id: MODULE:kallikrein_kinin_cascade title: Kallikrein-kinin cascade — contact activation, kinin release from kininogen, B1/B2 receptor signaling, kininase inactivation and serpin control description: >- The kallikrein-kinin system is an extracellular protease cascade that releases the vasoactive kinin peptides bradykinin and kallidin (Lys-bradykinin) from a single precursor, kininogen, and terminates them by peptidase cleavage. Two routes feed the cascade. In the plasma (contact) route, coagulation factor XII (F12, Hageman factor) binds negatively charged surfaces or misfolded protein aggregates and is autoactivated or activated by traces of protease; surface-bound F12a then activates plasma prekallikrein (KLKB1), which circulates in complex with high-molecular-weight kininogen, and the formed kallikrein activates further F12 in a reciprocal positive-feedback loop. Prolylcarboxypeptidase (PRCP) on the endothelial membrane provides a factor XII-independent prekallikrein activator. Active plasma kallikrein cleaves high-molecular-weight kininogen and liberates the nonapeptide bradykinin. In the tissue route, tissue kallikrein (KLK1), secreted by kidney, pancreas and salivary gland, cleaves low-molecular-weight kininogen at two sites and releases the decapeptide kallidin. The kinins act as short-lived local hormones on two G protein-coupled receptors: the constitutively expressed B2 receptor (BDKRB2), whose agonists are bradykinin and kallidin, and the inducible B1 receptor (BDKRB1), whose agonists are the des-Arg metabolites generated at the kinin C terminus by the carboxypeptidases CPN1 (plasma, kininase I) and CPM (membrane-bound). Receptor occupancy raises intracellular calcium and drives vasodilation, increased vascular permeability, release of inflammatory mediators and stimulation of sensory neurons. Several peptidases act as kininases and destroy kinin activity: angiotensin-converting enzyme (ACE, kininase II), neprilysin (MME) and membrane-bound aminopeptidase P (XPNPEP2). The proteases of the cascade are restrained by serpins and by alpha-2-macroglobulin: C1 inhibitor (SERPING1) and A2M are the principal plasma inhibitors of kallikrein and F12a, and kallistatin (SERPINA4) inhibits tissue kallikrein. status: DRAFT scope: CONCRETE evidence: - source_id: PW:0000526 title: kallikrein-kinin cascade pathway statement: >- The module boundary and its members follow the RGD interactive diagram for this Pathway Ontology term. The diagram draws Kng1 giving rise to highKng1 and lowKng1, highKng1 associated with prekallikrein (pKlkb1) and positively affecting BK, Klk1 acting on lowKng1 to give KD, F12a in the contact step, Cpm and Cpn1 converting BK and KD to des-Arg-kinins, Bdkrb2 associated with BK and KD and Bdkrb1 with the des-Arg kinins, the kinins positively affecting vasodilation, inflammatory mediator release and sensory neuron stimulation, and the inhibitory edges Serping1 -| F12a, Serping1 -| Klkb1, A2m -| Klkb1 and Serpina4 -| Klk1. The diagram also links out to the coagulation cascade (PW:0000474), classical complement (PW:0000503) and kinin signaling (PW:0001480) pathways, which are outside this module. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0000526.yaml). - source_id: GO:0002254 title: kinin cascade statement: >- The module as a whole is the kinin cascade: the extracellular reaction series whose ultimate products are kallidin and bradykinin. Its two initiating routes are the specific children GO:0002353 plasma kallikrein-kinin cascade and GO:0002255 tissue kallikrein-kinin cascade, which are used on the respective parts rather than on the module node. - source_id: GO:0002353 title: plasma kallikrein-kinin cascade statement: >- The contact-activation route. Human F12 carries this term by IDA (PMID:18725990, PMID:6793628), and mouse Prcp by IMP, so the term covers both the factor XII-dependent and the prolylcarboxypeptidase-dependent entry into prekallikrein activation. - source_id: GO:0002255 title: tissue kallikrein-kinin cascade statement: >- The tissue (glandular) route, in which kallikrein-1 acts on low-molecular-weight kininogen. The term is annotated experimentally to a mouse tissue kallikrein (UniProtKB:P00755, Klk1b1, IMP); human KLK1 itself has no direct GO annotation to it, which is recorded in the notes rather than asserted here. - source_id: gomodel:6246724f00000632 title: Bradykinin degradation by ACE and bradykin-binding to its receptor (Human) statement: >- An independent, curator-built human GO-CAM (cached under gocams/6246724f00000632/) models three of this module's gene products with matching molecular functions: ACE peptidyl-dipeptidase activity (GO:0008241) in bradykinin catabolic process (GO:0010815), KNG1 hormone activity (GO:0005179) in vasodilation (GO:0042311) and BDKRB2 bradykinin receptor activity (GO:0004947) in vasodilation. The ACE activity is drawn causally upstream of the KNG1 hormone activity. Those three annotons carry gocam_associations here; no production GO-CAM was found for the contact-activation, tissue-kallikrein, carboxypeptidase or inhibitor steps. - source_id: PMID:18725990 title: Misfolded proteins activate factor XII in humans, leading to kallikrein formation without initiating coagulation. statement: >- Establishes the entry point of the cascade and separates it from coagulation: surface-adsorbed or denatured protein aggregates activate factor XII and form kallikrein without triggering clotting. supporting_text: Factor XII was activated by misfolded protein aggregates that formed by denaturation or by surface adsorption, which specifically led to the activation of the kallikrein-kinin system without inducing coagulation. - source_id: PMID:273926 title: Role of surface in surface-dependent activation of Hageman factor (blood coagulation factor XII). statement: >- Defines what an activating surface does and identifies kallikrein as the physiologically potent activator of surface-bound factor XII, the reciprocal step of this module. supporting_text: The results showed that surface-bound Hageman factor was 500 times more susceptible than soluble Hageman factor to proteolytic