| Structure | Plasma kallikrein possesses a unique structure in vertebrates and is composed of four apple domains followedby a trypsin domain. The apple domain is aconserved protein folding with three disulfide bridges,and is often found on diverse proteins for protein-proteinor protein-carbohydrate interactions. The apple domainson KLKB1 interact with the D6 domain of molecularweight kininogen (HMW-KNG), which is highly glycosylated. In teleost genomes, the KLKB1-like gene is absentand only lectins with four apple domains but no trypsindomain were found. These lectins were not found inother vertebrates, suggesting that the two genes couldshare the same origin but the trypsin domain was lostin the teleost lineage during evolution. Tissue kallikreinspossess a single trypsin domain and are closely related toother serine proteases. It is not clear what enzyme isinvolved in the cleavage of KNG to form bradykinin(BK) in the fish and lamprey, given that KLKB1 andKLK are not identified. |
| Gene and mRNA | Plasma kallikrein (EC 3.4.21.34) is transcribed byKLKB1 located on chromosome 4q35 in humans. In mammals, KLKB1 is duplicated to form factor XI (F11) by tandem duplication.1 KLKB1 in plasma is mostly in aninactive form known as prekallikrein, and it is activatedby contact activation involving HMW-KNG and factorXII. Tissue kallikreins (EC 3.4.21.35) are transcribed bythe KLK genes located on chromosome 19q13 in humans.In tetrapods, the tissue kallikreins are tandemly duplicated into a large family (KLK1-KLK15 on human chromosome 19). Human KLKB1 possesses four appledomains followed by a trypsin domain and KLK possesses only a trypsin domain. The sequencesof the trypsin domain are highly variable, but the catalytic domains (trypsin triads) are similar. KLK-likesequences were identified in teleosts, but the catalyticdomains are mutated, indicating a possible loss of function of these enzymes and the genes became pseudogenes. Therefore, other trypsin-like enzymes may havetaken the role of these KLK-like enezymes in teleosts toproduce [Arg0]-BK from KNG.
|
| Synthesis and release | Although KLKB1 and F11 are tandem duplicatedorthologs, their regulations are different. Hepatic nuclearfactor 4α (HNF4α) deletion decreased F11 but not KLKB1.Estrogen or thyroid hormone treatment increased F11expression but not KLKB1 while a high-fat diet increasedboth F11 and KLKB1 expression. For KLK, the regulation of synthesis and release wasmost studied in detail in KLK3 and multiple androgenresponsive elements were identified upstream of KLK3. |
| Biological functions | KLKB1 selectively cleaves Arg/Xaa and Lys/Xaabonds, including Lys/Arg and Arg/Ser bonds in humanKNG, to release BK. It also digests plasminogen to plasmin, and participates in the surface-dependent activationof blood coagulation, fibrinolysis, and inflammation. Itconverts prorenin to renin to activate the RAS. TeleostKLKB1-like lectin facilitates hemagglutination by binding to the pathogen-like glycoproteins, and could beinvolved in immune function. KLK is highly selective to release [Lys0]-BK from bothHMW- and LMW-KNGs, which involves the hydrolysisof Met/Xaa or Leu/Xaa. Besides acting as an enzymefor KKS, KLK is also involved in proteolytic cascadesfor semen liquefaction through the hydrolysis of seminogelin and the desquamation of the skin by the cleavage ofcellular adhesion proteins. |
| Description | Plasma kallikrein possesses a unique protein structurewith four apple domains and a trypsin domain, which evolvedbefore coagulation factor XI. Tissue kallikreins are trypsinbased enzymes, and some members are highly correlated withprostate cancer. The evidence that human urine induces hypotensionwhen injected intravenously into anesthetized dogs wasfirst described in 1909. Two major kallikreins, plasma kallikrein (KLKB1) and tissue (glandular) kallikrein (KLK),were found in mammals, and they were transcribed bydifferent genes. Glandular KLK was an old name andwas replaced by tissue KLK in the modern nomenclature. |
| Chemical Properties | Kinin releasing enzyme is a substance with vasodilatory effect extracted from the submandibular gland or pancreas of pigs. It is white or off-white powder; easily soluble in water (10%), dilute alcohol, insoluble in concentrated ethanol and general organic solvents. Dissolved in water or saline into a colorless or yellowish clear solution.Ph4.5-7.8 is stable. It is unstable to heat, strong acid, strong base and oxidizer. Isoelectric point is 3.9～4.37. Generally speaking, the higher the purity, the worse the stability. The dry powder is kept at -200 for several months with no change in activity. In Ph=8 water and buffer, frozen preservation can last quite a long time without inactivation. Heavy metal ions Hg2+, Ca2+, Mn2+, Ni2+, etc. have the same degree of inhibition (Ca2+, Mg2+ has no effect on enzyme activity), mercaptan compounds and chelating agent EDTA, etc. can reverse the inhibition of metal ions on it. On the contrary, a high concentration of Ca2+ (1 molL^-{-1 can make the enzyme activity increased by 15% ~ 20%. Certain trypsin inhibitors such as peptidase, diisopropylphosphate, etc. have an inhibitory effect on pancreatic and submandibular gland kinin releasing enzyme. |
| Uses | Kallikrein from porcine pancreas has been used:
- as a matrix metalloproteinase-9 (MMP-9) zymogen activator
- as a component of cell culture to test its effect on rat subventricular zone (SVZ) cells and oligodendrocyte progenitor cells (OPC) proliferation and survival
- as a model enzyme to track kinetic data and visual detection limits of hydrolysis by hydrolytic enzymes in the two-phases array
|
| General Description | Kallikrein exists as an inactive prokallikrein in the porcine pancreas. The porcine kallikrein gene region is localized on chromosome 6q12-q21. |
| Biochem/physiol Actions | Kallikrein active forms are generated by the enzymatic action of trypsin. It is a serine protease that mediates the activation of growth factors and substrates. |
| Clinical Use | Kallikreins are drug targets for the control of hypertension, inflammation, and blood coagulation diseases. Theyare also possible biomarkers for cancer. KLK2 and KLK3 [prostate-specific antigen (PSA)] areused as the serum biomarker for prostate cancer. |
