Page last updated: 2024-10-24

negative regulation of plasminogen activation

Definition

Target type: biologicalprocess

Any process that decreases the rate, frequency or extent of plasminogen activation. Plasminogen activation is the process in which plasminogen is processed to plasmin. [GOC:BHF, GOC:dph, GOC:tb]

Negative regulation of plasminogen activation is a crucial biological process that controls the conversion of plasminogen to plasmin, a potent serine protease involved in various physiological processes, including fibrinolysis, wound healing, and tissue remodeling. Plasminogen activation is tightly regulated to prevent uncontrolled proteolysis and tissue damage. The primary mechanism involves the inhibition of the key enzyme responsible for plasminogen activation, tissue plasminogen activator (tPA). This inhibition can occur through multiple pathways:

1. **Inhibition of tPA activity:**
- **Plasminogen activator inhibitor-1 (PAI-1):** PAI-1 is the primary inhibitor of tPA in circulation and tissues. It binds to tPA and forms a stable complex that prevents tPA from activating plasminogen.
- **α2-antiplasmin:** This protein is a fast-acting inhibitor of plasmin, effectively preventing its proteolytic activity. It can also indirectly inhibit tPA by binding to plasmin, preventing it from activating more plasminogen.
- **Thrombin-activatable fibrinolysis inhibitor (TAFI):** TAFI is a carboxypeptidase that cleaves lysine residues from fibrin, decreasing the affinity of tPA for fibrin. This reduces the efficiency of tPA in activating plasminogen bound to fibrin.

2. **Regulation of tPA expression and release:**
- **Cytokines and growth factors:** Factors like TNF-α, IL-1β, and TGF-β can suppress tPA production in various cell types.
- **Hormones:** Estrogens promote PAI-1 production, leading to reduced tPA activity.
- **Cellular signaling pathways:** Multiple intracellular signaling pathways, including the MAPK and PI3K pathways, can regulate tPA expression and release.

3. **Removal of tPA from circulation:**
- **Liver clearance:** tPA is cleared from circulation mainly by the liver.

The intricate interplay of these regulatory mechanisms ensures that plasminogen activation occurs only when and where it is required, preventing excessive fibrinolysis and maintaining tissue integrity. Dysregulation of negative regulation of plasminogen activation can lead to pathological conditions such as thrombosis, bleeding disorders, and cancer progression.'
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Proteins (5)

ProteinDefinitionTaxonomy
Cathepsin ZA cathepsin Z that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9UBR2]Homo sapiens (human)
Carboxypeptidase B2A carboxypeptidase B2 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q96IY4]Homo sapiens (human)
Plasminogen activator inhibitor 1A plasminogen activator inhibitor 1 that is encoded in the genome of human. [PRO:CNA, UniProtKB:P05121]Homo sapiens (human)
Tissue-type plasminogen activatorA tissue-type plasminogen activator that is encoded in the genome of human. [PRO:DNx, UniProtKB:P00750]Homo sapiens (human)
Urokinase-type plasminogen activatorA urokinase-type plasminogen activator that is encoded in the genome of human. [PRO:DNx, UniProtKB:P00749]Homo sapiens (human)

Compounds (71)

CompoundDefinitionClassesRoles
gallic acidgallate : A trihydroxybenzoate that is the conjugate base of gallic acid.trihydroxybenzoic acidantineoplastic agent;
antioxidant;
apoptosis inducer;
astringent;
cyclooxygenase 2 inhibitor;
EC 1.13.11.33 (arachidonate 15-lipoxygenase) inhibitor;
geroprotector;
human xenobiotic metabolite;
plant metabolite
4-aminobenzamidine4-aminobenzamidine: a urokinase inhibitor; inhibits acrosin; structure given in first source
4-iodine-benzo(b)thiophene-2-carboxamidine
5-(n,n-hexamethylene)amiloride5-(N,N-hexamethylene)amiloride : A member of the class of pyrazines that is amiloride in which the two amino hydrogens at position N-5 are replaced by a hexamethylene moiety, resulting in the formation of an azepane ring.