activation by kallikrein in the presence of high molecular weight kininogen. - source_id: PMID:386794 title: Molecular assembly in the contact phase of the Hageman factor system. statement: >- States the assembly logic used for parts 1 and 2: high-molecular-weight kininogen is the surface cofactor that brings prekallikrein next to factor XII, and activation of the two zymogens is reciprocal. supporting_text: High MW kininogen serves as a surface cofactor to assemble prekallikrein or factor XI in proximity to surface-bound Hageman factor. Reciprocal proteolytic activation of Hageman factor and prekallikrein represents an essential step in the rapid activation of the contact phase. - source_id: PMID:11830581 title: Identification and characterization of prolylcarboxypeptidase as an endothelial cell prekallikrein activator. statement: >- Identifies the factor XII-independent prekallikrein activator on the endothelial membrane as prolylcarboxypeptidase. supporting_text: PRCP appears to be a HUVEC-associated PK activator. - source_id: PMID:104988 title: "Studies on human kininogens. I. Isolation, characterization, and cleavage by plasma kallikrein of high molecular weight (HMW)-kininogen." statement: >- The plasma-route product step: human plasma kallikrein liberates bradykinin from human high-molecular-weight kininogen, leaving the kinin-free heavy and light chains. supporting_text: We investigated whether the liberation of kinin from human HMW-kininogen by human plasma kallikrein was accompanied by liberation of histidine-rich fragments - source_id: PMID:7749384 title: Cleavage of human kininogen fragments at Met-Lys by human tissue kallikrein. statement: >- The tissue-route product step, including the two cleavage sites and the TK-specific Met-Lys bond. supporting_text: Tissue kallikrein (TK) cleaves low molecular weight kininogen (LK) at two sites to release kallidin - source_id: PMID:1282629 title: "Bradykinin-degrading enzymes: structure, function, distribution, and potential roles in cardiovascular pharmacology." statement: >- Frames the inactivation part: several distinct peptidases qualify as kininases, and which one matters depends on where it is and what else is present. This is why the module models them as parallel annotons of one step. supporting_text: These include aminopeptidase P, meprin, endopeptidase 24.15, prolyl endopeptidase, neutral endopeptidase 24.11, angiotensin I-converting enzyme, carboxypeptidase N, carboxypeptidase M, and deamidase. - source_id: PMID:7692967 title: "High molecular weight kininogen potentiates the heparin-accelerated inhibition of plasma kallikrein by antithrombin: role for antithrombin in the regulation of kallikrein." statement: >- Names C1 inhibitor and alpha-2-macroglobulin as the primary plasma inhibitors of kallikrein and gives their rate constants, grounding the inhibitor part. supporting_text: nor did the protein enhance the rate constants of 1.7 x 10(4) and 3.4 x 10(4) M-1 s-1 for kallikrein reactions with its primary plasma inhibitors C1-inhibitor and alpha 2-macroglobulin, respectively notes: >- Derived from the RGD Pathway Ontology diagram PW:0000526 through the RGD_PATHWAY_ONTOLOGY project (seed in projects/RGD_PATHWAY_ONTOLOGY/data/module_seeds.yaml). The diagram supplied the boundary, the members and the topology; every molecular function was then chosen against the participant's experimental GOA rows in QuickGO rather than from the diagram: F12 and KLKB1 serine-type endopeptidase activity GO:0004252 (F12 IDA/EXP PMID:18725990, PMID:6793628, PMID:11204562; KLKB1 TAS PMID:1993180), KLK1 GO:0004252 (TAS PMID:2686621, NAS PMID:7749372, IBA), PRCP serine-type carboxypeptidase activity GO:0004185 (TAS PMID:28321), KNG1 hormone activity GO:0005179 (IDA PMID:1314587, PMID:1329734), BDKRB2 and BDKRB1 bradykinin receptor activity GO:0004947 (IDA PMID:1314587, PMID:1329734, PMID:17077303 and IDA PMID:10422787, PMID:1314587 respectively), CPN1 and CPM metallocarboxypeptidase activity GO:0004181 (TAS PMID:2912725, PMID:2753907, IBA), ACE peptidyl-dipeptidase activity GO:0008241 (EXP), MME metalloendopeptidase activity GO:0004222 (EXP PMID:8168535, IDA), XPNPEP2 aminopeptidase activity GO:0004177 (EXP PMID:15361070), SERPING1 and SERPINA4 serine-type endopeptidase inhibitor activity GO:0004867 (IDA PMID:11527969; TAS PMID:1334488) and A2M endopeptidase inhibitor activity GO:0004866 (IDA PMID:7679575, matching the core function of its gene review in genes/human/A2M/). GO:0005515 protein binding is deliberately never used. The cytosolic aminopeptidase P, XPNPEP1, is on RGD's gene list and degrades bradykinin in vitro (PMID:18515364), but it is left out of the kinin-inactivation step: that step acts on kinins in plasma and at the vascular surface, where the GPI-anchored XPNPEP2 is the aminopeptidase P that acts. KNG1 is the substrate the kallikreins cleave, so it is given no proteolysis or protein-processing process term here: the cleaving is done by KLKB1 and KLK1, and GO's convention is that a process under proteolysis belongs to the enzyme (the same reasoning recorded for AGT and GO:0002003 in CLAUDE.md; a comparator check finds no kininogen in GO:0002353 or GO:0002255 in human, mouse or rat). What KNG1 does perform is the agonist step: the released bradykinin acts as a local hormone, which is exactly the activity GOA records by IDA and the human GO-CAM gomodel:6246724f00000632 models, and that is how it appears in the receptor part. Hand-offs deliberately left out: F12a activation of factor XI and the rest of the intrinsic coagulation cascade belong to modules/coagulation_cascade.yaml (the RGD diagram's PW:0000474 link; PMID:386794 notes that alpha-HFa, but not beta-HFa, activates factor XI, so the branch point is in the contact step modeled here); plasmin generation and fibrinolysis, which contact activation also feeds (PMID:89876), belong to modules/fibrinolysis.yaml; the classical complement pathway that F12a can stimulate (PW:0000503) is out of scope. ACE's other role, converting angiotensin I, is out of scope and is modeled in the human GO-CAM gocams/6246724f00000549 (renin-angiotensin