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 (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.

File:Bradykinin Picture.png

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 (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,{{Cite journal |doi = 10.1016/S0047-6374(98)00107-9|title = T-Kininogen is a biomarker of senescence in rats|year = 1998|last1 = Walter|first1 = Robin|last2 = Murasko|first2 = Donna M.|last3 = Sierra|first3 = Felipe|journal = Mechanisms of Ageing and Development|volume = 106|issue = 1–2|pages = 129–144|pmid = 9883978|s2cid = 8850085}} which can be measured by the level of endothelial cell production during the aging process.{{Cite journal|last1=Pérez|first1=Viviana|last2=Leiva-Salcedo|first2=Elías|last3=Acuña-Castillo|first3=Claudio|last4=Aravena|first4=Mauricio|last5=Gómez|first5=Christian|last6=Sabaj|first6=Valeria|last7=Colombo|first7=Alicia|last8=Nishimura|first8=Sumiyo|last9=Pérez|first9=Claudio|last10=Walter|first10=Robin|date=March 2006|title=T-kininogen induces endothelial cell proliferation|journal=Mechanisms of Ageing and Development|language=en|volume=127|issue=3|pages=282–289|doi=10.1016/j.mad.2005.11.002|pmid=16378635|hdl=10533/177941|s2cid=22878426|hdl-access=free}}

HK consists of 644 amino acid residues, which are separated into six different domains.{{Cite book|last=Wong|first=M. K. S.|url=https://linkinghub.elsevier.com/retrieve/pii/C20130153950|title=Handbook of Hormones|date=2016|publisher=Elsevier|isbn=978-0-12-801028-0|language=en|doi=10.1016/c2013-0-15395-0}} Domains 1, 2, and 3 are called the “heavy chain” with Domains 2 and 3 having cysteine protease activity.{{Cite journal|last1=Weisel|first1=J. W.|last2=Nagaswami|first2=C.|last3=Woodhead|first3=J. L.|last4=DeLa Cadena|first4=R. A.|last5=Page|first5=J. D.|last6=Colman|first6=R. W.|date=1994-04-01|title=The shape of high molecular weight kininogen. Organization into structural domains, changes with activation, and interactions with prekallikrein, as determined by electron microscopy|journal=The Journal of Biological Chemistry|volume=269|issue=13|pages=10100–10106|doi=10.1016/S0021-9258(17)36995-8|issn=0021-9258|pmid=8144509|doi-access=free}} 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.{{Cite journal|last=Colman|first=Robert W.|date=2001-01-06|title=Role of the Light Chain of High Molecular Weight Kininogen in Adhesion, Cell-Associated Proteolysis and Angiogenesis|journal=Biological Chemistry|volume=382|issue=1|pages=65–70|doi=10.1515/BC.2001.011|pmid=11258675|s2cid=28382339|issn=1431-6730}} Domain 4 connects the heavy chain and light chain together, and its cleavage at this site releases bradykinin.{{Cite journal|last1=Damasceno|first1=Igor Z.|last2=Melo|first2=Katia R. B.|last3=Nascimento|first3=Fabio D.|last4=Souza|first4=Daianne S. P.|last5=Araujo|first5=Mariana S.|last6=Souza|first6=Sinval E. G.|last7=Sampaio|first7=Misako U.|last8=Nader|first8=Helena B.|last9=Tersariol|first9=Ivarne L. S.|last10=Motta|first10=Guacyara|date=2015-03-30|editor-last=Sands|editor-first=Jeff M|title=Bradykinin Release Avoids High Molecular Weight Kininogen Endocytosis|journal=PLOS ONE|language=en|volume=10|issue=3|pages=e0121721|doi=10.1371/journal.pone.0121721|issn=1932-6203|pmc=4379145|pmid=25822177|bibcode=2015PLoSO..1021721D|doi-access=free}}

