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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
TIMPs seem to be selective for enzymes of the matrix metalloproteinase (MMP) superfamily found exclusively (at present) in animals.130 They do not inhibit metalloproteinases from bacteria, nor members of the astacin superfamily of metalloproteinases.134 The MMPs currently number about 11 members whose functions are thought to be to degrade connective tissue proteins during development (following apoptosis, for example), inflammation, and wound healing.130 TIMP-1 is found in association with proMMP-9 (92-kDa gelatinase/type IV collagenase) and TIMP-2 with proMMP-2 (72-kDa gelatinase/type IV collagenase) during the production of these two proteinase zymogens in cell culture,135,136 in associations that are apparently not dependent on the inhibitory site of the inhibitors.137 Since all known MMPs are secreted as inactive precursors (whether or not they have TIMPs attached), the significance of TIMP association is obscure. Cross-linked higher-order complexes consisting of two molecules of MMP and one molecule of TIMP have been observed in cell culture,138 but the significance of these observations is also obscure. It is presumed that the function of TIMPs is to regulate the activity of MMPs, but since they do not seem to be highly selective, it is difficult to decide upon which interactions are likely to take place in vivo, although Howard et al.139 have made a good case for some specificity in the interaction of TIMP-2 and MMP-2 and MMP-9.
Centipede Envenomation Effects on Human Beings and Scientific Research on Traditional Antivenom Agents
Published in Parimelazhagan Thangaraj, Medicinal Plants, 2018
Dhivya Sivaraj, Revathi Ponnusamy, Rahul Chandran, Parimelazhagan Thangaraj
The literature reports that blister formation, hemorrhages, necrosis, itching (pruritus) and skin damage are due to metalloprotease enzyme. It is also responsible for vasodilatation by degrading the extracellular matrix, preventing blood clot formation (Gutierrez and Rucavado 2000), sturdy myotoxicity (Hamza et al. 2010) and hyperalgesic, oedematogenic activities (Malta et al. 2008). Therefore, it appears to be in the dominant form of proteases in centipede venom and serine proteases too play a role in toxin processing (Knapp et al. 2010; Siezen et al. 1997). In addition, to metalloproetase, there is serine protease (S1 and S8) found in Scolopendrid venom (Malta et al. 2008). They are involved in smooth muscle contraction, anticoagulation and immunosuppression (Fry et al. 2009; Low et al. 2013; Ma et al. 2012; Weston et al. 2013). The structure of metalloprotease resembles astacin metalloendoprotease (MEROPS family M12, subfamily A) (Undheim et al. 2014).
Enzymatic Degradation of Bradykinin
Published in Sami I. Said, Proinflammatory and Antiinflammatory Peptides, 2020
Randal A. Skidgel, Ervin G. Erdös
Meprin was purified from a mouse kidney membrane fraction; it is the mouse homolog of human PABA-peptide hydrolase and rat endopeptidase 2 (Beynon et al., 1981; Butler et al., 1987; Dumermuth et al., 1991; Wolz and Bond, 1995). Meprin contains two unique but related subunits, named α and β, and it is a member of the astacin family of metalloproteases (Gorbea et al., 1991; Dumermuth et al., 1991; Jiang et al., 1992; Johnson and Hersh, 1992; Wolz and Bond, 1995; Bond and Beynon, 1995). The enzyme is an oligomeric, cell-surface protein, bound via the transmembrane β subunit to which the α subunits are either disulfide-linked or noncovalently bound (Gorbea et al., 1991; Johnson and Hersh, 1994; Marchand et al., 1994). Meprin so far has been detected only in kidney and intestine, and its expression varies from species to species (Gorbea et al., 1991; Jiang et al., 1992, 1993). In contrast to endopeptidases 24.15 and 24.11 and ACE, which hydrolyze only short peptides, meprin cleaves large protein substrates such as azocasein (Butler et al., 1987). The α subunit of meprin hydrolyzes peptide and protein substrates longer than seven amino acids and cleaves the Gly4-Phe5 bond of Bk (Butler et al., 1987; Fig. 1). Of the peptides tested, Bk was hydrolyzed fastest among those cleaved at a single site (Wolz et al., 1991; Table 1, Fig. 1). This finding led to the synthesis of Phe5 (4-nitro)-Bk used in a spectrophotometric assay for meprin (Wolz and Bond, 1990, 1995). The (3 subunit does not cleave Bk even after activation (Kounnas et al., 1991; Wolz and Bond, 1995). Meprin α has a very broad substrate specificity and does not have strict requirements for residues adjacent to the cleavage site but seems to prefer Pro in the p’2 or P’3 position (Wolz et al., 1991). Meprin α cleaves biologically active peptides such as α-MSH, neurotensin, and LH-RH, and also Ang I and II, but rather slowly (Wolz et al., 1991).
