Kininogen

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Kininogens are precursor proteins for kinins, biologically active polypeptides involved in blood coagulation, vasodilation, smooth muscle contraction, inflammatory regulation, and the regulation of the cardiovascular and renal systems.

Contents

Types of kininogen

There are two main types of kininogen (KNG), high-molecular-weight-kininogen and low-molecular-weight-kininogen, with a third type – T-kininogen – only found in rats but not humans.

High molecular weight kininogen

High-molecular-weight-kininogen (HK) is a non-enzymatic cofactor involved in the kinin-kallikrein system, which plays a role in blood coagulation, blood pressure regulation, and inflammation. It is synthesized in endothelial cells and is produced mostly by the liver. It is also a precursor protein for bradykinin.

Protein structure of bradykinin. Bradykinin is a nine amino acid-long polypeptide made by the cleavage of high-molecular-weight kininogen at D4. It acts as an inflammatory mediator. Bradykinin Picture.png
Protein structure of bradykinin. Bradykinin is a nine amino acid-long polypeptide made by the cleavage of high-molecular-weight kininogen at D4. It acts as an inflammatory mediator.

Low molecular weight kininogen

Low-molecular-weight-kininogen (LK) is mainly a precursor protein for kallidin. LK, however, is not actively involved in blood coagulation, but its byproducts can be later converted and introduced to the coagulation pathway.

T-kininogen

T-kininogen (TK) is only found in rats and a protein whose function is still being researched. TK is believed to be a biological indicator of senescence in rats, [1] which can be measured by the level of endothelial cell production during the aging process. [2]

Structure

HK consists of 644 amino acid residues, which are separated into six different domains. [3] Domains 1, 2, and 3 are called the “heavy chain” with Domains 2 and 3 having cysteine protease activity. [4] Domains 5 and 6 are called the “light chain,” both of which bind specific molecules: Domain 5 binds heparin and zinc and selectively binds to anionic surfaces while Domain 6 binds prekallikrein, the protease precursor to plasma kallikrein. [5] Domain 4 connects the heavy chain and light chain together, and its cleavage at this site releases bradykinin. [6]

LK consists of 427 amino acid residues, which can also be separated into a “heavy chain” and a “light chain." [7]

T-kininogen consists of 430 amino acid residues. [8]

HK and LK are created by the alternative splicing of the same kininogen (KNG) gene, which in humans, is located at chromosome 3q27. [9] Kininogens are related to cystatins through their similar glycosylated regions. [10]

Function

High-molecular weight kininogen

During the contact activation system (CAS), also known as the intrinsic pathway, the binding of HK, factor XII (FXII), and prekallikrein (PK) to an anionic surface initiates blood coagulation and the kinin-kallikrein system through the activation of a cascade of enzymes. [11] Factor XII is a zymogen, and upon binding with tissue to the anionic surface, exhibits some protease activity, starting the enzymatic cascade. [12] Both the intrinsic and its corresponding extrinsic pathway, which is activated when outside trauma activates tissue factor (TF), an important glycoprotein, culminate in the activation of a serine protease called Factor X. Factor X is responsible for the conversion of prothrombin into an important protease in clotting called thrombin, which itself participates in the clotting cascade by activating more enzymes and proteins downstream in order to create even more thrombin.

In the kinin-kallikrein system, the proteolytic cleavage of HK by the enzyme plasma kallikrein makes bradykinin, an inflammatory mediator that can lower blood pressure by way of vasodilation. The kinin-kallikrein system plays a small role in coagulation.

Blood clotting cascade. The blood clotting cascade consists of the intrinsic and extrinsic pathway, both of which create thrombin, a protease involved in blood clotting. The intrinsic pathway requires kininogen, specifically high molecular weight kininogen, as a cofactor. Blood Clotting Cascade.png
Blood clotting cascade. The blood clotting cascade consists of the intrinsic and extrinsic pathway, both of which create thrombin, a protease involved in blood clotting. The intrinsic pathway requires kininogen, specifically high molecular weight kininogen, as a cofactor.

