Protease inhibitors from venomous animals. The Kunitz-type motif was first observed in the bovine pancreatic trypsin inhibitor (BPTI)-like protease inhibitors, which strongly inhibit serine proteases such as trypsin and chymotrypsin. Non-prime and prime designations specify amino- and carboxy-terminal sides of cleavage site, respectively. The standard mechanism implies that substrates/inhibitors contain the reactive site residues P3, P2, P1, P1′, P2′, P3′, located in the most exposed region of the protease-binding loop, that bind to the substrate amino acid side chains S3, S2, S1, S1′, S2′, S3′, which form the groove or cleft where amide bond hydrolysis occurs. The Kunitz-type inhibitors interact with proteases by the classical substrate-like mechanism mainly through the P1–S1 interaction, based on the nomenclature of Schechter and Berger. The Kunitz-type motif consists of a polypeptide chain of ~60 amino acid residues stabilized by three disulfide bridges (C I–C VI, C II–C IV, C III–C V). Among these, serine protease inhibitors are the largest and most widely distributed superfamily of PIs, and based upon their possession of conserved functional motifs they can be subdivided in many classes, being the Kunitz-type inhibitors the best characterized of them, probably due to their abundance in several organisms. The key-residues for the K + channel blocking activity was also compared.Īccording to the proteases they inhibit, PIs can be grouped primarily as serine, cysteine, aspartic and metallo protease inhibitors. A representative alignment of PIs from these venomous animals shows that, despite eventual differences in Cys assignment, the key-residues for the protease inhibitory activity in all of them occupy similar positions in primary sequence. Whereas sea anemone, snakes and other venomous animals present mainly Kunitz-type inhibitors, PIs from Anurans present the major variety in structure length and number of Cys residues, with at least six distinguishable classes. Their biological sources, specificity against different proteases, and other molecular blanks (being also K + channel blockers) are presented, followed by their molecular diversity. More emphasis was given to the Kunitz-type inhibitors, once they are found in all these organisms. In this review we present the protease inhibitors (PIs) described to date from marine venomous animals, such as from sea anemone extracts and Conus venom, as well as their counterparts in terrestrial venomous animals, such as snakes, scorpions, spiders, Anurans, and Hymenopterans. These inhibitors consist of a chain of ~60 amino acid residues stabilized by three disulfide bridges, and was first observed in the bovine pancreatic trypsin inhibitor (BPTI)-like protease inhibitors, which strongly inhibit trypsin and chymotrypsin. ![]() The Kunitz-type protease inhibitors are the best-characterized family of serine protease inhibitors, probably due to their abundance in several organisms.
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