pathway); only its kininase II function is used here. Receptor desensitization by GRK4, ARRB1 and ARRB2, which the adjacent RGD kinin-signaling diagram PW:0001480 draws, is deliberately omitted: the experimental GOA rows that place those three in desensitization of G protein-coupled receptor signaling (GO:0002029) and the GO-CAMs that model them (for example gomodel:67f85f2b00004426) concern other receptors, and no annotation or cached model was found tying them to BDKRB1 or BDKRB2, so asserting it would go beyond the evidence. Of the module's sixteen gene products only A2M currently has a gene review (genes/human/A2M/); the rest are curation follow-up recorded in the project plan, not knowledge gaps. PANTHER family ids are omitted throughout: every participant is a concrete human gene product, and no family id was checked against the PANTHER member index. module: id: kallikrein_kinin_cascade label: Kallikrein-kinin cascade module_type: BIOLOGICAL_PROCESS concepts: - preferred_term: kinin cascade term: id: GO:0002254 label: kinin cascade description: >- Extracellular protease cascade whose products are the kinins bradykinin and kallidin, acting through the B1 and B2 bradykinin receptors. context: cellular_components: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane description: >- The receptors, the membrane-anchored kininases (ACE, MME, XPNPEP2, CPM) and the endothelial prekallikrein activator PRCP act at the cell surface, facing the same extracellular compartment as the soluble steps. parts: - order: 1 role: contact activation of factor XII node: id: kks_contact_activation label: Surface-dependent activation of factor XII module_type: REACTION description: >- Factor XII binds negatively charged surfaces or misfolded protein aggregates. Surface binding both allows slow autoactivation and makes the zymogen far more susceptible to cleavage by proteases, above all by kallikrein, which is the reciprocal feedback arm of this cascade. annotons: - id: f12_surface_activation label: Factor XII autoactivation on surfaces participant: selector_type: GENE_PRODUCT gene_product: preferred_term: F12 term: id: UniProtKB:P00748 label: Coagulation factor XII function: preferred_term: serine-type endopeptidase activity term: id: GO:0004252 label: serine-type endopeptidase activity substrates: - preferred_term: factor XII zymogen (autoactivation) term: id: UniProtKB:P00748 label: Coagulation factor XII processes: - preferred_term: protein autoprocessing term: id: GO:0016540 label: protein autoprocessing - preferred_term: plasma kallikrein-kinin cascade term: id: GO:0002353 label: plasma kallikrein-kinin cascade locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Initiating zymogen of the plasma route. Contact with an anionic surface or a misfolded protein aggregate converts a small amount of F12 to F12a, which is then amplified by kallikrein feedback. evidence: - source_id: PMID:18725990 statement: >- Misfolded protein aggregates, formed by denaturation or surface adsorption, activate factor XII and selectively drive the kallikrein-kinin system. supporting_text: Factor XII was activated by misfolded protein aggregates that formed by denaturation or by surface adsorption, which specifically led to the activation of the kallikrein-kinin system without inducing coagulation. - source_id: PMID:18725990 statement: >- The cascade is initiated by autoactivation of factor XII and feeds both coagulation and the kinin arm. supporting_text: This cascade is initiated by autoactivation of Factor XII and leads to both coagulation (via Factor XI) and an inflammatory response (via the kallikrein-kinin system). - source_id: PMID:273926 statement: >- Surface binding alters factor XII so that other proteases, not the surface itself, carry out the activating cleavage. supporting_text: These results suggest that substances classically known as "activating surfaces" promote the activation of Hageman factor indirectly by altering its structure such that it is much more susceptible to proteolytic activation by other plasma or cellular proteases. - id: klkb1_f12_feedback label: Plasma kallikrein activation of factor XII (reciprocal feedback) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: KLKB1 term: id: UniProtKB:P03952 label: Plasma kallikrein function: preferred_term: serine-type endopeptidase activity term: id: GO:0004252 label: serine-type endopeptidase activity substrates: - preferred_term: surface-bound factor XII term: id: UniProtKB:P00748 label: Coagulation factor XII processes: - preferred_term: Factor XII activation term: id: GO:0002542 label: Factor XII activation - preferred_term: zymogen activation term: id: GO:0031638 label: zymogen activation locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Amplification arm: formed kallikrein cleaves surface-bound factor XII far faster than the surface alone can autoactivate it, so a trace of either enzyme rapidly activates the whole contact phase. evidence: - source_id: PMID:273926 statement: >- Kallikrein is the most potent activator of surface-bound factor XII, effective at a thousandth of the plasma prekallikrein concentration. supporting_text: Kallikrein even at concentrations as low as 0.5 nM (i.e., 1/1000th of the concentration of prekallikrein in plasma) was very potent in the limited proteolysis of the surface-bound Hageman factor. - source_id: PMID:386794 statement: Activation of the two zymogens is reciprocal. supporting_text: Reciprocal proteolytic activation of Hageman factor and prekallikrein represents an essential step in the rapid activation of the contact phase. - order: 2 role: prekallikrein activation node: id: kks_prekallikrein_activation label: Activation of plasma prekallikrein to kallikrein module_type: REACTION description: >- Prekallikrein circulates bound to high-molecular-weight kininogen, which assembles it next to surface-bound factor XII. F12a cleaves it to kallikrein; on endothelial cells, membrane-expressed prolylcarboxypeptidase does the same independently of factor XII. annotons: - id: f12a_pk_activation label: Factor XIIa activation of prekallikrein participant: selector_type: GENE_PRODUCT gene_product: preferred_term: F12 term: id: UniProtKB:P00748 label: Coagulation factor XII function: preferred_term: serine-type endopeptidase activity term: id: GO:0004252 label: serine-type endopeptidase activity substrates: - preferred_term: plasma prekallikrein term: id: UniProtKB:P03952 label: Plasma kallikrein processes: - preferred_term: zymogen activation term: id: GO:0031638 label: zymogen activation - preferred_term: plasma kallikrein-kinin cascade term: id: GO:0002353 label: plasma kallikrein-kinin cascade locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- First committed step of the plasma route. The surface-bound alpha form of F12a activates prekallikrein and factor XI; the soluble beta form activates prekallikrein only, which disseminates kinin formation while keeping intrinsic clotting local. evidence: - source_id: PMID:386794 statement: >- High-molecular-weight kininogen assembles prekallikrein next to surface-bound factor XII, and the two F12a forms differ in which substrates they reach. supporting_text: High MW kininogen serves as a surface cofactor to assemble prekallikrein or factor XI in proximity to surface-bound Hageman factor. - source_id: PMID:386794 statement: >- Soluble beta-F12a leaves the surface and activates further prekallikrein but not factor XI, separating the kinin output from intrinsic clotting. supporting_text: The other form of activated Hageman factor, beta HFa, leaves the surface, going into solution where it readily activates additional prekallikrein but not factor XI. - source_id: PMID:18725990 statement: >- In patients with systemic amyloidosis, factor XII but not factor XI is activated and kallikrein is formed, showing the two outputs can be uncoupled in vivo. supporting_text: we found that Factor XII, but not Factor XI, was activated and kallikrein was formed in blood from patients with systemic amyloidosis - id: prcp_pk_activation label: Prolylcarboxypeptidase activation of prekallikrein on endothelium participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PRCP term: id: UniProtKB:P42785 label: Lysosomal Pro-X carboxypeptidase function: preferred_term: serine-type carboxypeptidase activity term: id: GO:0004185 label: serine-type carboxypeptidase activity processes: - preferred_term: plasma kallikrein-kinin cascade term: id: GO:0002353 label: plasma kallikrein-kinin cascade locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Factor XII-independent entry to the cascade: membrane-expressed PRCP activates prekallikrein that has assembled on high-molecular-weight kininogen at the endothelial surface, with a Km in the nanomolar range. evidence: - source_id: PMID:11830581 statement: >- PRCP was purified from endothelial cells as the prekallikrein activator acting on kininogen-bound prekallikrein. supporting_text: When prekallikrein (PK) assembles on high molecular weight kininogen on HUVEC, PK is activated to kallikrein. - source_id: PMID:11830581 statement: >- The activity is not factor XII: it does not correct factor XII-deficient plasma, is not recognised by anti-factor XII and does not activate factor XI. supporting_text: PKA did not correct the coagulant defect in factor XII deficient plasma, was purified from HUVEC cultured in factor XII-deficient serum, was not detected by antibody to factor XII, did not activate FXI, and was not inhibited by a neutralizing antibody to FXII. - source_id: PMID:11830581 statement: PRCP activates prekallikrein with nanomolar affinity. supporting_text: The K(m) of PK activation by PRCP is 6.7 nm. - order: 3 role: kinin release from kininogen node: id: kks_kinin_release label: Release of kinins from kininogen by a kallikrein module_type: REACTION description: >- Both active kinins come from kininogen (KNG1), whose alternative transcripts give the high- and low-molecular-weight forms. Which kinin is produced depends on which kallikrein does the cleaving, so the two routes are modeled as alternatives along the enzyme axis. Both can operate in the same organism, in different compartments. variant_sets: - id: kinin_release_route label: Plasma versus tissue kallikrein route axis: enzyme and substrate route selection: ONE_OR_MORE notes: >- ONE_OR_MORE rather than EXACTLY_ONE: the plasma route operates in the intravascular compartment on high-molecular-weight kininogen and the tissue route in glandular tissue and their fluids on the low-molecular-weight form, and tissue kallikrein can also cleave the high form. A concrete realization may therefore have one or both. variants: - id: plasma_kallikrein_route label: Plasma kallikrein releasing bradykinin from high-molecular-weight kininogen module_type: REACTION description: >- Active plasma kallikrein cleaves high-molecular-weight kininogen in the intravascular compartment, liberating the nonapeptide bradykinin and leaving the disulfide-linked kinin-free heavy and light chains. annotons: - id: klkb1_hk_cleavage label: Plasma kallikrein cleavage of high-molecular-weight kininogen participant: selector_type: GENE_PRODUCT gene_product: preferred_term: KLKB1 term: id: UniProtKB:P03952 label: Plasma kallikrein function: preferred_term: serine-type endopeptidase activity term: id: GO:0004252 label: serine-type endopeptidase activity substrates: - preferred_term: high-molecular-weight kininogen term: id: UniProtKB:P01042 label: Kininogen-1 products: - preferred_term: bradykinin (kinin-9) term: id: CHEBI:3165 label: bradykinin processes: - preferred_term: plasma kallikrein-kinin cascade term: id: GO:0002353 label: plasma kallikrein-kinin cascade locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Product-forming step of the plasma route; the enzyme performs the cleavage, kininogen is its substrate. evidence: - source_id: PMID:104988 statement: >- Human plasma kallikrein liberates kinin from human high-molecular-weight kininogen. supporting_text: We investigated whether the liberation of kinin from human HMW-kininogen by human plasma kallikrein was accompanied by liberation of histidine-rich fragments - source_id: PMID:104988 statement: >- Bradykinin is isolated from the digest, with