HK and LK are noncompetitive inhibitors of activated thrombin. [13]

Low-molecular weight kininogen

The proteolytical cleavage of LK by tissue kallikreins creates kallidin, which is a possible substrate for carboxypeptidase M. [14] Kallidin can be converted into bradykinin by Aminopeptidase B, [15] creating a connection between LK and the kinin-kallikrein system.

T-kininogen

Research has shown that T-kininogen is a possible biomarker for senescence within rats. [1]

Disease and medical relevance

Increased levels of kininogen in the plasma and tissues are associated with injury, inflammation, myocardial infarction, and diabetes. [3] Additionally, kininogen's role in the contact activation system means that increased levels of kininogen can also contribute to the development of hereditary angioedema, [16] a disorder characterized by periodic episodes of swelling.

KNG is believed to play a role in the formation of thrombi, or blood clots that obstruct a vessel, and in inflammation. The inhibition of KNG is potentially a selective strategy to fight stroke, deep vein thrombosis (DVT), [17] and other venous thromboembolic diseases. Kininogen-1 has also been found to be an effective biomarker in detecting certain types of cancer, namely colorectal cancer. [18]

Bradykinin, the cleavage product of high molecular weight kininogen, is implicated by a class of drugs called angiotensin converting enzyme inhibitors (ACE inhibitors) that aim to increase bradykinin levels by impeding its degradation. [19]

Related Research Articles

<span class="mw-page-title-main">Coagulation</span> Process by which blood changes from liquid into a gel, forming blood clots

Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.

<span class="mw-page-title-main">Thrombin</span> Enzyme involved in blood coagulation in humans

Thrombin is a serine protease, an enzyme that, in humans, is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the clotting process. Thrombin in turn acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions.

<span class="mw-page-title-main">Antithrombin</span> Mammalian protein found in Homo sapiens

Antithrombin (AT) is a small glycoprotein that inactivates several enzymes of the coagulation system. It is a 432-amino-acid protein produced by the liver. It contains three disulfide bonds and a total of four possible glycosylation sites. α-Antithrombin is the dominant form of antithrombin found in blood plasma and has an oligosaccharide occupying each of its four glycosylation sites. A single glycosylation site remains consistently un-occupied in the minor form of antithrombin, β-antithrombin. Its activity is increased manyfold by the anticoagulant drug heparin, which enhances the binding of antithrombin to factor IIa (prothrombin) and factor Xa.

<span class="mw-page-title-main">Bradykinin</span> Chemical compound

Bradykinin (BK) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and makes veins constrict, via prostaglandin F2, thereby leading to leakage into capillary beds, due to the increased pressure in the capillaries. Bradykinin is a physiologically and pharmacologically active peptide of the kinin group of proteins, consisting of nine amino acids.

<span class="mw-page-title-main">Factor XII</span> Mammalian protein involved in blood clotting

Coagulation factor XII, also known as Hageman factor, is a plasma protein. It is the zymogen form of factor XIIa, an enzyme of the serine protease class. In humans, factor XII is encoded by the F12 gene.

High-molecular-weight kininogen is a circulating plasma protein which participates in the initiation of blood coagulation, and in the generation of the vasodilator bradykinin via the kallikrein-kinin system. HMWK is inactive until it either adheres to binding proteins beneath an endothelium disrupted by injury, thereby initiating coagulation; or it binds to intact endothelial cells or platelets for functions other than coagulation.

The kinin–kallikrein system or simply kinin system is a poorly understood hormonal system with limited available research. It consists of blood proteins that play a role in inflammation, blood pressure control, coagulation and pain. Its important mediators bradykinin and kallidin are vasodilators and act on many cell types. Clinical symptoms include marked weakness, tachycardia, fever, leukocytosis and acceleration of ESR.

<span class="mw-page-title-main">Factor XI</span> Mammalian protein found in Homo sapiens

Factor XI or plasma thromboplastin antecedent is the zymogen form of factor XIa, one of the enzymes of the coagulation cascade. Like many other coagulation factors, it is a serine protease. In humans, Factor XI is encoded by the F11 gene.

