA, suggests that zebrafish uPA functions without uPAR binding.[10]

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.

uPa also interacts with protein C inhibitor.[11][12]

zfuPA-a and zfuPA-b are poor activators of human plasminogen, while human uPA is a poor activator of salmon plasminogen. With the primary difference between the zebrafish uPA and human uPA being in the EGF domain.[10]

Urokinase and cancer

Elevated

murine 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.[13]

uPA breakdown of the extracellular matrix is crucial for initiating the angiogenesis which is associated with cancer growth.[14]

uPA antigen is elevated in breast cancer tissue, which correlates with poor prognosis in breast cancer patients.[14] For this reason, uPA can be used as a diagnostic biomarker in breast cancer.[14]

Through its interaction with the

mitotic
pathways.

As of December 7, 2012, Mesupron (upamostat), a small molecule serine protease inhibitor developed by the WILEX pharmaceutical company, has completed phase II trials.[17] Mesupron appears to be safe when combined with chemotherapeutic drug Capecitabine for the progression-free survival in human breast cancer.[18]

Clinical applications

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

recombinant tissue plasminogen activator
(e.g., alteplase) as a thrombolytic drug.

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).

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.

deep venous thrombosis
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.  

A revolutionary method for the production of urokinase was patented by Evelyn Nicol 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.[21]

Society and culture

The presence of a

plasminogen has anything to do with a protease, but a kinase is thought to play a role regardless.[25]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000122861 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021822 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. PMID 21711231
    .
  6. PMID 23201006
    .
  7. PMID 2415429
    .
  8. ^ "Entrez Gene: PLAU plasminogen activator, urokinase".
  9. PMID 19273310
    .
  10. ^
    PMID 22733817
    .
  11. PMID 2752144
    .
  12. PMID 2551064
    .
  13. ^
    PMID 30419600
    .
  14. ^
    PMID 29484286
    .
  15. PMID 10738907
    .
  16. S2CID 205943879
    .
  17. ^ "Gemcitabine With or Without WX-671 in Treating Patients With Locally Advanced Pancreatic Cancer That Cannot Be Removed By Surgery". ClinicalTrials.gov. 28 March 2012.
  18. ^ "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.
  19. PMID 10735422
    .
  20. S2CID 470599
    .
  21. ^ "Evelyn Nicol 1930 - 2020 - Obituary". www.legacy.com. Retrieved 2020-08-28.
  22. S2CID 4125748
    .
  23. ^ 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.
  24. doi:10.1152/ajplegacy.1952.171.3.704
    . 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.
  25. PMID 13808740
    .

Further reading

External links
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