# KLKB1

## Overview
The KLKB1 gene encodes the protein kallikrein B1, a serine protease that is a critical component of the kallikrein-kinin system. This system is integral to various physiological processes, including blood coagulation, fibrinolysis, and inflammation. Kallikrein B1, also known as plasma kallikrein, is synthesized as an inactive precursor in the liver and becomes activated in the bloodstream, primarily by factor XIIa. It plays a pivotal role in the intrinsic pathway of coagulation by converting kininogen to bradykinin, a peptide that influences vascular homeostasis and inflammatory responses (Lundwall2008Kallikreinrelated; Adamopoulos2015KLKB1). The activity of kallikrein B1 is modulated through interactions with high molecular weight kininogen and is essential for regulating blood pressure via the renin-angiotensin system (Biswas2016Polymorphisms). As a serine protease, kallikrein B1 is structurally related to coagulation factor XI and is involved in the plasma contact activation system, highlighting its significance in maintaining hemostatic balance (Lundwall2008Kallikreinrelated).

## Structure


## Function
The KLKB1 gene encodes plasma kallikrein, a serine protease that plays a significant role in the kallikrein-kinin system. Plasma kallikrein is primarily involved in the conversion of kininogen to bradykinin, a peptide that contributes to processes such as blood coagulation, fibrinolysis, and inflammation (Lundwall2008Kallikreinrelated; Adamopoulos2015KLKB1). This enzyme is synthesized as a precursor in hepatocytes and is activated in the bloodstream by factor XIIa, participating in the intrinsic pathway of coagulation by activating factor XII, which leads to thrombin generation (Stavrou2015Reduced; Adamopoulos2015KLKB1).

In healthy human cells, plasma kallikrein is involved in maintaining vascular homeostasis and modulating inflammatory responses. It is part of the plasma contact activation system and is structurally related to coagulation factor XI (Lundwall2008Kallikreinrelated). The activity of plasma kallikrein is crucial for the regulation of blood pressure through the renin-angiotensin system, where it interacts with pro-renin to generate active renin, subsequently influencing angiotensin I production (Biswas2016Polymorphisms). The enzyme's activity is modulated by its interaction with high molecular weight kininogen, which enhances its functional activity (Scott1980Function).

## Clinical Significance
Mutations in the KLKB1 gene, which encodes plasma kallikrein, are associated with several clinical conditions. Plasma prekallikrein deficiency (PKD) is a notable condition linked to mutations in KLKB1, such as Gly104Arg and Asn124Ser, which affect the binding of plasma kallikrein to high molecular weight kininogen (HMWK), crucial for blood coagulation. This deficiency is characterized by an elongated activated partial thromboplastin time (APTT) and can lead to abnormalities in the intrinsic blood coagulation pathway, although it does not always manifest with clinical symptoms (Katsuda2007A).

Severe PK deficiency, often resulting from mutations like c.451dupT, is more prevalent in individuals of African ancestry. This condition is associated with prolonged APTT and a low prevalence of bleeding events, but it may increase the risk of arterial cardiovascular and cerebrovascular events (Barco2020Severe; Adenaeuer2021c.451dupT).

Alterations in KLKB1 expression can also influence cardiovascular diseases. The G allele of KLKB1 rs3733402 is associated with reduced plasma kallikrein activity and a decreased history of coronary disease, suggesting a protective role against cardiovascular conditions (Gittleman2016A). In Klkb1 knockout mice, reduced thrombosis is observed, indicating that KLKB1 plays a role in modulating thrombosis risk (Stavrou2015Reduced).

## Interactions
The KLKB1 gene encodes prekallikrein, which is involved in several protein interactions crucial for its function in the kallikrein-kinin system. Prekallikrein circulates in plasma as a complex with high-molecular-weight kininogen (HK), binding through interactions with its Apple domains (Schmaier2016The). This complex is essential for the activation of prekallikrein to plasma kallikrein, a process primarily mediated by Factor XIIa during contact activation. Prolylcarboxypeptidase (PRCP) also plays a significant role in activating prekallikrein on endothelial cells, acting as an endoproteinase (Schmaier2016The).