The prothrombinase complex consists of the serine protease, Factor Xa, and the protein cofactor, Factor Va. The complex assembles on negatively charged phospholipid membranes in the presence of calcium ions. The prothrombinase complex catalyzes the conversion of prothrombin (Factor II), an inactive zymogen, to thrombin (Factor IIa), an active serine protease. The activation of thrombin is a critical reaction in the coagulation cascade, which functions to regulate hemostasis in the body. To produce thrombin, the prothrombinase complex cleaves two peptide bonds in prothrombin, one after Arg271 and the other after Arg320. Although it has been shown that Factor Xa can activate prothrombin when unassociated with the prothrombinase complex, the rate of thrombin formation is severely decreased under such circumstances. The prothrombinase complex can catalyze the activation of prothrombin at a rate 3 x 105-fold faster than can Factor Xa alone. Thus, the prothrombinase complex is required for the efficient production of activated thrombin and also for adequate hemostasis.

A kinin is any of various structurally related polypeptides, such as bradykinin and kallidin. They are members of the autacoid family. Kinins are peptides that are cleaved from kininogens by the process of kallikreins. Kallikreins activate kinins when stimulated.

Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein has no known paralogue, while tissue kallikrein-related peptidases (KLKs) encode a family of fifteen closely related serine proteases. These genes are localised to chromosome 19q13, forming the largest contiguous cluster of proteases within the human genome. Kallikreins are responsible for the coordination of various physiological functions including blood pressure, semen liquefaction and skin desquamation.

Prekallikrein (PK), also known as Fletcher factor, is an 85,000 Mr serine protease that complexes with high-molecular-weight kininogen. PK is the precursor of plasma kallikrein, which is a serine protease that activates kinins. PK is cleaved to produce kallikrein by activated Factor XII.

<span class="mw-page-title-main">Kallidin</span> Chemical compound

Kallidin is a bioactive kinin formed in response to injury from kininogen precursors through the action of kallikreins.

Tissue kallikrein is an enzyme. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Protein C inhibitor</span>

Protein C inhibitor is a serine protease inhibitor (serpin) that limits the activity of protein C.

<span class="mw-page-title-main">KLKB1</span> Protein-coding gene in the species Homo sapiens

KLKB1 is a gene that, in humans, encodes the Plasma kallikrein protein.

<span class="mw-page-title-main">Kininogen 1</span>

Kininogen-1 (KNG1), also known as alpha-2-thiol proteinase inhibitor, Williams-Fitzgerald-Flaujeac factor or the HMWK-kallikrein factor is a protein that in humans is encoded by the KNG1 gene. Kininogen-1 is the precursor protein to high-molecular-weight kininogen (HMWK), low-molecular-weight kininogen (LMWK), and bradykinin.

Ecallantide is a drug used for the treatment of hereditary angioedema (HAE) and in the prevention of blood loss in cardiothoracic surgery. It is an inhibitor of the protein kallikrein and a 60-amino acid polypeptide which was developed from a Kunitz domain through phage display to mimic antibodies inhibiting kallikrein.

<span class="mw-page-title-main">Glutamyl endopeptidase GluV8</span>

Glutamyl endopeptidase is an extracellular bacterial serine protease of the glutamyl endopeptidase I family that was initially isolated from the Staphylococcus aureus strain V8. The protease is, hence, commonly referred to as "V8 protease", or alternatively SspA from its corresponding gene.

<span class="mw-page-title-main">Contact activation system</span>

In the contact activation system or CAS, three proteins in the blood, factor XII (FXII), prekallikrein (PK) and high molecular weight kininogen (HK), bind to a surface and cause blood coagulation and inflammation. FXII and PK are proteases and HK is a non-enzymatic co-factor. The CAS can activate the kinin–kallikrein system and blood coagulation through its ability to activate multiple downstream proteins. The CAS is initiated when FXII binds to a surface and reciprocal activation of FXII and PK occurs, forming FXIIa and PKa. FXIIa can initiate the coagulation cascade by cleaving and activating factor XI (FXI), which leads to formation of a blood clot. Additionally, the CAS can activate the kinin–kallikrein system when PKa cleaves HK to form cHK, releasing a peptide known as bradykinin (BK). BK and its derivatives bind to bradykinin receptors B1 and B2 to mediate inflammation.

