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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).
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.
Therapeutic potential of human serum albumin nanoparticles encapsulated actinonin in murine model of lung adenocarcinoma
Published in Drug Delivery, 2022
Priyanca Ahlawat, Kanika Phutela, Amanjit Bal, Navneet Singh, Sadhna Sharma
Considering the lack of sufficient literature on actinonin’s in vivo anti-cancerous effects, the present experimental work is of critical importance. In a solid tumor, heterogeneous cell populations can be differentiated upon mitochondrial membrane potential. Loss in P2 population clearly reflects positive effects of therapy which may be aided by ROS generation. At the 10 months latency period, induction of necrosis by the nano actinonin group was observed which has not been reported so far in the limited literature available, specifically on actinonin’s mechanism of action. As the current study is first of its kind to evaluate the apoptotic status of in vivo urethane-induced lung adenocarcinoma in treated mice, therefore effects of actinonin need further exploration with respect to in vivo models. Further, as per anticipation, actinonin in its free and nanoformulated form intraperitoneally showed downregulation in egfr mRNA levels. This can be contributed by meprin α which is inhibited by actinonin, which is shown to be involved in the chronic inflammation by activating IL-6 trans-signaling (Arnold et al., 2017; Wculek et al., 2020; ). IL-6 as a proinflammatory cytokine promotes inflammation thereby contributing in worse prognosis of NSCLC (Silva et al. 2017). Also, activated EGFR and ERK1/2 signaling via ligand shedding pathway may support tumor cell proliferation, migration as well as invasion (Minder et al., 2012). Overall experimental evidence indicate that actinonin may have a potential indirect inhibitory effect on egfr expression. Similarly, folate receptor α expression was considerably downregulated in groups treated with actinonin as free and nanoformulation for both latency groups. Also, folate receptor α has better discriminatory ability to distinguish between adenocarcinoma and squamous cell carcinoma (Nunez et al., 2012). Its downregulation indicates therapeutic benefits of treatment regimens of nanoformulated and free actinonin. Next, mitochondrial effector gene such as peptide deformylase was evaluated. In 10 months latency model, free and nano actinonin, however, showed more pronounced downregulation of pdf than the 6 months latency period model. These findings established the benefits of incorporation of folate conjugated actinonin nanoformulation as an improved and reliable chemotherapeutic option against lung adenocarcinoma as it demonstrated aforementioned anti-cancerous effects in low dose frequency as compared to actinonin in free form through intraperitoneal administration.
Pathogenesis of Common Ocular Diseases: Emerging Trends in Extracellular Matrix Remodeling
Published in Seminars in Ophthalmology, 2023
Raziyeh Ghorbani, Mehdi Rasouli, Farshid Sefat, Saeed Heidari Keshel
ECM is a three-dimensional, reticular structure composed of collagen fibrous proteins and other proteins such as fibronectin, fibrillin, laminin, fibulins,7 and elastic fibers. Another common component of ECM is a glycosaminoglycan that includes heparan sulfate, chondroitin sulfate, and creatine sulfate. Matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), adamalysins, and meprins are among the most important enzymes in the ECM that cause the ECM to break down and change its composition.8 Meprin is a protease that plays a pivotal role in the breakdown of pro-collagen and its conversion to collagen.9 In addition, this protease, through activating the MMP enzymes, indirectly participates in the remodeling of the ECM.10 MMPs are zinc endopeptidase, which usually form as pro-enzymes in the form of soluble or, in rare cases, clinging to membranes.11 There are currently more than 20 different family members of MMPs in vertebrates and other organisms. The members of this family are divided into four general groups. The first group is collagenase, which can detect and cut the peptide bonds in type I to III collagen. The second group is gelatinase (Type IV collagenase), which breaks down collagen types IV to VII and X, elastin, fibronectin, and gelatin. These neutral metalloproteinases are classified into two types, gelatinases A and B, that need Ca2+ for catalytic activity. The next group is stromelysins, which degrade proteoglycans, laminin, fibronectin, and the fourth type of fibrillar collagen. Membrane-type MMPs (MT-MMPs) are the last group that are attached to cell membranes and involved in many biological processes.12 Another protein family that cuts out the ECM is adamalysins. It includes disintegrins, metalloproteinases (ADAMs), and ADAMs with a thrombospondin motif.13 In addition to the above, components of the immune system such as vitronectin, complement factor H, and growth factors are also present in this section and are constantly and actively remodeling.14 ECM exists in every organ, and the compounds in each organ are specific. In general, two types of ECM exist around cells, including the one that exists in the interstitial connective tissue that has a role and is found in most tissues, and the second type is the basement membrane (BM), which includes fibronectin and collagen I. The difference between BM and the intermediate matrix is that BM is denser and contains collagen IV, laminins, heparan sulfate proteoglycans, and nidogen. The BM forms a sheet-like ECM for anchoring epithelial cells and interacting directly with the epithelium and endothelium.15 Although the function of the collagen IV network is to maintain the mechanical stability of the cell, laminin networks are more active than the collagen IV network. Biochemical and biophysical properties such as the contents, structure, and organization of the ECM directly affect cell proliferation, differentiation, migration, and interactions.16