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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
A classification system for proteinase inhibitors based on specificities for target enzyme presents problems due to the overlapping specificity of individual inhibitors. Consequently, we classify proteinase inhibitors by superfamily relationships (see Table 1). This may actually aid in determining functional and evolutionary relationships. In mammals, we currently recognize seven protein superfamilies, each containing at least two individuals, whose members are often proteinase inhibitors: the serpins, the kunins, the kazals, the ALPs, the α-macroglobulins, the cystatins, and the TIMPs.* There also exists an inhibitor, calpastatin, that seems to be in a superfamily of one member. This protein is selective for the intracellular calpains (distant papain relatives). Since this review concentrates on extracellular proteolysis, we do not consider the calpain/calpastatin system further.
Enzymes
Published in Stephen W. Carmichael, Susan L. Stoddard, The Adrenal Medulla 1986 - 1988, 2017
Stephen W. Carmichael, Susan L. Stoddard
Togari, Ichikawa and Nagatsu (1986) found that two molecular species of the calcium-dependent neutral protease, calpains I and II, activated TH that had been purified from bovine adrenal medulla. This activation was inhibited by the endogenous inhibitor of calpain, calpastatin. It remains to be seen whether or not this mechanism of proteolytic activation of TH operates in vivo.
The Calcium-Calmodulin System
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
The calpains are neutral proteases that have an absolute Ca2+ dependence for activity.226 They have been isolated from the cytosolic fraction of animal tissues or cells, but may be translocated to the cell membrane under certain conditions. The two calpains, calpain I and calpain II, have an indentical 30-kDa regulatory subunit but two distinct 80-kDa catalytic subunits. Both types of calpain subunits contain calmodulin-like Ca2+-binding domains at their carboxy-terminal ends, and these domains confer Ca2+ sensitivity to the calpains. The activity of calpains is also regulated by an endogenous calpain inhibitor protein, termed calpastatin. The biological functions of calpains are little understood; however, it is clear that they do not have general proteolytic activity, but rather catalyze specific and limited cleavage of specific substrates. Calpain I and calpain II appear to have identical substrate specificities. Endogenous substrates for calpains include enzymes such as kinases as well as myofibrilar, membrane, cytoskeletal, and receptor proteins. More than half of calmodulin-binding proteins are calpain substrates in vitro.226 These proteins are recognized by calpains through the presence of specific amino acid sequences in them, called PEST sequences, which contain proline (P), glutamic acid (E), serine (S), and threonine (T). The Jun and Fos oncoproteins, which contain PEST sequences and form heterodimers with binding activity for AP-1 DNA sites, are substrates for calpain.227 Some small proteins not containing PEST sequences may also be calpain substrates.
Effects of 6-(Methylsulfinyl)hexyl Isothiocyanate Ingestion on Muscle Damage after Eccentric Exercise in Healthy Males: A Pilot Placebo-Controlled Double-Blind Crossover Study
Published in Journal of Dietary Supplements, 2022
Yoko Tanabe, Nobuhiko Akazawa, Mio Nishimaki, Kazuhiro Shimizu, Naoto Fujii, Hideyuki Takahashi
The present study has several limitations. First, our study rationale regarding the effect of 6-MSITC on calpain levels relies on results provided in a patent application only (18). To the best of our knowledge, there is no peer-reviewed published research article that assessed this effect. Second, our sample size of eight might be insufficient to detect significant differences. Third, we assessed calpain-1 levels from blood samples. Given that calpain-1 is ubiquitously expressed throughout the body, the measured calpain-1 levels in this study might not purely reflect that in skeletal muscles. Fourth, we did not assess calpastatin, an endogenous selective inhibitor of calpain, which is involved in the regulation of calpain activity (41). Had we assessed calpastatin, we could have been able to delineate how 6-MSITC influenced the regulation of calpain activity. Fifth, the diet during the experiment was not strictly controlled, which might have influenced our results. Sixth, we did not assess the acute effect of 6-MSITC (e.g. after <24 h). Despite several limitations, it is noteworthy highlighting that the present study was well conducted with appropriate methods and design (e.g. a randomized, double-blind, crossover design). Therefore, data obtained in the present study is highly reliable and valuable.
Calpain as a therapeutic target in cancer
Published in Expert Opinion on Therapeutic Targets, 2022
Ivan Shapovalov, Danielle Harper, Peter A. Greer
Calpain-1 and −2 are also regulated by calpastatin (encoded by the CAST gene) which binds the PEF(L) and PEF(S) domains as well as near the active site to sterically hinder substrate access (Figure 2) [17]. The calpain-calpastatin system is regulated by phosphorylation modifications of either calpain or calpastatin. Phospho-CAST has repressed activity, and as such, dephosphorylation is required for CAST to inhibit calpain [18,19]. Phosphorylation of calpain may result in activation or inhibition depending on the kinase. For example, ERK- and protein kinase C-mediated phosphorylation of calpain-2 increases its activity, while phosphorylation by protein kinase A (PKA) decreases calpain-2 activity [20,21]. Our understanding of calpain-calpastatin cross-talk in normal health and diseases, including cancer, is incomplete. There is evidence in glioblastoma cell lines that radiation-induced CAST phosphorylation is associated with activation of calpain-1 and increased cell survival [22]; and while calpain-1 is inhibited by CAST regardless of the calpain-1 phosphorylation status, PKA phosphorylated calpain-1 is more sensitive to CAST inhibition [23]. In addition, the threshold for calpain-2 activation by Ca2+ can be reduced by autolysis of the N-terminus or interaction with phosphatidylinositol mono- or bis-phosphate (reviewed in [2]). Binding sites on calpain-2 for Ca2+, calpastatin, and selected small molecule inhibitors (as determined in co-crystal structures) are shown in Figure 2.
An update on the therapeutic potential of calpain inhibitors: a patent review
Published in Expert Opinion on Therapeutic Patents, 2020
Calpain continues to be of interest as a therapeutic target for various diseases hence inhibitors of the enzyme have been evaluated in preclinical studies as potential drug candidates. In this review, calpain inhibitors that were disclosed in the patent and scientific literature over the last 5 years (2015–2019) are broadly classified into peptidomimetic and nonpeptide inhibitors. Calpastatin was used as a template to direct the design of novel peptidomimetic inhibitors. Advantage was taken of the conserved tetrapeptide β-turn residues of calpastatin in the region where it binds to the active site of calpain to generate compounds that specifically inhibited calpain compared to cathepsin B [31]. Another report focused on using the 27-mer calpastatin peptide to generate a novel BBB-permeable specific calpain inhibitor that was used to demonstrate the involvement of calpain in postischemic neurological and cerebrovascular dysfunction [33]. Thalassospiramides were disclosed as a novel class of lipopeptide natural product inhibitors of calpain. The compounds have a conserved 12-membered ring that incorporates an electrophilic-unsaturated amide functionality, which was demonstrated to be essential for inhibiting calpain. The compounds are of interest as a scaffold for the discovery of new calpain inhibitors because they appear to be devoid of nonspecific macromolecular interactions despite the presence of the electrophilic functionality [47].