References

  1. 1 2 Walter, Robin; Murasko, Donna M.; Sierra, Felipe (1998). "T-Kininogen is a biomarker of senescence in rats". Mechanisms of Ageing and Development. 106 (1–2): 129–144. doi:10.1016/S0047-6374(98)00107-9. PMID   9883978. S2CID   8850085.
  2. ↑ Pérez, Viviana; Leiva-Salcedo, Elías; Acuña-Castillo, Claudio; Aravena, Mauricio; Gómez, Christian; Sabaj, Valeria; Colombo, Alicia; Nishimura, Sumiyo; Pérez, Claudio; Walter, Robin (March 2006). "T-kininogen induces endothelial cell proliferation". Mechanisms of Ageing and Development. 127 (3): 282–289. doi:10.1016/j.mad.2005.11.002. hdl: 10533/177941 . PMID   16378635. S2CID   22878426.
  3. 1 2 Wong, M. K. S. (2016). Handbook of Hormones. Elsevier. doi:10.1016/c2013-0-15395-0. ISBN   978-0-12-801028-0.
  4. ↑ Weisel, J. W.; Nagaswami, C.; Woodhead, J. L.; DeLa Cadena, R. A.; Page, J. D.; Colman, R. W. (1994-04-01). "The shape of high molecular weight kininogen. Organization into structural domains, changes with activation, and interactions with prekallikrein, as determined by electron microscopy". The Journal of Biological Chemistry. 269 (13): 10100–10106. doi: 10.1016/S0021-9258(17)36995-8 . ISSN   0021-9258. PMID   8144509.
  5. ↑ Colman, Robert W. (2001-01-06). "Role of the Light Chain of High Molecular Weight Kininogen in Adhesion, Cell-Associated Proteolysis and Angiogenesis". Biological Chemistry. 382 (1): 65–70. doi:10.1515/BC.2001.011. ISSN   1431-6730. PMID   11258675. S2CID   28382339.
  6. ↑ Damasceno, Igor Z.; Melo, Katia R. B.; Nascimento, Fabio D.; Souza, Daianne S. P.; Araujo, Mariana S.; Souza, Sinval E. G.; Sampaio, Misako U.; Nader, Helena B.; Tersariol, Ivarne L. S.; Motta, Guacyara (2015-03-30). Sands, Jeff M (ed.). "Bradykinin Release Avoids High Molecular Weight Kininogen Endocytosis". PLOS ONE. 10 (3): e0121721. Bibcode:2015PLoSO..1021721D. doi: 10.1371/journal.pone.0121721 . ISSN   1932-6203. PMC   4379145 . PMID   25822177.
  7. ↑ Takagaki, Y.; Kitamura, N.; Nakanishi, S. (1985-07-15). "Cloning and sequence analysis of cDNAs for human high molecular weight and low molecular weight prekininogens. Primary structures of two human prekininogens". The Journal of Biological Chemistry. 260 (14): 8601–8609. doi: 10.1016/S0021-9258(17)39515-7 . ISSN   0021-9258. PMID   2989293.
  8. ↑ Furuto-Kato, S.; Matsumoto, A.; Kitamura, N.; Nakanishi, S. (1985-10-05). "Primary structures of the mRNAs encoding the rat precursors for bradykinin and T-kinin. Structural relationship of kininogens with major acute phase protein and alpha 1-cysteine proteinase inhibitor". The Journal of Biological Chemistry. 260 (22): 12054–12059. doi: 10.1016/S0021-9258(17)38984-6 . ISSN   0021-9258. PMID   2413018.
  9. ↑ Veloso, D. (July 1998). "Evidence for the presence of a kininogen-like species in a case of total deficiency of low and high molecular weight kininogens". Brazilian Journal of Medical and Biological Research. 31 (7): 901–910. doi: 10.1590/S0100-879X1998000700004 . ISSN   0100-879X. PMID   9698753.