5-(N,N-hexamethylene)amiloride: inhibitor of Na+-H+ exchange; has anti-HIV-1 activity
aromatic amine;
azepanes;
guanidines;
monocarboxylic acid amide;
organochlorine compound;
pyrazines
antineoplastic agent;
apoptosis inducer;
odorant receptor antagonist;
sodium channel blocker
benzamidinebenzamidine : A carboxamidine that is benzene carrying an amidino group.

benzamidine: RN given refers to parent cpd
benzenes;
carboxamidine
serine protease inhibitor
bis(5-amidino-2-benzimidazolyl)methanebis(5-amidino-2-benzimidazolyl)methane: aromatic diamidine which has a significant suppressive effect on the cytopathology & yield of respiratory synctial (RS) virus; RN given refers to parent cpd
gabexateGabexate: A serine proteinase inhibitor used therapeutically in the treatment of pancreatitis, disseminated intravascular coagulation (DIC), and as a regional anticoagulant for hemodialysis. The drug inhibits the hydrolytic effects of thrombin, plasmin, and kallikrein, but not of chymotrypsin and aprotinin.benzoate ester
hexachlorophenehexachlorophene : An organochlorine compound that is diphenylmethane in which each of the phenyl groups is substituted by chlorines at positions 2, 3, and 5, and by a hydroxy group at position 6. An antiseptic that is effective against Gram-positive organisms, it is used in soaps and creams for the treatment of various skin disorders. It is also used in agriculture as an acaricide and fungicide, but is not approved for such use within the European Union.

Hexachlorophene: A chlorinated bisphenol antiseptic with a bacteriostatic action against Gram-positive organisms, but much less effective against Gram-negative organisms. It is mainly used in soaps and creams and is an ingredient of various preparations used for skin disorders. (From Martindale, The Extra Pharmacopoeia, 30th ed, p797)
bridged diphenyl fungicide;
polyphenol;
trichlorobenzene
acaricide;
antibacterial agent;
antifungal agrochemical;
antiseptic drug
benzylsuccinic acid2-benzylsuccinic acid : A dicarboxylic acid consisting of succinic acid carrying a 2-benzyl substituent.

benzylsuccinic acid: inhibitor of carboxypeptidase A
dicarboxylic acidbacterial xenobiotic metabolite
netropsinNetropsin: A basic polypeptide isolated from Streptomyces netropsis. It is cytotoxic and its strong, specific binding to A-T areas of DNA is useful to genetics research.
n-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamideN-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide: structure given in first source

NS-398 : A C-nitro compound that is N-methylsulfonyl-4-nitroaniline bearing an additional cyclohexyloxy substituent at position 2.
aromatic ether;
C-nitro compound;
sulfonamide
antineoplastic agent;
cyclooxygenase 2 inhibitor
pentamidinepentamidine : A diether consisting of pentane-1,5-diol in which both hydroxyl hydrogens have been replaced by 4-amidinophenyl groups. A trypanocidal drug that is used for treatment of cutaneous leishmaniasis and Chagas disease.

Pentamidine: Antiprotozoal agent effective in trypanosomiasis, leishmaniasis, and some fungal infections; used in treatment of PNEUMOCYSTIS pneumonia in HIV-infected patients. It may cause diabetes mellitus, central nervous system damage, and other toxic effects.
aromatic ether;
carboxamidine;
diether
anti-inflammatory agent;
antifungal agent;
calmodulin antagonist;
chemokine receptor 5 antagonist;
EC 2.3.1.48 (histone acetyltransferase) inhibitor;
NMDA receptor antagonist;
S100 calcium-binding protein B inhibitor;
trypanocidal drug;
xenobiotic
1,2,5,8-tetrahydroxy anthraquinone1,2,5,8-tetrahydroxy anthraquinone: structure in first source

quinalizarin : A tetrahydroxyanthraquinone having the four hydroxy groups at the 1-, 2-, 5- and 8-positions.
tetrahydroxyanthraquinoneEC 2.7.11.1 (non-specific serine/threonine protein kinase) inhibitor
vorinostatvorinostat : A dicarboxylic acid diamide comprising suberic (octanedioic) acid coupled to aniline and hydroxylamine. A histone deacetylase inhibitor, it is marketed under the name Zolinza for the treatment of cutaneous T cell lymphoma (CTCL).

Vorinostat: A hydroxamic acid and anilide derivative that acts as a HISTONE DEACETYLASE inhibitor. It is used in the treatment of CUTANEOUS T-CELL LYMPHOMA and SEZARY SYNDROME.
dicarboxylic acid diamide;
hydroxamic acid
antineoplastic agent;
apoptosis inducer;
EC 3.5.1.98 (histone deacetylase) inhibitor
tranexamic acidTranexamic Acid: Antifibrinolytic hemostatic used in severe hemorrhage.amino acid
dibrompropamidinearomatic ether
2-aminobenzimidazole2-aminobenzimidazole : A member of the class of benzimidazoles that is benzimidazole in which the hydrogen at position 2 is replaced by an amino group.