On endothelial cells, the assembly and activation of the HK-prekallikrein complex lead to the liberation of bradykinin, which stimulates nitric oxide formation. This process is dependent on the presence of zinc ions, which facilitate HK binding and prekallikrein activation (Zhao2001Assembly). The activation of prekallikrein to kallikrein is inhibited by antipain, indicating the specificity of this interaction (Zhao2001Assembly).

Kallikrein also interacts with the protein C system, enhancing the anticoagulant effects of thrombomodulin and activated protein C during thrombin generation. This interaction is contact system-dependent, as shown by the absence of this effect when a contact pathway inhibitor is used (Wan2022Kallikrein).


## References


[1. (Lundwall2008Kallikreinrelated) Å. Lundwall and M. Brattsand. Kallikrein-related peptidases. Cellular and Molecular Life Sciences, 65(13):2019–2038, March 2008. URL: http://dx.doi.org/10.1007/s00018-008-8024-3, doi:10.1007/s00018-008-8024-3. This article has 115 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1007/s00018-008-8024-3)

[2. (Barco2020Severe) Stefano Barco, Stefanie Sollfrank, Alice Trinchero, Anke Adenaeuer, Hassan Abolghasemi, Laura Conti, Friederike Häuser, Johanna A. Kremer Hovinga, Karl J. Lackner, Felicia Loewecke, Erwin Miloni, Nader Vazifeh Shiran, Luigi Tomao, Walter A. Wuillemin, Barbara Zieger, Bernhard Lämmle, and Heidi Rossmann. Severe plasma prekallikrein deficiency: clinical characteristics, novel klkb1 mutations, and estimated prevalence. Journal of Thrombosis and Haemostasis, 18(7):1598–1617, July 2020. URL: http://dx.doi.org/10.1111/jth.14805, doi:10.1111/jth.14805. This article has 22 citations and is from a peer-reviewed journal.](https://doi.org/10.1111/jth.14805)

[3. (Schmaier2016The) A.H. Schmaier. The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities. Journal of Thrombosis and Haemostasis, 14(1):28–39, January 2016. URL: http://dx.doi.org/10.1111/jth.13194, doi:10.1111/jth.13194. This article has 287 citations and is from a peer-reviewed journal.](https://doi.org/10.1111/jth.13194)

[4. (Zhao2001Assembly) Yongqiang Zhao, Qianyao Qiu, Fakhri Mahdi, Zia Shariat-Madar, Rasmus Røjkjær, and Alvin H. Schmaier. Assembly and activation of hk-pk complex on endothelial cells results in bradykinin liberation and no formation. American Journal of Physiology-Heart and Circulatory Physiology, 280(4):H1821–H1829, April 2001. URL: http://dx.doi.org/10.1152/ajpheart.2001.280.4.H1821, doi:10.1152/ajpheart.2001.280.4.h1821. This article has 124 citations.](https://doi.org/10.1152/ajpheart.2001.280.4.H1821)

[5. (Wan2022Kallikrein) Jun Wan, Nadira Vadaq, Joke Konings, Martin Jaeger, Vinod Kumar, Bas de Laat, Leo Joosten, Mihai G. Netea, Andre J. van der Ven, Philip G. de Groot, Quirijn de Mast, and Mark Roest. Kallikrein augments the anticoagulant function of the protein c system in thrombin generation. Journal of Thrombosis and Haemostasis, 20(1):48–57, January 2022. URL: http://dx.doi.org/10.1111/jth.15530, doi:10.1111/jth.15530. This article has 5 citations and is from a peer-reviewed journal.](https://doi.org/10.1111/jth.15530)

[6. (Gittleman2016A) Haley R. Gittleman, Alona Merkulova, Omar Alhalabi, Evi X. Stavrou, Martina L. Veigl, Jill S. Barnholtz-Sloan, and Alvin H. Schmaier. A cross-sectional study of klkb1 and prcp polymorphisms in patient samples with cardiovascular disease. Frontiers in Medicine, April 2016. URL: http://dx.doi.org/10.3389/fmed.2016.00017, doi:10.3389/fmed.2016.00017. This article has 9 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fmed.2016.00017)