the histidine-rich sequence staying on the light chain of the kinin-free protein. supporting_text: Most of the histidine in human HMW-kininogen was recovered in the kinin-free protein, and the light chain of kinin-free protein was found to be rich in histidine compared with the heavy chain. - id: tissue_kallikrein_route label: Tissue kallikrein releasing kallidin from low-molecular-weight kininogen module_type: REACTION description: >- Tissue kallikrein, secreted by kidney, pancreas and salivary gland, cleaves low-molecular-weight kininogen at two sites, one of them the unusual Met-Lys bond, releasing the decapeptide kallidin (Lys-bradykinin). annotons: - id: klk1_lk_cleavage label: Tissue kallikrein cleavage of low-molecular-weight kininogen participant: selector_type: GENE_PRODUCT gene_product: preferred_term: KLK1 term: id: UniProtKB:P06870 label: Kallikrein-1 function: preferred_term: serine-type endopeptidase activity term: id: GO:0004252 label: serine-type endopeptidase activity substrates: - preferred_term: low-molecular-weight kininogen term: id: UniProtKB:P01042 label: Kininogen-1 products: - preferred_term: kallidin (Lys-bradykinin) term: id: CHEBI:6102 label: Kallidin processes: - preferred_term: tissue kallikrein-kinin cascade term: id: GO:0002255 label: tissue kallikrein-kinin cascade locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Product-forming step of the tissue route. Cleavage at site II (Met-Lys) is unique to tissue kallikrein and is what makes the product a decapeptide with an N-terminal lysine. evidence: - source_id: PMID:7749384 statement: >- Tissue kallikrein cleaves low-molecular-weight kininogen at two sites to release kallidin, one of them the TK-specific Met-Lys bond. supporting_text: Tissue kallikrein (TK) cleaves low molecular weight kininogen (LK) at two sites to release kallidin - source_id: PMID:7749384 statement: >- Site I is a trypsin-like Arg-Ser bond and site II the unusual Met-Lys bond unique to tissue kallikrein. supporting_text: site I (between Arg389 and Ser390) is a typical cleavage point for a trypsin-like enzyme whereas site II (between Met379 and Lys380) is unusual and unique to TK - source_id: PMID:2686621 statement: >- The salivary, pancreatic and renal tissue kallikreins are one protein, cloned and shown to be proteolytically active. supporting_text: The protein was identified by Western-blot analysis and by demonstration of its specific proteolytic activity. - order: 4 role: kinin receptor signaling node: id: kks_kinin_signaling label: Kinin signaling through the B2 and B1 bradykinin receptors module_type: SIGNALING_PATHWAY description: >- The released kinins act as short-lived local hormones. Bradykinin and kallidin are agonists of the constitutively expressed B2 receptor; the des-Arg metabolites made in part 5 are the agonists of the inducible B1 receptor. Both are G protein-coupled receptors that raise intracellular calcium and drive vasodilation and inflammatory mediator release. annotons: - id: kng1_kinin_hormone label: Kinin released from kininogen acting as a local hormone participant: selector_type: GENE_PRODUCT gene_product: preferred_term: KNG1 term: id: UniProtKB:P01042 label: Kininogen-1 function: preferred_term: hormone activity term: id: GO:0005179 label: hormone activity targets: - preferred_term: B2 bradykinin receptor term: id: UniProtKB:P30411 label: B2 bradykinin receptor processes: - preferred_term: vasodilation term: id: GO:0042311 label: vasodilation locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- The one step kininogen itself performs: its bradykinin moiety, once released, is the receptor agonist. Kininogen is the substrate of the kallikreins, not a participant in their proteolysis, so it carries no processing term here. evidence: - source_id: PMID:1314587 statement: >- Bradykinin binds the cloned human B2 receptor with sub-nanomolar affinity, the agonist activity annotated to KNG1 by IDA. supporting_text: Saturation binding analysis indicates that the human BK-2 receptor expressed in COS-7 cells binds BK with a KD of 0.13 nM. gocam_associations: - model: gomodel:6246724f00000632 activity: gomodel:6246724f00000632/6246724f00000645 title: KNG1 hormone activity (GO:0005179), part of GO:0042311 vasodilation - id: bdkrb2_signaling label: B2 bradykinin receptor signaling participant: selector_type: GENE_PRODUCT gene_product: preferred_term: BDKRB2 term: id: UniProtKB:P30411 label: B2 bradykinin receptor function: preferred_term: bradykinin receptor activity term: id: GO:0004947 label: bradykinin receptor activity processes: - preferred_term: G protein-coupled receptor signaling pathway term: id: GO:0007186 label: G protein-coupled receptor signaling pathway - preferred_term: vasodilation term: id: GO:0042311 label: vasodilation locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Constitutively expressed receptor for the intact kinins bradykinin and kallidin; couples to the calcium-phosphatidylinositol cascade. evidence: - source_id: PMID:1329734 statement: >- The cloned human B2 receptor is a high-affinity bradykinin receptor coupling to calcium and inositol phosphate signaling. supporting_text: Functional coupling to the Ca(2+)-phosphatidylinositol cascade was demonstrated in transfected CHO cells where inositol phosphates accumulation and intracellular calcium concentration were elevated in response to BK stimulation. - source_id: PMID:1314587 statement: >- The receptor is a seven-transmembrane G protein-coupled receptor of the B2 subtype. supporting_text: The cDNA clone encodes a 364 amino acid protein that has the characteristics of a seven transmembrane domain G-protein coupled receptor. - source_id: PMID:17077303 statement: >- ACE and the B2 receptor form a complex at the plasma membrane, placing the receptor and its kininase side by side at the cell surface. supporting_text: Human ACE and bradykinin B2 receptors form a complex at the plasma membrane. gocam_associations: - model: gomodel:6246724f00000632 activity: gomodel:6246724f00000632/6246724f00000659 title: BDKRB2 bradykinin receptor activity (GO:0004947), part of GO:0042311 