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Proteinase Inhibitors: An Overview of their Structure and Possible Function in the Acute Phase
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Serpins encompass a superfamily of proteins homologous with human α1-proteinase inhibitor (α – PI), which serves as the archetype of the group. The term serpin was coined by Carrell and Travis,6 and is a contraction of serine proteinase inhibitor, yet it should not be assumed that all members of the superfamily are inhibitors of serine proteinases. For example, angiotensinogen74 and hen ovalbumin75 are both homologs of α1-PI and are classified as serpins, yet it is almost certain that they possess no proteinase inhibitory activity. Moreover, human blood contains two other serpins, corticosteroid-binding globulin and thyroxin-binding globulin, that are hormone transporters and not, apparently, proteinase inhibitors. Nevertheless, giving the superfamily an easily remembered name has helped to establish the relatedness of proteins from disparate sources, and we now recognize more than 60 serpins from vertebrates, insects, plants, and viruses, although there is yet no evidence for their presence in prokaryotes or lower eukaryotes such as fungi.
Spontaneous (Unexplained) Thrombosis: The Inherited Basis for the Thrombohemorrhagic Balance
Published in E. Nigel Harris, Thomas Exner, Graham R. V. Hughes, Ronald A. Asherson, Phospholipid-Binding Antibodies, 2020
A serine protease inhibitor (serpin) of possible importance in this context besides AT-III, HC II, a2AP, PC AI and PAI has recently been identified (Protease nexin 1 [PN-1]). It forms a stable 1:1 complex with enzymes such as thrombin and t-PA.43-44 A similar cellular serpin, a platelet surface protein, has also been isolated and characterized.45-47 Furthermore, a plasma nexin has been isolated recently, tetranexin, which is a plasminogen binding protein and thus a potential modulator of fibrinolysis.48
Coagulation Theory, Principles, and Concepts
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
A number of inhibitors have been identified which inhibit the activity of tPA and urokinase. These inhibitors are related to antithrombin III and are classified as serpins. Plasminogen activator inhibitor 1 (PAI-1) is found in plasma and platelets, and is produced by endothelial cells, hepatocytes, smooth muscle cells, fibroblasts, and various malignant cell types. PAI-1 inhibits the activity of both forms of tPA, and two-chained urokinase, but not prourokinase or the streptokinase-plasminogen complex (103,104).
Serpina3n: Potential drug and challenges, mini review
Published in Journal of Drug Targeting, 2020
Mehwish Saba Aslam, Liudi Yuan
Serpins interact with proteases in two ways, inhibitory pathway and substrate pathway. In inhibitory pathway, serpin irreversbly bind with target protease to impede its function while in substrate pathway, protease blocks the function of structurally unmodified serpin by binding to it [48]. According to well established understanding of inhibitory serine proteases, upon the formation of non-covalent stable Michealis complex and the subsequent cleavage of the peptide bond, the loop is integrated into the protein core giving rise to an additional beta-sheet and transported the tethered enzyme along with it, to the distal end of the serpin. In this way bounded peptidase is distorted leading to its inactivation which fails to complete peptide bond hydrolysis [9]. Serpina3n/SERPINA3 follow inhibitory pathway. Like other inhibitory serpins, Serpina3n/SERPINA3 commonly exist in two distinct conformations, innate meta-stable stressed form and relaxed stable form (after binding with target protease). Thus attain irreversible stable conformation through inhibition by compromising functional integrity [5,33,48,49]. Energy released during this conformational change is used for the distortion of the target protease [21].
Granzyme B as a therapeutic target for wound healing
Published in Expert Opinion on Therapeutic Targets, 2019
Christopher T. Turner, Sho Hiroyasu, David J. Granville
Serpins are serine protease inhibitors belonging to the largest protease inhibitor superfamily [95]. Inhibitory serpins form enzymatically inactive and irreversible stoichiometric complexes, where substrate binding to the reactive center loop triggers irreversible protease inhibition and a cleaved C-terminal fragment [96]. Of the 35 human serpins, three can inhibit granzymes, including serpinb9 which specifically inhibits granzyme B [41]. However, serpinb9 only inhibits granzyme B internally within cells and is therefore unlikely to be function outside the cell due to oxidation sensitivity [41]. Additional granzyme inhibitors, however, have been identified in mice (serpinb9b and serpina3n). Of these, only serpina3n, a mouse orthologue of human anti-chymotrypsin that is not found in humans, has been identified in vitro as an inhibitor of both mouse and human granzyme B [97]. Unlike in humans where a single-gene encodes anti-chymotrypsin, in mice, there is a cluster of 13 closely related genes at the same locus resulting from repeated duplications [98]. The role of serpina3n in disease pathogenesis has been evaluated in a variety of mouse models of disease, with these discussed below.
Human plasma-derived C1 esterase inhibitor for on-demand or prophylaxis treatment of patients with hereditary angioedema: intravenous and subcutaneous formulations
Published in Expert Opinion on Orphan Drugs, 2018
C1-INH is a major and important inhibitor of proteases in the contact system and the classical and lectin pathways of the complement cascade [1–3]. It is a member of a large family of serine protease inhibitors (serpin) and inhibits several other serine proteases. In the contact system, C1-INH inhibits the autoactivation of factor XII, the conversion of prekallikrein to kallikrein, the activation of factor XII by kallikrein, and the cleaving of bradykinin from high-molecular-weight kininogen (Figure 1). Absence of C1-INH leads to instability in these pathways, resulting in excess factor XIIa, kallikrein, and bradykinin. Angioedema attacks result from the binding of bradykinin to the B2 receptor on endothelial cells, which causes vasodilation, increased vascular permeability, and leakage of plasma into the extracellular space.