[7. (Adenaeuer2021c.451dupT) Anke Adenaeuer, Eyiuche D. Ezigbo, Hanan Fawzy Nazir, Stefano Barco, Alice Trinchero, Dagmar Laubert‐Reh, Konstantin Strauch, Philipp S. Wild, Karl J. Lackner, Bernhard Lämmle, and Heidi Rossmann. C.451dupt in klkb1 is common in nigerians, confirming a higher prevalence of severe prekallikrein deficiency in africans compared to europeans. Journal of Thrombosis and Haemostasis, 19(1):147–152, January 2021. URL: http://dx.doi.org/10.1111/jth.15137, doi:10.1111/jth.15137. This article has 5 citations and is from a peer-reviewed journal.](https://doi.org/10.1111/jth.15137)

[8. (Katsuda2007A) Itsuro Katsuda, Fumio Maruyama, Kohji Ezaki, Toru Sawamura, and Yoshikazu Ichihara. A new type of plasma prekallikrein deficiency associated with homozygosity for gly104arg and asn124ser in apple domain 2 of the heavy‐chain region. European Journal of Haematology, 79(1):59–68, June 2007. URL: http://dx.doi.org/10.1111/j.1600-0609.2007.00871.x, doi:10.1111/j.1600-0609.2007.00871.x. This article has 33 citations and is from a peer-reviewed journal.](https://doi.org/10.1111/j.1600-0609.2007.00871.x)

[9. (Adamopoulos2015KLKB1) Panagiotis G. Adamopoulos, Christos K. Kontos, Sotirios G. Papageorgiou, Vassiliki Pappa, and Andreas Scorilas. Klkb1 mrna overexpression: a novel molecular biomarker for the diagnosis of chronic lymphocytic leukemia. Clinical Biochemistry, 48(13–14):849–854, September 2015. URL: http://dx.doi.org/10.1016/j.clinbiochem.2015.04.007, doi:10.1016/j.clinbiochem.2015.04.007. This article has 20 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.clinbiochem.2015.04.007)

[10. (Stavrou2015Reduced) Evi X. Stavrou, Chao Fang, Alona Merkulova, Omar Alhalabi, Nadja Grobe, Silvio Antoniak, Nigel Mackman, and Alvin H. Schmaier. Reduced thrombosis in klkb1−/− mice is mediated by increased mas receptor, prostacyclin, sirt1, and klf4 and decreased tissue factor. Blood, 125(4):710–719, January 2015. URL: http://dx.doi.org/10.1182/blood-2014-01-550285, doi:10.1182/blood-2014-01-550285. This article has 70 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1182/blood-2014-01-550285)

[11. (Biswas2016Polymorphisms) Nilima Biswas, Adam X. Maihofer, Saiful Anam Mir, Fangwen Rao, Kuixing Zhang, Srikrishna Khandrika, Manjula Mahata, Ryan S. Friese, C. Makena Hightower, Sushil K. Mahata, Dewleen G. Baker, Caroline M. Nievergelt, Sucheta M. Vaingankar, and Daniel T. O’Connor. Polymorphisms at the f12 and klkb1 loci have significant trait association with activation of the renin-angiotensin system. BMC Medical Genetics, March 2016. URL: http://dx.doi.org/10.1186/s12881-016-0283-5, doi:10.1186/s12881-016-0283-5. This article has 13 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s12881-016-0283-5)

[12. (Scott1980Function) Cheryl F. Scott and Robert W. Colman. Function and immunochemistry of prekallikrein-high molecular weight kininogen complex in plasma. Journal of Clinical Investigation, 65(2):413–421, February 1980. URL: http://dx.doi.org/10.1172/jci109684, doi:10.1172/jci109684. This article has 63 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1172/jci109684)