vasodilation - id: bdkrb1_signaling label: B1 bradykinin receptor signaling participant: selector_type: GENE_PRODUCT gene_product: preferred_term: BDKRB1 term: id: UniProtKB:P46663 label: B1 bradykinin receptor function: preferred_term: bradykinin receptor activity term: id: GO:0004947 label: bradykinin receptor activity processes: - preferred_term: G protein-coupled receptor signaling pathway term: id: GO:0007186 label: G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Inducible receptor whose agonists are the des-Arg kinins produced in part 5; in human the dominant ligand is des-Arg10-kallidin. evidence: - source_id: PMID:10422787 statement: >- The cloned human B1 receptor is characterised with the des-Arg kinin ligand des-Arg10-kallidin. supporting_text: A ligand binding assay with [3H]des-Arg10-kallidin was used to compare their pharmacology with respect to known bradykinin B1 and B2 receptor ligands. - source_id: PMID:10422787 statement: >- Kallidin and its des-Arg derivatives are the major physiological B1 ligands in human, bradykinin-derived ones in rat. supporting_text: the presence of T-kinin, bradykinin and their des-Arg derivatives as the major physiological peptides in rat and the predominance of kallidin and its derivatives in human - order: 5 role: carboxy-terminal processing to des-Arg kinins node: id: kks_des_arg_generation label: Carboxypeptidase removal of the C-terminal arginine from kinins module_type: REACTION description: >- Two basic-residue carboxypeptidases remove the C-terminal arginine of bradykinin and kallidin: plasma carboxypeptidase N (kininase I) and the GPI-anchored carboxypeptidase M at cell surfaces. The products lose B2 agonism but are the agonists of the B1 receptor, so this step converts rather than only destroys the signal. annotons: - id: cpn1_des_arg label: Carboxypeptidase N (kininase I) removal of C-terminal Arg participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CPN1 term: id: UniProtKB:P15169 label: Carboxypeptidase N catalytic chain function: preferred_term: metallocarboxypeptidase activity term: id: GO:0004181 label: metallocarboxypeptidase activity substrates: - preferred_term: bradykinin term: id: CHEBI:3165 label: bradykinin processes: - preferred_term: protein processing term: id: GO:0016485 label: protein processing locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- The plasma kininase I activity; the catalytic small subunit is held in a 280 kDa complex with large subunits that stabilise it in plasma. evidence: - source_id: PMID:2912725 statement: >- Carboxypeptidase N, the plasma kininase 1, is a metalloprotease whose catalytic small subunits sit in a large plasma complex. supporting_text: The human plasma metallo-protease carboxypeptidase N of Mr 280,000 consists of two small, enzymatically active subunits of Mr 50,000 and two large subunits. - id: cpm_des_arg label: Carboxypeptidase M removal of C-terminal Arg at the cell surface participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CPM term: id: UniProtKB:P14384 label: Carboxypeptidase M function: preferred_term: metallocarboxypeptidase activity term: id: GO:0004181 label: metallocarboxypeptidase activity substrates: - preferred_term: bradykinin term: id: CHEBI:3165 label: bradykinin processes: - preferred_term: protein processing term: id: GO:0016485 label: protein processing locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Membrane-anchored kininase I-type enzyme; being on the plasma membrane at neutral pH, it can convert kinins immediately next to their receptors. evidence: - source_id: PMID:2914904 statement: >- Purified human carboxypeptidase M is a membrane-bound metallopeptidase that cleaves the C-terminal Arg or Lys of peptides including bradykinin. supporting_text: bradykinin (Km = 16 microM, kcat = 147 min-1) - source_id: PMID:2914904 statement: >- Its membrane localization and neutral pH optimum let it modulate peptide hormones at the receptor. supporting_text: Because of its localization on the plasma membrane and optimal activity at neutral pH, carboxypeptidase M could inactivate or modulate the activity of peptide hormones either before or after their interaction with plasma membrane receptors. - source_id: PMID:2394713 statement: >- The kininase I-type activity that inactivates bradykinin by releasing Arg9 in kidney cells is carboxypeptidase M. supporting_text: Cultured Madin-Darby canine kidney (MDCK) distal tubular cells contain a kininase I-type enzyme that inactivates bradykinin by releasing Arg9. We found the properties of this kininase to be identical with carboxypeptidase M. - order: 6 role: kinin inactivation by kininases node: id: kks_kinin_inactivation label: Destruction of kinin activity by kininases module_type: REACTION description: >- Cleavage of any peptide bond of bradykinin abolishes its B2 agonism, so several unrelated peptidases act in parallel as kininases: ACE (kininase II) removes C-terminal dipeptides, neprilysin cleaves internally, and membrane-bound aminopeptidase P (XPNPEP2) removes the N-terminal residue before the proline. Which one dominates depends on localization and access. annotons: - id: ace_kininase label: ACE (kininase II) degradation of bradykinin participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ACE term: id: UniProtKB:P12821 label: Angiotensin-converting enzyme function: preferred_term: peptidyl-dipeptidase activity term: id: GO:0008241 label: peptidyl-dipeptidase activity substrates: - preferred_term: bradykinin term: id: CHEBI:3165 label: bradykinin processes: - preferred_term: bradykinin catabolic process term: id: GO:0010815 label: bradykinin catabolic process locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- The classical kininase II. Both of its active sites hydrolyse bradykinin, and more efficiently than angiotensin I, which is why ACE inhibition raises kinin levels. evidence: - source_id: PMID:7683654 statement: >- Both ACE active sites convert bradykinin to BK1-7 and BK1-5, with higher efficiency than for angiotensin I. supporting_text: Both active sites converted bradykinin (BK) to BK1-7 and BK1-5 with similar kinetics