LK consists of 427 amino acid residues, which can also be separated into a “heavy chain” and a “light chain."{{Cite journal|last1=Takagaki|first1=Y.|last2=Kitamura|first2=N.|last3=Nakanishi|first3=S.|date=1985-07-15|title=Cloning and sequence analysis of cDNAs for human high molecular weight and low molecular weight prekininogens. Primary structures of two human prekininogens|journal=The Journal of Biological Chemistry|volume=260|issue=14|pages=8601–8609|doi=10.1016/S0021-9258(17)39515-7|issn=0021-9258|pmid=2989293|doi-access=free}}

T-kininogen consists of 430 amino acid residues.{{Cite journal|last1=Furuto-Kato|first1=S.|last2=Matsumoto|first2=A.|last3=Kitamura|first3=N.|last4=Nakanishi|first4=S.|date=1985-10-05|title=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|journal=The Journal of Biological Chemistry|volume=260|issue=22|pages=12054–12059|doi=10.1016/S0021-9258(17)38984-6|issn=0021-9258|pmid=2413018|doi-access=free}}

HK and LK are created by the alternative splicing of the same kininogen (KNG) gene, which in humans, is located at chromosome 3q27.{{Cite journal|last=Veloso|first=D.|date=July 1998|title=Evidence for the presence of a kininogen-like species in a case of total deficiency of low and high molecular weight kininogens|journal=Brazilian Journal of Medical and Biological Research|volume=31|issue=7|pages=901–910|doi=10.1590/S0100-879X1998000700004|pmid=9698753|issn=0100-879X|doi-access=free}} Kininogens are related to cystatins through their similar glycosylated regions.{{Cite journal|last1=Lalmanach|first1=Gilles|last2=Naudin|first2=Clément|last3=Lecaille|first3=Fabien|last4=Fritz|first4=Hans|date=November 2010|title=Kininogens: More than cysteine protease inhibitors and kinin precursors|journal=Biochimie|language=en|volume=92|issue=11|pages=1568–1579|doi=10.1016/j.biochi.2010.03.011|pmid=20346387}}

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.{{Cite journal|last=Schmaier|first=A. H.|date=January 2016|title=The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities|journal=Journal of Thrombosis and Haemostasis|language=en|volume=14|issue=1|pages=28–39|doi=10.1111/jth.13194|pmid=26565070|doi-access=free}} Factor XII is a zymogen, and upon binding with tissue to the anionic surface, exhibits some protease activity, starting the enzymatic cascade.{{Cite journal|last1=Naudin|first1=Clément|last2=Burillo|first2=Elena|last3=Blankenberg|first3=Stefan|last4=Butler|first4=Lynn|last5=Renné|first5=Thomas|date=November 2017|title=Factor XII Contact Activation|journal=Seminars in Thrombosis and Hemostasis|language=en|volume=43|issue=8|pages=814–826|doi=10.1055/s-0036-1598003|pmid=28346966|s2cid=22844127 |issn=0094-6176}} 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.

File:Blood Clotting Cascade.png

HK and LK are noncompetitive inhibitors of activated thrombin.{{Cite journal|last1=Meloni|first1=F. J.|last2=Schmaier|first2=A. H.|date=1991-04-15|title=Low molecular weight kininogen binds to platelets to modulate thrombin-induced platelet activation|journal=The Journal of Biological Chemistry|volume=266|issue=11|pages=6786–6794|doi=10.1016/S0021-9258(20)89569-6|issn=0021-9258|pmid=2016293|doi-access=free}}

