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Review
. 2013 Jun 14;11(6):2069-112.
doi: 10.3390/md11062069.

Protease inhibitors from marine venomous animals and their counterparts in terrestrial venomous animals

Caroline B F Mourão  1 , Elisabeth F Schwartz
Affiliations
Review

Protease inhibitors from marine venomous animals and their counterparts in terrestrial venomous animals

Caroline B F Mourão et al. Mar Drugs. .

Abstract

The Kunitz-type protease inhibitors are the best-characterized family of serine protease inhibitors, probably due to their abundance in several organisms. 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. 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. More emphasis was given to the Kunitz-type inhibitors, once they are found in all these organisms. Their biological sources, specificity against different proteases, and other molecular blanks (being also K+ channel blockers) are presented, followed by their molecular diversity. 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. 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. The key-residues for the K+ channel blocking activity was also compared.

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Figures

Figure 1
Figure 1
Representative alignment of toxins with the Kunitz-type motif from venomous animals. Organisms from which the polypeptides were obtained are indicated by the colored lines at left: blue, sea anemones; grey, snakes; red, scorpions; yellow, spider; green, Anurans; purple, Hymenopterans; black, cone snail. The toxins that present potassium channel blocking activity are indicated by symbols after their names: ●, K+ channel blockers with no protease inhibitory activity or still not tested against proteases; ♦ and ◊, dual-function toxins, where ♦ denotes toxins with stronger potency in K+ channels than those indicated by ◊. The other polypeptides, without symbols, are all serine protease inhibitors. The alignment was generated by ClustalW [170] and the consensus sequence was colored using Chroma and manual edition [171]. Key residues for K+ channel blocking activity are highlighted in red. Key residues for protease inhibition with more specificity to trypsin or chymotrypsin are highlighted in magenta and cyan, respectively. Some of them were suggested to be key residues by sequence similarity with other toxins. The P1 site residues are pointed by an arrow. Capital letters denote amino acids. Lower-case letters denote: b, big; p, polar; h, hydrophobic; a, aromatic. The known conserved disulfide bridges are labeled in black lines. The black dotted line suggests a possible new disulfide bridge in scorpion venom PIs [99]. The numbers within parenthesis mean amino acid residues from the C-terminus of the peptides that were not completely shown in this alignment.
Figure 2
Figure 2
Tridimensional structures of polypeptides from venomous animals with the Kunitz-type inhibitor motif (A–D) and bovine pancreatic trypsin inhibitor (BPTI): trypsin complex (E). (A) ShPI-1 (PDB code 1SHP) from the sea anemone Stoichactis helianthus; (B) conkunitzin-S1 (PDB code 2CA7) from the cone snail Conus striatus; (C) HWTX-XI (PDB code 2JOT) from the spider Ornithoctonus huwena; (D) anntoxin (PDB code 2KCR) from the frog Hyla annectans; (E) BPTI:trypsin complex (PDB code 3OTJ). The structures are shown as ribbon diagrams, where α-helixes are indicated by red color, β-strands by yellow, 310-helix by dark blue; and disordered structure by silver. In detail, Lys residue at P1 position (cyan at A, C and D). In BPTI:trypsin complex, interacting amino acid residues are shown in dark grey for BPTI (Lys15 residue at P1 position) and in orange for trypsin (Asp189 at S1 position). A, C, D and E were obtained with the software VMD (visual molecular dynamics) [185], whereas B was obtained with the software Discovery Studio 3.5 (Accelrys, Inc., San Diego, CA, USA).
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