and with Kappm at least 30 times lower and kcat/kappm 10 times higher than for AI. - source_id: PMID:1282629 statement: >- Angiotensin I-converting enzyme is one of the peptidases that degrade bradykinin. supporting_text: These include aminopeptidase P, meprin, endopeptidase 24.15, prolyl endopeptidase, neutral endopeptidase 24.11, angiotensin I-converting enzyme, carboxypeptidase N, carboxypeptidase M, and deamidase. gocam_associations: - model: gomodel:6246724f00000632 activity: gomodel:6246724f00000632/6246724f00000633 title: ACE peptidyl-dipeptidase activity (GO:0008241), part of GO:0010815 bradykinin catabolic process - id: mme_kininase label: Neprilysin cleavage of kinins participant: selector_type: GENE_PRODUCT gene_product: preferred_term: MME term: id: UniProtKB:P08473 label: Neprilysin function: preferred_term: metalloendopeptidase activity term: id: GO:0004222 label: metalloendopeptidase activity substrates: - preferred_term: bradykinin term: id: CHEBI:3165 label: bradykinin processes: - preferred_term: bradykinin catabolic process term: id: GO:0010815 label: bradykinin catabolic process locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Neutral endopeptidase 24.11; an internal cut is enough to abolish kinin activity, and neprilysin is one of the kininases targeted together with ACE by vasopeptidase inhibitors. evidence: - source_id: PMID:1282629 statement: >- Neutral endopeptidase 24.11 is among the bradykinin-degrading peptidases, and any peptide-bond cleavage inactivates the kinin. supporting_text: Because bradykinin is inactivated (for binding the B2 receptor) when any of its peptide bonds are cleaved, all of these enzymes qualify as potential "kininases" in vivo - id: xpnpep2_kininase label: Membrane-bound aminopeptidase P degradation of kinins participant: selector_type: GENE_PRODUCT gene_product: preferred_term: XPNPEP2 term: id: UniProtKB:O43895 label: Xaa-Pro aminopeptidase 2 function: preferred_term: aminopeptidase activity term: id: GO:0004177 label: aminopeptidase activity substrates: - preferred_term: bradykinin term: id: CHEBI:3165 label: bradykinin processes: - preferred_term: bradykinin catabolic process term: id: GO:0010815 label: bradykinin catabolic process locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- GPI-anchored vascular form of aminopeptidase P, whose natural substrates are the kinins; its activity is the clinical correlate of ACE-inhibitor-associated angioedema risk. evidence: - source_id: PMID:15361070 statement: >- Aminopeptidase P cleaves the N-terminal residue of peptides with proline at P1', and the kinins are its natural substrates. supporting_text: APP (aminopeptidase P) has the unique ability to cleave the N-terminal amino acid residue from peptides exhibiting a proline at P(1)'. - source_id: PMID:15361070 statement: >- The engineered soluble form of the human membrane-bound enzyme is fully functional and its substrates are the kinins. supporting_text: we synthesized three internally quenched fluorescent peptide substrates that exhibit a similar affinity for the enzyme than its natural substrates, the kinins - order: 7 role: inhibition of the cascade proteases node: id: kks_protease_inhibition label: Serpin and alpha-2-macroglobulin control of the kallikreins and factor XIIa module_type: REGULATORY_STEP description: >- The cascade is held off by inhibitors of its proteases rather than of its peptides. C1 inhibitor is the principal regulator of factor XIIa and plasma kallikrein, alpha-2-macroglobulin traps kallikrein by conformational capture, and kallistatin inhibits tissue kallikrein. annotons: - id: serping1_inhibition label: C1 inhibitor inhibition of factor XIIa and plasma kallikrein participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SERPING1 term: id: UniProtKB:P05155 label: Plasma protease C1 inhibitor function: preferred_term: serine-type endopeptidase inhibitor activity term: id: GO:0004867 label: serine-type endopeptidase inhibitor activity targets: - preferred_term: plasma kallikrein term: id: UniProtKB:P03952 label: Plasma kallikrein - preferred_term: factor XIIa term: id: UniProtKB:P00748 label: Coagulation factor XII processes: - preferred_term: negative regulation of endopeptidase activity term: id: GO:0010951 label: negative regulation of endopeptidase activity locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- The principal plasma regulator of contact activation; its deficiency causes hereditary angioedema, a bradykinin-mediated disease, which is the clinical demonstration that this is the module's main brake. evidence: - source_id: PMID:7692967 statement: >- C1 inhibitor and alpha-2-macroglobulin are kallikrein's primary plasma inhibitors, with second-order rate constants of 1.7e4 and 3.4e4 M-1 s-1. supporting_text: nor did the protein enhance the rate constants of 1.7 x 10(4) and 3.4 x 10(4) M-1 s-1 for kallikrein reactions with its primary plasma inhibitors C1-inhibitor and alpha 2-macroglobulin, respectively - source_id: PMID:7692967 statement: >- In plasma, kallikrein is partitioned predominantly into C1-inhibitor and alpha-2-macroglobulin complexes. supporting_text: significantly altered the partitioning of radiolabeled kallikrein from predominantly C1-inhibitor and alpha 2-macroglobulin complexes (86-92%) to mostly antithrombin complexes (50-53%) - id: a2m_inhibition label: Alpha-2-macroglobulin trapping of plasma kallikrein participant: selector_type: GENE_PRODUCT gene_product: preferred_term: A2M term: id: UniProtKB:P01023 label: Alpha-2-macroglobulin function: preferred_term: endopeptidase inhibitor activity term: id: GO:0004866 label: endopeptidase inhibitor activity targets: - preferred_term: plasma kallikrein term: id: UniProtKB:P03952 label: Plasma kallikrein processes: - preferred_term: negative regulation of endopeptidase activity term: id: GO:0010951 label: negative regulation of endopeptidase activity locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Broad-spectrum trap rather than a serpin: bait-region cleavage collapses the tetramer around the protease. Together with C1 inhibitor it accounts for most kallikrein