The proteolytical cleavage of LK by tissue kallikreins creates kallidin, which is a possible substrate for carboxypeptidase M.{{Cite journal|last1=Zhang|first1=Xianming|last2=Tan|first2=Fulong|last3=Zhang|first3=Yongkang|last4=Skidgel|first4=Randal A.|date=2008-03-21|title=Carboxypeptidase M and Kinin B1 Receptors Interact to Facilitate Efficient B1 Signaling from B2 Agonists|journal=Journal of Biological Chemistry|language=en|volume=283|issue=12|pages=7994–8004|doi=10.1074/jbc.M709837200|pmid=18187413|issn=0021-9258|doi-access=free}} Kallidin can be converted into bradykinin by Aminopeptidase B,{{cite journal |doi=10.1038/2121271a0|pmid=21090475|title=Formation of Bradykinin from Kallidin-10 by Aminopeptidase B|year=1966|last1=Hopsu-Havu|first1=V. K.|last2=Mäkinen|first2=K. K.|last3=Glenner|first3=G. G.|journal=Nature|volume=212|issue=5067|pages=1271–1272|bibcode=1966Natur.212.1271H|s2cid=4161553}} creating a connection between LK and the kinin-kallikrein system.

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

== Disease and medical relevance ==

Increased levels of kininogen in the plasma and tissues are associated with injury, inflammation, myocardial infarction, and diabetes. Additionally, kininogen's role in the contact activation system means that increased levels of kininogen can also contribute to the development of hereditary angioedema,{{Cite journal|last1=Moreno|first1=Adriana|last2=Nunes|first2=Fernanda L.|last3=Januario|first3=Yunan C.|last4=Maia|first4=Luana S.M.|last5=Ferriani|first5=Mariana P.L.|last6=Dias|first6=Marina M.|last7=Aragon|first7=Davi C.|last8=Suffritti|first8=Chiara|last9=Cicardi|first9=Marco|last10=da Silva|first10=Luis L.P.|last11=Arruda|first11=Luisa Karla P.|date=February 2019|title=Cleaved High Molecular Weight Kininogen Correlates With Hereditary Angioedema Due To C1-Inhibitor Deficiency|journal=Journal of Allergy and Clinical Immunology|language=en|volume=143|issue=2|pages=AB42|doi=10.1016/j.jaci.2018.12.127|doi-access=free}} 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),{{Cite journal|last1=Langhauser|first1=Friederike|last2=Göb|first2=Eva|last3=Kraft|first3=Peter|last4=Geis|first4=Christian|last5=Schmitt|first5=Joachim|last6=Brede|first6=Marc|last7=Göbel|first7=Kerstin|last8=Helluy|first8=Xavier|last9=Pham|first9=Mirko|last10=Bendszus|first10=Martin|last11=Jakob|first11=Peter|date=2012-11-08|title=Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation|journal=Blood|language=en|volume=120|issue=19|pages=4082–4092|doi=10.1182/blood-2012-06-440057|issn=0006-4971|pmc=3543983|pmid=22936662}} 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.{{Cite journal|last1=Wang|first1=Jing|last2=Wang|first2=Xinying|last3=Lin|first3=Shiyong|last4=Chen|first4=Chudi|last5=Wang|first5=Congrong|last6=Ma|first6=Qunying|last7=Jiang|first7=Bo|date=2013-07-23|editor-last=Kano|editor-first=Mitsunobu R.|title=Identification of Kininogen-1 as a Serum Biomarker for the Early Detection of Advanced Colorectal Adenoma and Colorectal Cancer|journal=PLOS ONE|language=en|volume=8|issue=7|pages=e70519|doi=10.1371/journal.pone.0070519|issn=1932-6203|pmc=3720899|pmid=23894665|bibcode=2013PLoSO...870519W|doi-access=free}}

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.{{Cite journal|last1=Taddei|first1=Stefano|last2=Bortolotto|first2=L.|date=October 2016|title=Unraveling the Pivotal Role of Bradykinin in ACE Inhibitor Activity|journal=American Journal of Cardiovascular Drugs|language=en|volume=16|issue=5|pages=309–321|doi=10.1007/s40256-016-0173-4|pmid=27260014|s2cid=25709248|issn=1175-3277}}

{{reflist}}

• {{MeshName|Kininogens}}
• [https://web.archive.org/web/20051212005239/http://nic.sav.sk/logos/books/scientific/node31.html The kinin-forming system at sav.sk]

{{Autacoids}}

{{Coagulation}}

Category:Kinin–kallikrein system

Category:Precursor proteins