Target type: biologicalprocess
A series of reactions that takes place outside the cell occurring in response to tissue damage and initiated within blood plasma by the action of activated Factor XII (Hageman Factor) on prekallikrein to convert it to plasma kallikrein, and the subsequent reaction of plasma kallikrein with high molecular weight kininogen. The ultimate product of the plasma kallikrein-kinin cascade is bradykinin, an agent known to induce smooth muscle contraction, vasoconstriction, and increased vascular permeability. [GOC:add, ISBN:0721601871, PMID:11842287, PMID:14501145]
The plasma kallikrein-kinin cascade is a complex enzymatic system involved in various physiological and pathological processes, including inflammation, blood pressure regulation, and pain perception. It's initiated by the activation of Hageman factor (Factor XII), a zymogen (inactive enzyme precursor) in plasma, which can be triggered by contact with negatively charged surfaces like collagen or activated platelets.
Here's a detailed breakdown of the cascade:
1. **Activation of Hageman Factor (Factor XII):** When Factor XII encounters an activating surface, it undergoes a conformational change, becoming Factor XIIa.
2. **Activation of Prekallikrein:** Factor XIIa catalyzes the conversion of prekallikrein, another zymogen, into kallikrein.
3. **Generation of Bradykinin:** Kallikrein cleaves high molecular weight kininogen (HMWK), a large protein in plasma, to release bradykinin, a potent vasodilator and pain-inducing peptide.
4. **Bradykinin's Actions:** Bradykinin exerts a wide range of biological effects, including:
* Vasodilation: It relaxes smooth muscle in blood vessels, leading to increased blood flow.
* Increased vascular permeability: It widens blood vessels, allowing fluid and immune cells to leak out, contributing to inflammation.
* Pain sensation: It activates sensory neurons, triggering pain perception.
* Other effects: Bradykinin can also stimulate the release of other inflammatory mediators and influence blood clotting processes.
5. **Feedback Loops:** The kallikrein-kinin cascade is regulated by feedback loops:
* **Negative Feedback:** Bradykinin itself can activate kallikrein inhibitors, such as α2-macroglobulin and C1-inhibitor, which limit the cascade's activity.
* **Positive Feedback:** Bradykinin can also activate Factor XII, amplifying the cascade.
6. **Clinical Relevance:** The kallikrein-kinin cascade is implicated in various conditions:
* **Inflammation:** It plays a crucial role in mediating the inflammatory response, contributing to swelling, redness, and pain.
* **Blood Pressure Regulation:** Bradykinin's vasodilatory effect helps regulate blood pressure.
* **Pain Perception:** Its involvement in pain transmission makes it a target for pain relief therapies.
* **Hereditary Angioedema:** Deficiencies in C1-inhibitor, a key regulator of the cascade, can lead to hereditary angioedema, a condition characterized by recurrent episodes of swelling in various parts of the body.
The kallikrein-kinin cascade is a complex and tightly regulated system essential for various physiological processes. Dysregulation of the cascade can contribute to various pathological conditions, highlighting its importance in human health.'