2-aminobenzimidazole: metabolite of benomyl; RN given refers to parent cpd
benzimidazolesmarine xenobiotic metabolite
phenylguanidinephenylguanidine: RN given refers to parent cpd
amilorideamiloride : A member of the class of pyrazines resulting from the formal monoacylation of guanidine with the carboxy group of 3,5-diamino-6-chloropyrazine-2-carboxylic acid.

Amiloride: A pyrazine compound inhibiting SODIUM reabsorption through SODIUM CHANNELS in renal EPITHELIAL CELLS. This inhibition creates a negative potential in the luminal membranes of principal cells, located in the distal convoluted tubule and collecting duct. Negative potential reduces secretion of potassium and hydrogen ions. Amiloride is used in conjunction with DIURETICS to spare POTASSIUM loss. (From Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed, p705)
aromatic amine;
guanidines;
organochlorine compound;
pyrazines
diuretic;
sodium channel blocker
2-aminotetralin2-aminotetralin: RN given refers to parent cpd without isomeric designation; structuretetralins
epigallocatechin gallate(-)-epigallocatechin 3-gallate : A gallate ester obtained by the formal condensation of gallic acid with the (3R)-hydroxy group of (-)-epigallocatechin.

epigallocatechin gallate: a steroid 5alpha-reductase inhibitor and antimutagen in green tea (Camellia sinensis)
flavans;
gallate ester;
polyphenol
antineoplastic agent;
antioxidant;
apoptosis inducer;
geroprotector;
Hsp90 inhibitor;
neuroprotective agent;
plant metabolite
hexamidinehexamidine : A polyether that is the bis(4-guanidinophenyl) ether of hexane-1,6-diol.aromatic ether;
guanidines;
polyether
antimicrobial agent;
antiseptic drug
amiloride hydrochlorideamiloride hydrochloride dihydrate : A hydrate that is the dihydrate of amiloride hydrochloride.hydratediuretic;
sodium channel blocker
sennoside Asennoside A : A member of the class of sennosides that is rel-(9R,9'R)-9,9',10,10'-tetrahydro-9,9'-bianthracene-2,2'-dicarboxylic acid which is substituted by hydroxy groups at positions 4 and 4', by beta-D-glucopyranosyloxy groups at positions 5 and 5', and by oxo groups at positions 10 and 10'. The exact stereochemisty at positions 9 and 9' is not known - it may be R,R (as shown) or S,S.oxo dicarboxylic acid;
sennosides
1-aminoisoquinoline
mci 9038peptide
sivelestatsivelestat: inhibitor of neutrophil elastase; structure given in first sourceN-acylglycine;
pivalate ester
dx 9065
efegatranefegatran: RN & structure given in first source; RN given refers to parent cpd (D)-isomer
5-amidinoindole
4-guanidinobenzoate4-guanidinobenzoate: RN given refers to parent cpd

4-guanidinobenzoic acid : Benzoic acid substituted at the para position by a guanidino group.
benzoic acids;
guanidines
melagatranazetidines;
carboxamidine;
dicarboxylic acid monoamide;
non-proteinogenic alpha-amino acid;
secondary amino compound
anticoagulant;
EC 3.4.21.5 (thrombin) inhibitor;
serine protease inhibitor
beta-naphthamidinebeta-naphthamidine: RN given refers to parent cpd
sq 247982-mercaptomethyl-5-guanidinopentanoic acid: structure
3-(3-amino-1,2,4-oxadiazol-5-yl)-5-chloro-2,6-pyrazinediamine3-(3-amino-1,2,4-oxadiazol-5-yl)-5-chloro-2,6-pyrazinediamine: amiloride prodrug; structure given in first source
7-amino-3-(2-bromoethoxy)-4-chloroisocoumarin7-amino-3-(2-bromoethoxy)-4-chloroisocoumarin: RN & structure given in first source
razaxabanrazaxaban: structure in first source
dabigatrandabigatran : An aromatic amide obtained by formal condensation of the carboxy group of 2-{[(4-carbamimidoylphenyl)amino]methyl}-1-methyl-1H-benzimidazole-5-carboxylic acid with the secondary amoino group of N-pyridin-2-yl-beta-alanine. The active metabolite of the prodrug dabigatran etexilate, it acts as an anticoagulant which is used for the prevention of stroke and systemic embolism.