Skin proteomics – analysis of the extracellular matrix in health and disease
Published in Expert Review of Proteomics, 2020
Jörn Dengjel, Leena Bruckner-Tuderman, Alexander Nyström
Proteolytic activity of the astacin-like proteinase BMP‐1/tolloid‐like is essential for the assembly of a functional DEJZ, papillary, and reticular dermal ECM. These proteinases process proforms of multiple ECM components to mature functional molecules, including the SLRP biglycan, the N-terminal end of the laminin γ2 chain, and the C-terminal end of laminin α3 in laminin-332, procollagen VII, and the C-terminal ends of procollagens I and III [51–53]. In addition, the other members of the astacin-like proteinases – meprin α and β – have been shown to be involved in processing of the N- and C-terminal ends of fibrillar procollagens in the skin [54]. ADAMTS2, −3, and −13 are generally considered the main proteases involved in removal of the procollagen N-pro-termini [55]. Although often considered to be ECM degrading proteases, also matrix metalloproteinases (MMPs) are involved in the assembly of the DEJZ through e.g. processing of laminin-332 [56].
Synthesis and structure–activity relationships of pyrazole-based inhibitors of meprin α and β
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Kathrin Tan, Christian Jäger, Stefanie Geissler, Dagmar Schlenzig, Mirko Buchholz, Daniel Ramsbeck
Proteases are involved in numerous processes that regulate the proper function of organisms. An impaired function of proteases or a dysregulation of proteolytic networks could lead to the development of diseases. Thus, proteases have always been important and promising drug targets1. An important family of proteases are metalloproteases, in particular the metzincins. This family includes matrix metalloproteases (MMPs), disintegrin and metalloproteases (ADAMs), ADAMs with thrombospondin motifs (ADAMTSs), and the astacins. The latter comprises bone-morphogenetic protein 1 (BMP-1), ovastacin, and the meprins α and β in human2. However, unlike MMPs or ADAMs, astacins received only a little attention in drug discovery in the past. Nevertheless, continuously growing knowledge of astacin biology increases the evidence that they are potential drug targets as well. In particular, meprin α and β seem to be involved in the pathophysiology of various diseases. Thus, they emerged as promising drug targets during the last years. While meprin α is expressed as soluble homodimer, meprin β homodimers mainly remain membrane-bound, but can also be shed from the cell surface3,4. In tissues co-expressing both meprins, meprin α is also bound to the cell membrane via the formation of meprin α/β heterodimers5. These differences in expression and localisation also determine different cleavage specificities and thus different roles in health and disease.6,7 Meprin α is supposed to act as pro-migratory protease in the context of colorectal and hepatocytic cancer8–13 and was also linked to vascular diseases like arteriosclerosis, cardiac remodelling, and aneurysms, recently14–16. Meprin β is also involved in cancer cell invasion17,18 and moreover is able to act as an alternative beta-secretase, contributing to the progression of Alzheimer’s disease via the release of neurotoxic amyloid peptides4,19–23. Both proteases act as procollagenases and are involved in the biosynthesis and assembly of collagen fibrils. Hence, they are potentially involved in the development of fibrotic diseases, e.g. keloids or lung fibrosis24–26. Further substrates include different cytokines and components of the extracellular matrix, rendering meprin α and β potential drug targets in inflammatory or kidney diseases27–33.