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| Protein | Definition | Taxonomy |
|---|---|---|
| Lysosomal Pro-X carboxypeptidase | A lysosomal Pro-X carboxypeptidase that is encoded in the genome of human. [PRO:DNx, UniProtKB:P42785] | Homo sapiens (human) |
| Coagulation factor XII | A coagulation factor XII that is encoded in the genome of human. [PRO:DNx, UniProtKB:P00748] | Homo sapiens (human) |
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| 4-methylumbelliferyl acetate | 4-methylumbelliferyl acetate : An acetate ester consiting of umbelliferone carrying a 7-O-acetyl group. | acetate ester; coumarins | plant metabolite |
| diacetyl | butane-2,3-dione : An alpha-diketone that is butane substituted by oxo groups at positions 2 and 3. It is a metabolite produced during the malolactic fermentation. | alpha-diketone | Escherichia coli metabolite; Saccharomyces cerevisiae metabolite |
| 6,7-dichloroquinoxaline-2,3-dione | quinoxaline derivative | ||
| tacrine | tacrine : A member of the class of acridines that is 1,2,3,4-tetrahydroacridine substituted by an amino group at position 9. It is used in the treatment of Alzheimer's disease. Tacrine: A cholinesterase inhibitor that crosses the blood-brain barrier. Tacrine has been used to counter the effects of muscle relaxants, as a respiratory stimulant, and in the treatment of Alzheimer's disease and other central nervous system disorders. | acridines; aromatic amine | EC 3.1.1.7 (acetylcholinesterase) inhibitor |
| ethacridine | Ethacridine: A topically applied anti-infective agent. | acridines | |
| benzophenone | benzophenone : The simplest member of the class of benzophenones, being formaldehyde in which both hydrogens are replaced by phenyl groups. | benzophenones | photosensitizing agent; plant metabolite |
| gabexate | Gabexate: 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 | |
| nafamostat | nafamostat: inhibitor of trypsin, plasmin, pancreatic kallikrein, plasma kallikrein & thrombin; strongly inhibits esterolytic activities of C1r & C1 esterase complement-mediated hemolysis; antineoplastic | benzoic acids; guanidines | |
| quinone | 1,4-benzoquinone : The simplest member of the class of 1,4-benzoquinones, obtained by the formal oxidation of hydroquinone to the corresponding diketone. It is a metabolite of benzene. benzoquinone : The simplest members of the class of benzoquinones, consisting of cyclohexadiene which is substituted by two oxo groups. quinone : Compounds having a fully conjugated cyclic dione structure, such as that of benzoquinones, derived from aromatic compounds by conversion of an even number of -CH= groups into -C(=O)- groups with any necessary rearrangement of double bonds (polycyclic and heterocyclic analogues are included). | 1,4-benzoquinones | cofactor; human xenobiotic metabolite; mouse metabolite |
| phencyclidine | phencyclidine : A member of the class of piperidines that is piperidine in which the nitrogen is substituted with a 1-phenylcyclohexyl group. Formerly used as an anaesthetic agent, it exhibits both hallucinogenic and neurotoxic effects. Phencyclidine: A hallucinogen formerly used as a veterinary anesthetic, and briefly as a general anesthetic for humans. Phencyclidine is similar to KETAMINE in structure and in many of its effects. Like ketamine, it can produce a dissociative state. It exerts its pharmacological action through inhibition of NMDA receptors (RECEPTORS, N-METHYL-D-ASPARTATE). As a drug of abuse, it is known as PCP and Angel Dust. | benzenes; piperidines | anaesthetic; neurotoxin; NMDA receptor antagonist; psychotropic drug |
| acenaphthenequinone | acenaphthoquinone : An orthoquinone that is the 1,2-dioxo derivative of acenaphthene. | orthoquinones | chain carrier; epitope |