inhibitory capacity of plasma. This matches the core function of its gene review (genes/human/A2M/). evidence: - source_id: PMID:7692967 statement: >- Alpha-2-macroglobulin is one of kallikrein's two primary plasma inhibitors. supporting_text: its primary plasma inhibitors C1-inhibitor and alpha 2-macroglobulin - source_id: PMID:7692967 statement: >- In plasma most kallikrein ends up trapped in C1-inhibitor and alpha-2-macroglobulin complexes. supporting_text: predominantly C1-inhibitor and alpha 2-macroglobulin complexes (86-92%) - id: serpina4_inhibition label: Kallistatin inhibition of tissue kallikrein participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SERPINA4 term: id: UniProtKB:P29622 label: Kallistatin function: preferred_term: serine-type endopeptidase inhibitor activity term: id: GO:0004867 label: serine-type endopeptidase inhibitor activity targets: - preferred_term: tissue kallikrein (KLK1) term: id: UniProtKB:P06870 label: Kallikrein-1 processes: - preferred_term: negative regulation of endopeptidase activity term: id: GO:0010951 label: negative regulation of endopeptidase activity locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- The serpin specific to the tissue route: it forms an equimolar complex with tissue kallikrein and blocks its action on kininogen; heparin abolishes the inhibition. evidence: - source_id: PMID:1334488 statement: >- Kallistatin inhibits human tissue kallikrein acting on kininogen, in an equimolar serpin complex. supporting_text: Kallistatin inhibits human tissue kallikrein's activity toward kininogen and tripeptide substrates. - source_id: PMID:1334488 statement: Heparin blocks kallistatin's inhibition of tissue kallikrein. supporting_text: Heparin blocks kallistatin's complex formation with tissue kallikrein and abolishes its inhibitory effect on tissue kallikrein's activity. connections: - source: kks_contact_activation target: kks_prekallikrein_activation connection_type: PROVIDES_INPUT_FOR description: >- Surface-bound factor XIIa is the protease that cleaves prekallikrein to kallikrein. - source: kks_prekallikrein_activation target: kks_contact_activation connection_type: POSITIVELY_REGULATES description: >- Reciprocal feedback: formed kallikrein activates further factor XII far faster than the surface alone, amplifying the contact phase (PMID:273926, PMID:386794). - source: kks_prekallikrein_activation target: kks_kinin_release connection_type: PROVIDES_INPUT_FOR description: >- Active plasma kallikrein is the enzyme of the plasma route of kinin release. The tissue route does not depend on this step. - source: kks_kinin_release target: kks_kinin_signaling connection_type: PROVIDES_INPUT_FOR description: >- Released bradykinin and kallidin are the agonists of the B2 receptor. - source: kks_kinin_release target: kks_des_arg_generation connection_type: PROVIDES_INPUT_FOR description: >- The intact kinins are the substrates of carboxypeptidases N and M. - source: kks_des_arg_generation target: kks_kinin_signaling connection_type: PROVIDES_INPUT_FOR description: >- The des-Arg kinins are the agonists of the inducible B1 receptor, so this step switches the signal from B2 to B1 rather than only terminating it. - source: kks_kinin_inactivation target: kks_kinin_signaling connection_type: NEGATIVELY_REGULATES description: >- ACE, neprilysin and aminopeptidase P destroy kinin activity; ACE sits in a complex with the B2 receptor itself (PMID:17077303). - source: kks_protease_inhibition target: kks_prekallikrein_activation connection_type: NEGATIVELY_REGULATES description: >- C1 inhibitor and alpha-2-macroglobulin inactivate kallikrein and factor XIIa, shutting down the plasma route. - source: kks_protease_inhibition target: kks_kinin_release connection_type: NEGATIVELY_REGULATES description: >- Kallistatin blocks tissue kallikrein's action on kininogen, and C1 inhibitor and A2M block plasma kallikrein's. knowledge_gaps: - gap_statement: >- Which kininase actually terminates a kinin signal at a given site in vivo is not established. ACE, neprilysin, carboxypeptidases N and M and both aminopeptidases P can all cleave bradykinin in vitro, and the outcome depends on local concentration, membrane localization and competition between them, which no current measurement resolves in intact tissue. gap_kind: - BIOLOGY status: OPEN significance: >- It determines which peptidase inhibitors raise kinin levels where, and so which drugs carry bradykinin-mediated angioedema risk. provenance: - reference_id: PMID:1282629 supporting_text: Determination of the importance of a peptidase in the inactivation of bradykinin during a particular physiological response can be difficult - gap_statement: >- What physiologically initiates factor XII activation is unresolved. Anionic surfaces activate it in vitro but factor XII is dispensable for haemostasis, and although misfolded protein aggregates activate it selectively towards the kinin arm, the endogenous activating structures and the conditions under which they form in healthy tissue are unknown. gap_kind: - BIOLOGY status: OPEN significance: >- The trigger determines whether the plasma route is normally quiescent and only engaged in disease, or continuously generating kinins at low level. provenance: - reference_id: PMID:18725990 supporting_text: the physiological role of the contact system remains elusive - gap_statement: >- The relative contribution of prolylcarboxypeptidase and factor XIIa to prekallikrein activation in vivo is unknown. PRCP activates kininogen-bound prekallikrein on endothelial cells independently of factor XII, but whether this is the dominant route in an intact vessel, and how it is regulated, has not been measured. gap_kind: - BIOLOGY status: OPEN significance: >- A constitutive endothelial route would make kinin generation a continuous local vascular function rather than an injury response. provenance: - reference_id: PMID:12489798 supporting_text: Understanding the importance and physiologic activity of the plasma kallikrein/kinin system (KKS) has been thwarted by the absence of an inclusive theory for its assembly and activation.