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.

Types of kininogen[edit]

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[edit]

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.

Low molecular weight kininogen[edit]

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[edit]

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[edit]

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[edit]

High-molecular weight kininogen[edit]

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.

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

Low-molecular weight kininogen[edit]

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[edit]

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

Disease and medical relevance[edit]

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]

References[edit]

  1. ^ a b 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. ^ a b 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. S2CID 22844127.
  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.

External links[edit]

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