| 9,10-phenanthrenequinone | 9,10-phenanthrenequinone: structure | phenanthrenes | |
| 5-bromoisatin | indoles | anticoronaviral agent | |
| isatin | tribulin: endogenous MONOAMINE OXIDASE inhibitory activity extractable into ethyl acetate found in brain and many mammalian tissues and fluids; ISATIN is a major component; produced in excess following alcohol withdrawal; | indoledione | EC 1.4.3.4 (monoamine oxidase) inhibitor; plant metabolite |
| chloranil | Chloranil: A quinone fungicide used for treatment of seeds and foliage. tetrachloro-1,4-benzoquinone : A member of the class of 1,4-benzoquiones that is 1,4-benzoquinone in which all four hydrogens are substituted by chlorines. | 1,4-benzoquinones; organochlorine compound | EC 2.7.1.33 (pantothenate kinase) inhibitor; metabolite |
| benzoin | benzoins; secondary alpha-hydroxy ketone | EC 3.1.1.1 (carboxylesterase) inhibitor | |
| dibenzoylmethane | dibenzoylmethane : A beta-diketone that is acetylacetone (acac) in which both methyl groups have been replaced by phenyl groups. It is a minor constituent of the root extract of licorice (Glycyrrhiza glabra) and exhibits antimutagenic and anticancer effects. | aromatic ketone; beta-diketone | antimutagen; antineoplastic agent; metabolite |
| benzil | benzil : An alpha-diketone that is ethane-1,2-dione substituted by phenyl groups at positions 1 and 2 respectively. benzil: structure | alpha-diketone; aromatic ketone | |
| 1,3-cyclohexanedione | 1,3-cyclohexanedione: structure cyclohexane-1,3-dione : A cyclohexanedione carrying oxo substituents at positions 1 and 3. | beta-diketone; cyclohexanedione | |
| dibromsalicil | dibromsalicil: brominated salicyclic acid deriv; antiplaque antiseptic | ||
| 1,2-naphthoquinone | 1,2-naphthoquinone : The parent structure of the family of 1,2-naphthoquinones, in which the oxo groups of the quinone moiety are at positions 1 and 2 of the naphthalene ring. It is a metabolite of naphthalene and is found in diesel exhaust particles. naphthalene-1,2-dione: structure given in first source | 1,2-naphthoquinones | aryl hydrocarbon receptor agonist; carcinogenic agent |
| 1-acetylisatin | 1-acetylisatin: structure in first source | indoledione | |
| 1-phenyl-1,2-propanedione | 1-phenyl-1,2-propanedione : An alpha-diketone that consists of 1-phenylpropane bearing keto substituents at positions 1 and 2. It is found in coffee. 1-phenyl-1,2-propanedione: an oxoglutarate carrier antagonist | alpha-diketone; aromatic ketone | plant metabolite |
| 2,3-pentanedione | pentane-2,3-dione : An alpha-diketone that is pentane substituted at the 2- and 3-positions by oxo groups. | alpha-diketone; methyl ketone | flavouring agent |
| 5-methylisatin | 5-methylisatin: structure in first source | ||
| 2-methyl-1,2,3,4-tetrahydroisoquinoline | |||
| n-methylisatin | N-methylisatin: structure given in first source | ||
| 9-amino-6-chloro-2-methoxyacridine | |||
| acetylacetone | acetylacetone : A beta-diketone that is pentane in which the hydrogens at positions 2 and 4 are replaced by oxo groups. | beta-diketone | |
| 5-Methoxyisatin | indoles | anticoronaviral agent | |
| 3-methyl-1,2-cyclopentanedione | 3-methyl-1,2-cyclopentanedione: a peroxynitrite scavenger isolated from coffee extract; structure in first source | cyclic ketone | |
| tenocyclidine | tenocyclidine : A tertiary amino compound that consists of cyclohexane having piperidin-1-yl and thiophen-2-yl groups attached at position 1. A dissociative anaesthetic drug with halluccinogenic and stimulant effects. Its effects are similar to those of phencyclidine (PCP, an analogue with the thienyl group replaced by phenyl), but it is rather more potent. | piperidines; tertiary amino compound; thiophenes | central nervous system stimulant; hallucinogen; neuroprotective agent; NMDA receptor antagonist |
