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• Structure

  Plasma kallikrein possesses a unique structure in vertebrates and is composed of four apple domains followed by a trypsin domain. The apple domain is a conserved protein folding with three disulfide bridges, and is often found on diverse proteins for protein-protein or protein-carbohydrate interactions. The apple domains on KLKB1 interact with the D6 domain of molecular weight kininogen (HMW-KNG), which is highly glycosylated. In teleost genomes, the KLKB1-like gene is absent and only lectins with four apple domains but no trypsin domain were found. These lectins were not found in other vertebrates, suggesting that the two genes could share the same origin but the trypsin domain was lost in the teleost lineage during evolution. Tissue kallikreins possess a single trypsin domain and are closely related to other serine proteases. It is not clear what enzyme is involved in the cleavage of KNG to form bradykinin (BK) in the fish and lamprey, given that KLKB1 and KLK are not identified.;

• Gene and mRNA

  Plasma kallikrein (EC 3.4.21.34) is transcribed by KLKB1 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 an inactive form known as prekallikrein, and it is activated by contact activation involving HMW-KNG and factor XII. Tissue kallikreins (EC 3.4.21.35) are transcribed by the 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 apple domains followed by a trypsin domain and KLK possesses only a trypsin domain. The sequences of the trypsin domain are highly variable, but the catalytic domains (trypsin triads) are similar. KLK-like sequences were identified in teleosts, but the catalytic domains are mutated, indicating a possible loss of function of these enzymes and the genes became pseudogenes. Therefore, other trypsin-like enzymes may have taken the role of these KLK-like enezymes in teleosts to produce [Arg0 ]-BK from KNG.
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• Synthesis and release

  Although KLKB1 and F11 are tandem duplicated orthologs, their regulations are different. Hepatic nuclear factor 4α (HNF4α) deletion decreased F11 but not KLKB1. Estrogen or thyroid hormone treatment increased F11 expression but not KLKB1 while a high-fat diet increased both F11 and KLKB1 expression. For KLK, the regulation of synthesis and release was most studied in detail in KLK3 and multiple androgenresponsive elements were identified upstream of KLK3.;

• Biological functions

  KLKB1 selectively cleaves Arg/Xaa and Lys/Xaa bonds, including Lys/Arg and Arg/Ser bonds in human KNG, to release BK. It also digests plasminogen to plasmin, and participates in the surface-dependent activation of blood coagulation, fibrinolysis, and inflammation. It converts prorenin to renin to activate the RAS. Teleost KLKB1-like lectin facilitates hemagglutination by binding to the pathogen-like glycoproteins, and could be involved in immune function. KLK is highly selective to release [Lys0 ]-BK from both HMW- and LMW-KNGs, which involves the hydrolysis of Met/Xaa or Leu/Xaa. Besides acting as an enzyme for KKS, KLK is also involved in proteolytic cascades for semen liquefaction through the hydrolysis of seminogelin and the desquamation of the skin by the cleavage of cellular adhesion proteins.;

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