Dabigatran: A THROMBIN inhibitor which acts by binding and blocking thrombogenic activity and the prevention of thrombus formation. It is used to reduce the risk of stroke and systemic EMBOLISM in patients with nonvalvular atrial fibrillation.
aromatic amide;
benzimidazoles;
beta-alanine derivative;
carboxamidine;
pyridines
anticoagulant;
EC 1.10.99.2 [ribosyldihydronicotinamide dehydrogenase (quinone)] inhibitor;
EC 3.4.21.5 (thrombin) inhibitor
actinoninactinonin: natural hydroxamic acid, pseudopeptide antibiotic isolated from Streptomyces species; structure
benzamidinecarboxamidinium ion
Epigallocatechin 3,5-Digallatecatechin
2-(4-chlorophenyl)guanidineorganochlorine compound
7-amino-4-chloro-3-(3-isothiureidopropoxy)isocoumarin7-amino-4-chloro-3-(3-isothiureidopropoxy)isocoumarin: structure given in first source
silybin
quercetin7-hydroxyflavonol;
pentahydroxyflavone
antibacterial agent;
antineoplastic agent;
antioxidant;
Aurora kinase inhibitor;
chelator;
EC 1.10.99.2 [ribosyldihydronicotinamide dehydrogenase (quinone)] inhibitor;
geroprotector;
phytoestrogen;
plant metabolite;
protein kinase inhibitor;
radical scavenger
rutinquercetin-3-O-rutinoside: structure in first sourceflavonoids;
glycoside
pai 039tiplaxtinin: inhibitor of plasminogen activator inhibitor-1indole-3-acetic acids
bms 7408081-(3-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-6-(2'-(3-hydroxy-N-pyrrolidinyl)methyl-(1,1')-biphen-4-yl)-1,4,5,6-tetrahydropyrazolo-(3,4-c)-pyridin-7-one: structure in first source
xr 334XR 334: a low molecular weight modulator of human plasminogen activator inhibitor-1 activity; structure given in first source; RN given refers to (Z,Z)-isomer
b 4284-iodine-benzo(b)thiophene-2-carboxamidine: structure in first source
bms-262084BMS-262084: an azetidinone-based tryptase inhibitor; structure in first source
upamostat
uk-356,202UK-356,202: structure in first source
n-alpha-(2,4,6-triisopropyl-phenylsulfonyl)-3-amidino-(l)-phenyl-alanine-4-ethoxycarbonyl-piperazide hydrochloride
dpc 423
gw 813893
lb 30057
odanacatibodanacatib: a selective inhibitor of cathepsin K for the treatment of post-menopausal osteoporosis; structure in first source
a-317567A-317567: acid sensing ion channel blocker; structure in first source
betrixabanbetrixaban : A secondary carboxamide obtained by formal condensation of the carboxy group of 4-(N,N-dimethylcarbamimidoyl)benzoic acid with the amino group of 2-amino-N-(5-chloropyridin-2-yl)-5-methoxybenzamide. A synthetic anticoagulant compound that targets activated factor Xa in the coagulation cascade.

betrixaban: a highly potent, selective, and orally efficacious factor Xa inhibitor; structure in first source
benzamides;
guanidines;
monochloropyridine;
monomethoxybenzene;
secondary carboxamide
anticoagulant;
EC 3.4.21.6 (coagulation factor Xa) inhibitor
ko 143beta-carbolines;
tert-butyl ester
rpr 120844
m-chlorophenylguanidine
sideroxylonal csideroxylonal C: formylated phloroglucinol from flowers of Eucalyptus albens; structure in first source
anabaenopeptin banabaenopeptin B: from cyanobacteria Planktothrix (Oscillatoria) rubescens
pf-429242PF-429242: a subtilisin kexin isozyme-1/site-1 protease inhibitor
6-(3,5-difluoroanilino)-9-ethyl-2-purinecarbonitrile6-aminopurines
6-(3,5-difluoroanilino)-9-(2,2-difluoroethyl)-2-purinecarbonitrile6-aminopurines
9-(3,5-difluorophenyl)-6-(ethylamino)-2-purinecarbonitrileimidazoles
grassystatin agrassystatin A: isolated from a cyanobacterium, identified as Lyngbya cf.; structure in first source
rpx7009RPX7009: a beta-lactamase inhibitor; structure in first source