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Enzymatic Degradation of Bradykinin
Published in Sami I. Said, Proinflammatory and Antiinflammatory Peptides, 2020
Randal A. Skidgel, Ervin G. Erdös
Aminopeptidases can release Bk from kallidin (or Lys1-Bk) that is a product of tissue kallikrein, whereas Bk is liberated by plasma kallikrein (Bhoola et al., 1992). Early studies showed that Lys1-Bk is converted to Bk by an aminopeptidase in the blood, and subsequently, similar activity was detected in a variety of tissues (Erdös, 1979; Erdös et al., 1963; Webster and Pierce, 1963).
Sensory and Inflammatory Peptide Receptors in Airways
Published in Devendra K. Agrawal, Robert G. Townley, Inflammatory Cells and Mediators in Bronchial Asthma, 2020
Bradykinin is generated from α-2 globulins in plasma (kininogens) by the action of enzymes (kininogenases) which are produced by the liver (plasma kallikrein) and by other tissues (tissue kallikrein).76 In addition, human lung mast cells and basophils release a kininogenase which is distinct from kallikreins77 and may be identical to tryptase. Both a high-molecular-weight kininogen and a low-molecular-weight kininogen are recognized, the former probably acting as a substitute for plasma kallikrein and the latter for tissue kallikrein, since it is formed extravascularly. Bradykinin has several actions which may be relevant to asthma.4
Inflammation
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Plasma kallikrein is a large molecule with a molecular weight of 97,000 Da.167 It is an immunologically and physicochemically distinct molecule and exists as an inert precursor in the liver. Tissue kallikreins occur in many organs and can be found in secretions or excretions of glands, such as saliva, sweat, tears, pancreatic juice, feces, and urine. The various tissue kalikreins are distinct entities, but they are closely related. Molecular weights of homogeneous kallikreins from submaxillary gland, pancreas, and urine are 32,000, 33,300, and 36,300 Da, respectively.132 They have different immunological and physicochemical characteristics and susceptibility to protease inhibitors.
The therapeutic relevance of the Kallikrein-Kinin axis in SARS-cov-2-induced vascular pathology
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Dorsa Sohaei, Morley Hollenberg, Sok-Ja Janket, Eleftherios P. Diamandis, Gennady Poda, Ioannis Prassas
Binding of SARS-CoV-2 to ACE2 not only downregulates ACE2 expression but also alters its catalytic activity, which in turn alters the ACE2-dependent regulation of the plasma kallikrein-kinin system (KKS) (Figure 2) [65,66]. The KKS produces bradykinin via proteolytic cleavage of the high-molecular-weight kininogen (HMWK or HK) by plasma kallikrein (KLK1B) or low-molecular-weight kininogen (LMWK) by tissue kallikrein (KLK1) [67]. Bradykinin is an acute-phase inflammatory hormone-like molecule [68] whose aberrant activity is physiologically controlled by ACE2 [67,69]. SARS-CoV-2-mediated ACE2 downregulation and modification of its activity can lead to aberrant bradykinin accumulation during the early stages of COVID-19. In turn, increased bradykinin can activate pro-inflammatory processes itself, driving endothelial permeability and causing vasodilating effects via bradykinin receptor 2 (BKB2R) activation. Bradykinin can also be processed further by carboxypeptidase N to produce DR9-bradykinin, which acts through bradykinin receptor 1 (BKB1R) to transmit pro-inflammatory signals [70,71]. This interplay between ACE2, the renin-angiotensin system (RAS), and the plasma KKS has been portrayed as generating a “bradykinin storm” that drives disease pathology in the setting of COVID-19 [71].
The discovery and development of transmembrane serine protease 2 (TMPRSS2) inhibitors as candidate drugs for the treatment of COVID-19
Published in Expert Opinion on Drug Discovery, 2022
Christiana Mantzourani, Sofia Vasilakaki, Velisaria-Eleni Gerogianni, George Kokotos
Kishk et al. identified proteins with known X-ray structure and high homology for TMPRSS2 using SWISS-MODEL and NCBI blastp [102]. These proteins included transmembrane protease serine 1 and 13 and a group of human plasma kallikrein. Homology models were built with SWISS-MODEL, evaluated, and subjected to molecular dynamics simulations to measure their energetic stability. Docking of nafamostat in the TMPRSS2 active site with MOE program revealed the position of the phenyl guanidine group in the S1 pocket and its hydrogen bond interactions with residues Asp435, Ser436, Ser463 and Gly462. The hydrophobic pocket, which consists of Thr459, Ser460, Trp461 and Val473, accommodates the phenyl ring. The active site was determined by site finder and positioned to contain the catalytic Ser441 and S1 pocket amino acids, including Glu389, Tyr416, Asp435, Ser436, Cys437, Gln438, Thr459, Ser460, Trp461, Gly462, Ser463, Gly464, Cys465, Ala466, Arg470, Pro471, Gly472 and Val473.
Genetic aspects of idiopathic asthenozoospermia as a cause of male infertility
Published in Human Fertility, 2020
Zohreh Heidary, Kioomars Saliminejad, Majid Zaki-Dizaji, Hamid Reza Khorram Khorshid
Hyperviscosity, or the persistence over time of a homogeneous semen stickiness and adherence, is a less explored infertility-related phenotype that has been thought to negatively impact spermatozoa motility, count and progression in the female reproductive tract, often impairing fertilization (Du Plessis, Gokul, & Agarwal, 2013). Several proteins are known to play key roles in the cascade of semen coagulation and liquefaction including the kallikrein (KLK) family, that was found on chromosome 19q13.3–13.4, and the whey-acidic-protein four-disulfide core domain (WFDC) cluster, located at chromosome 20q13 (Clauss, Lilja, & Lundwall, 2002). Human Kallikreins are a subgroup of serine proteases which are divided into the tissue and plasma kallikreins. The tissue Kallikrein loci encode a family of fifteen closely related serine proteases with pervasive activities in diverse proteolytic cascades; while the plasma kallikrein has no known paralogue and encode only one serine protease (KLKB1). Kallikreins are responsible for the coordination of various physiological functions including blood pressure, semen liquefaction and skin desquamation (Michael et al., 2006; Pathak, Wong, Dreveny, & Emsley, 2013).