| 4-benzoylbenzoic acid | 4-carboxybenzophenone: a photosensitizer agent | ||
| 1,10-phenanthroline-5,6-dione | 1,10-phenanthroline-5,6-dione: has antineoplastic, intercalating, and trypanocidal activities; structure given in first source | ||
| 2-chloranil | |||
| 3,5-di-tert-butyl-1,2-benzoquinone | |||
| 5-Chloro-1H-indole-2,3-dione | indoles | anticoronaviral agent | |
| 5-iodoisatin | 5-iodoisatin: structure in first source | indoles | anticoronaviral agent |
| 2,2-dimethoxy-2-phenylacetophenone | |||
| anisoin | |||
| hydrobenzoin | hydrobenzoin: structure in first source | ethanediol | |
| 1,2,3,4-tetrahydro-1-(phenylmethyl)isoquinoline | 1,2,3,4-tetrahydro-1-(phenylmethyl)isoquinoline: structure given in first source | benzyltetrahydroisoquinoline | |
| 1,2,3,4-tetrahydro-1-phenylisoquinoline | 1,2,3,4-tetrahydro-1-phenylisoquinoline: structure in first source | ||
| metaphit | metaphit: site-directed acylating agent of phencyclidine receptors in rat brain; structure given in first source | ||
| gidazepam | gidazepam: prodrug for 7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepine-2-one | ||
| 1,3-indandione | 1,2-indanedione: use for detection of latent fingerprints on porous surfaces; structure in first source | ||
| 1-(1-(2-benzo(b)thienyl)cyclohexyl)piperidine | 1-(1-(2-benzo(b)thienyl)cyclohexyl)piperidine: structure given in first source 1-[1-(1-benzothiophen-2-yl)cyclohexyl]piperidine : A tertiary amino compound that consists of cyclohexane having piperidin-1-yl and benzothiophen-2-yl groups attached at position 1. A potent dopamine re-uptake inhibitor with a behavioral profile different from that of phencyclidine (PCP) and similar to that of cocaine. | 1-benzothiophenes; piperidines; tertiary amino compound | dopamine uptake inhibitor |
| jtp 4819 | JTP 4819: a prolyl endopeptidase inhibitor; structure given in first source | ||
| dizocilpine | secondary amino compound; tetracyclic antidepressant | anaesthetic; anticonvulsant; neuroprotective agent; nicotinic antagonist; NMDA receptor antagonist | |
| dabigatran | dabigatran : 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 |
| 5-Fluoroisatin | indoles | anticoronaviral agent | |
| N-malonylanthranilic acid | dicarboxylic acid monoamide | ||
| cocaine | cocaine : A tropane alkaloid obtained from leaves of the South American shrub Erythroxylon coca. Cocaine: An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. | benzoate ester; methyl ester; tertiary amino compound; tropane alkaloid | adrenergic uptake inhibitor; central nervous system stimulant; dopamine uptake inhibitor; environmental contaminant; local anaesthetic; mouse metabolite; plant metabolite; serotonin uptake inhibitor; sodium channel blocker; sympathomimetic agent; vasoconstrictor agent; xenobiotic |
| 2-[2-[4-(2-fluorophenyl)-1-piperazinyl]-2-oxoethyl]-1,1-dioxo-1,2-benzothiazol-3-one | piperazines | ||
| 1-(4-fluorophenyl)-2-[[4-(2-furanylmethyl)-5-(phenoxymethyl)-1,2,4-triazol-3-yl]thio]ethanone | aromatic ketone | ||
| (4-Methyl-2-oxochromen-7-yl) furan-2-carboxylate | coumarins | anticoronaviral agent | |
| 3,4,5-trimethoxybenzoic acid [(3,5-dimethyl-4-oxo-1-cyclohexa-2,5-dienylidene)amino] ester | trihydroxybenzoic acid | ||
| 5-bromo-N-(4-propan-2-ylphenyl)-2-furancarboxamide | aromatic amide; furans | ||
| 2-furancarboxylic acid (2-acetyl-1-benzothiophen-3-yl) ester | carboxylic ester | ||
| (5-amino-3-phenyl-1,2,4-triazol-1-yl)-(2-methoxyphenyl)methanone | triazoles | ||
| (3-amino-1,2,4-triazol-4-yl)-(2,5-dimethylphenyl)methanone | benzoic acids | ||
| 3-[[(5-bromo-2-furanyl)-oxomethyl]amino]-2-methylbenzoic acid | aromatic amide; furans | ||
| 2-[[4-(4-methylphenyl)sulfonyl-1-piperazinyl]methyl]-4-propan-2-ylphenol | sulfonamide | ||