  10. ↑ Lalmanach, Gilles; Naudin, Clément; Lecaille, Fabien; Fritz, Hans (November 2010). "Kininogens: More than cysteine protease inhibitors and kinin precursors". Biochimie. 92 (11): 1568–1579. doi:10.1016/j.biochi.2010.03.011. PMID   20346387.
  11. ↑ Schmaier, A. H. (January 2016). "The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities". Journal of Thrombosis and Haemostasis. 14 (1): 28–39. doi: 10.1111/jth.13194 . PMID   26565070.
  12. ↑ Naudin, Clément; Burillo, Elena; Blankenberg, Stefan; Butler, Lynn; Renné, Thomas (November 2017). "Factor XII Contact Activation". Seminars in Thrombosis and Hemostasis. 43 (8): 814–826. doi:10.1055/s-0036-1598003. ISSN   0094-6176. PMID   28346966.
  13. ↑ Meloni, F. J.; Schmaier, A. H. (1991-04-15). "Low molecular weight kininogen binds to platelets to modulate thrombin-induced platelet activation". The Journal of Biological Chemistry. 266 (11): 6786–6794. doi: 10.1016/S0021-9258(20)89569-6 . ISSN   0021-9258. PMID   2016293.
  14. ↑ Zhang, Xianming; Tan, Fulong; Zhang, Yongkang; Skidgel, Randal A. (2008-03-21). "Carboxypeptidase M and Kinin B1 Receptors Interact to Facilitate Efficient B1 Signaling from B2 Agonists". Journal of Biological Chemistry. 283 (12): 7994–8004. doi: 10.1074/jbc.M709837200 . ISSN   0021-9258. PMID   18187413.
  15. ↑ Hopsu-Havu, V. K.; Mäkinen, K. K.; Glenner, G. G. (1966). "Formation of Bradykinin from Kallidin-10 by Aminopeptidase B". Nature. 212 (5067): 1271–1272. Bibcode:1966Natur.212.1271H. doi:10.1038/2121271a0. PMID   21090475. S2CID   4161553.
  16. ↑ Moreno, Adriana; Nunes, Fernanda L.; Januario, Yunan C.; Maia, Luana S.M.; Ferriani, Mariana P.L.; Dias, Marina M.; Aragon, Davi C.; Suffritti, Chiara; Cicardi, Marco; da Silva, Luis L.P.; Arruda, Luisa Karla P. (February 2019). "Cleaved High Molecular Weight Kininogen Correlates With Hereditary Angioedema Due To C1-Inhibitor Deficiency". Journal of Allergy and Clinical Immunology. 143 (2): AB42. doi: 10.1016/j.jaci.2018.12.127 .
  17. ↑ Langhauser, Friederike; Göb, Eva; Kraft, Peter; Geis, Christian; Schmitt, Joachim; Brede, Marc; Göbel, Kerstin; Helluy, Xavier; Pham, Mirko; Bendszus, Martin; Jakob, Peter (2012-11-08). "Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation". Blood. 120 (19): 4082–4092. doi:10.1182/blood-2012-06-440057. ISSN   0006-4971. PMC   3543983 . PMID   22936662.
  18. ↑ Wang, Jing; Wang, Xinying; Lin, Shiyong; Chen, Chudi; Wang, Congrong; Ma, Qunying; Jiang, Bo (2013-07-23). Kano, Mitsunobu R. (ed.). "Identification of Kininogen-1 as a Serum Biomarker for the Early Detection of Advanced Colorectal Adenoma and Colorectal Cancer". PLOS ONE. 8 (7): e70519. Bibcode:2013PLoSO...870519W. doi: 10.1371/journal.pone.0070519 . ISSN   1932-6203. PMC   3720899 . PMID   23894665.
  19. ↑ Taddei, Stefano; Bortolotto, L. (October 2016). "Unraveling the Pivotal Role of Bradykinin in ACE Inhibitor Activity". American Journal of Cardiovascular Drugs. 16 (5): 309–321. doi:10.1007/s40256-016-0173-4. ISSN   1175-3277. PMID   27260014. S2CID   25709248.
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