| 3-(1-piperidinylsulfonyl)-N-(2-thiazolyl)benzamide | sulfonamide | ||
| 2-[[2-(3,4-dimethylanilino)-2-oxoethyl]thio]acetamide | anilide | ||
| 2-furanyl-[4-(4-phenoxyphenyl)sulfonyl-1-piperazinyl]methanone | aromatic ether | ||
| N-(4-fluorophenyl)-3-([1,2,4]triazolo[4,3-a]quinolin-1-ylthio)propanamide | quinolines | ||
| LSM-32435 | triazolopyrimidines | ||
| 1-[1-ethyl-6-methyl-4-(4-phenyl-1-piperazinyl)-2-sulfanylidene-5-pyrimidinyl]ethanone | piperazines | ||
| 1-[(3,4-dichlorophenyl)methyl]indole-2,3-dione | indoles | ||
| 2-[[cyclohexyl(oxo)methyl]amino]acetic acid [2-(4-cyanoanilino)-2-oxoethyl] ester | depsipeptide | ||
| 6-(4-bromophenyl)-3-methyl-1-[2-(2H-tetrazol-5-yl)ethyl]-4-(trifluoromethyl)pyrazolo[3,4-b]pyridine | phenylpyridine | ||
| 2-ethoxy-N-[4-(2-pyrimidinylsulfamoyl)phenyl]acetamide | sulfonamide | ||
| 3-[[(4-tert-butylphenyl)-oxomethyl]amino]-1H-1,2,4-triazole-5-carboxylic acid methyl ester | benzamides | ||
| 3-(methoxymethyl)-2-benzofurancarboxylic acid [4-amino-6-(2-methylanilino)-1,3,5-triazin-2-yl]methyl ester | benzofurans | ||
| 3-chloro-1-(4-methoxyphenyl)-4-(3-methyl-1-piperidinyl)pyrrole-2,5-dione | maleimides | ||
| 2-[3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazole | (trifluoromethyl)benzenes | ||
| N-[2-furanyl-(8-hydroxy-7-quinolinyl)methyl]-2-methylpropanamide | hydroxyquinoline | ||
| 4-(1-methyl-3-indolyl)-N-propan-2-ylbutanamide | indoles | ||
| 1-(2,1,3-benzothiadiazol-4-ylsulfonyl)-N-(6-methyl-1,3-benzothiazol-2-yl)-3-piperidinecarboxamide | benzothiadiazole | ||
| 1-cyclopentyl-N-[2-(3,4-dihydro-1H-isoquinolin-2-yl)ethyl]-5-oxo-3-pyrrolidinecarboxamide | isoquinolines | ||
| 4-[2-(1-cyclohexenyl)ethyl]-1-cyclohexyl-3-pyridin-4-ylpiperazine-2,5-dione | piperazines; pyridines | ||
| N-(3-acetylphenyl)-3,5-dimethyl-4-isoxazolesulfonamide | aromatic ketone | ||
| N-[1-(cyclohexylamino)-2-methyl-1-oxobutan-2-yl]-N-(2-furanylmethyl)-2-pyridinecarboxamide | organonitrogen compound; organooxygen compound | ||
| 4-phenyl-1,2,3,4-tetrahydroisoquinoline | 4-phenyl-1,2,3,4-tetrahydroisoquinoline: RN given is for (R)-isomer; inhibits spinal reflex-enhancing effects of methamphetamine, phenylethylamine, and nomifensine | isoquinolines | |
| N-(2-methylphenyl)-1-phenazinecarboxamide | phenazines | ||
| 5-Nitroisatin | indoles | anticoronaviral agent | |
| 1-(3,4-dihydro-1H-isoquinolin-2-yl)-2-[[5-methyl-2-(4-methylphenyl)-4-oxazolyl]methylsulfonyl]ethanone | 1,3-oxazoles | ||
| phenylalanyl-prolyl-arginine methyl chloride | phenylalanyl-prolyl-arginine methyl chloride: selective affinity label for thrombin; RN given refers to parent (L-Pro-D-Phe-(S))-isomer | ||
| 1-(3-methoxyphenyl)-3-[2-(methylthio)phenyl]urea | ureas | ||
| 5-Chloro-3-pyridinyl 2-furoate | carboxylic ester | anticoronaviral agent | |
| rivaroxaban | rivaroxaban : A monocarboxylic acid amide obtained by formal condensation of the carboxy group of 5-chlorothiophene-2-carboxylic acid with the amino group of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one. An anticoagulant used for prophylaxis of venous thromboembolism in patients with knee or hip replacement surgery. Rivaroxaban: A morpholine and thiophene derivative that functions as a FACTOR XA INHIBITOR and is used in the treatment and prevention of DEEP-VEIN THROMBOSIS and PULMONARY EMBOLISM. It is also used for the prevention of STROKE and systemic embolization in patients with non-valvular ATRIAL FIBRILLATION, and for the prevention of atherothrombotic events in patients after an ACUTE CORONARY SYNDROME. | aromatic amide; lactam; monocarboxylic acid amide; morpholines; organochlorine compound; oxazolidinone; thiophenes | anticoagulant; EC 3.4.21.6 (coagulation factor Xa) inhibitor |
| N-[4-(6-chloro-5-nitro-1H-benzimidazol-2-yl)phenyl]acetamide | benzimidazoles |