Structural, Functional and Therapeutic Aspects of Snake Venom Metal- Loproteinases
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Send Orders for Reprints to [email protected] 28 Mini-Reviews in Organic Chemistry, 2014, 11, 28-44 Structural, Functional and Therapeutic Aspects of Snake Venom Metal- loproteinases P. Chellapandi* Department of Bioinformatics, School of Life Sciences, Bharathidasan University, Tiruchirappalli-620024, Tamil Nadu, India Abstract: Snake venoms are rich sources of metalloproteinases that are of biological interest due to their diverse molecu- lar diversity and selective therapeutic applications. Snake venoms metalloproteinases (SVMPs) belong to the MEROPS peptidase family M12B or reprolysin subfamily, which are consisted of four major domains include a reprolysin catalytic domain, a disintegrin domain, a reprolysin family propeptide domain and a cysteine-rich domain. The appropriate struc- tural and massive sequences information have been available for SVMPs family of enzymes in the Protein Data Bank and National Center for Biotechnology Information, respectively. Functional essentiality of every domain and a crucial contri- bution of binding geometry, primary specificity site, and structural motifs have been studied in details, pointing the way for designing potential anti-coagulation, antitumor, anti-complementary and anti-inflammatory drugs or peptides. These enzymes have been reported to degrade fibrinogen, fibrin and collagens, and to prevent progression of clot formation. An- giotensin-converting enzyme activity, antibacterial properties, haemorrhagic activity and platelet aggregation response of SVMPs have been studied earlier. Structural information of these enzymes together with recombinant DNA technology would strongly promote the construction of many recombinant therapeutic peptides, particularly fibrinogenases and vac- cines. We have comprehensively reviewed the structure-function-evolution relationships of SVMPs family proteins and their advances in the promising target models for structure-based inhibitors and peptides design. Moreover, structure- function-evolution integrity of metalloproteinase from Gloydius halys venom was preliminarily analyzed herein that may provide a conceptual idea for the future of antibacterial peptide design. Keywords: Reprolysin, Bioactive peptides, Family M12B, ADAMs, Adamalysin, Antimicrobial activity, Metalloproteinase, Snake venoms. 1. INTRODUCTION charged amino acid side chains are ligands for the metal ions in the binding packet. Side chain residues His, Glu, Asp or Proteinase is a hydrolytic enzyme that begins the Lys are the known metal ligands and at least one other hydrolytic breakdown of proteins and peptides, usually by residue (Glu) are required for catalysis [1]. splitting them into polypeptide chains. It occurs in all living kingdoms involving in major physiological phenomena. Proteomic study on snake venom proteins reported the Proteinase family can be classified into five major groups SVMPs belong to the MEROPS peptidase family M12B or based on the catalytic residue viz. serine, threonine, cysteine, reprolysin subfamily [10]. M12B reprolysin subfamily exists aspartate and metal-binding sites [1]. A significant pro- in a majority of snake venoms (Fig. 1). The current portion of serine and metalloproteinases present in snake bioinformatics data on reprolysin subfamily M12B pointed venoms proteins that are typically used in traditional out that there are 148, 145 and 122 species having reprolysin medicine or therapeutics [2-6]. Nevertheless, the majority of (PF01421), reprolysin propeptide (PF01562) and ADAMs snakes have metalloproteinases in the venoms for their (A Disintegrin And Metalloproteinase) cysteine-rich pathophysiological functions in the bitten preys [7]. (PF08516) subfamilies, respectively. Among Colubroidea superfamily (all snakes belong to this superfamily), a Snake venom metalloproteinases (SVMPs) are part of the predominant existence of reprolysin subfamily is reported in metzincin family of zinc-dependent metalloproteinases the venoms of Crotalinae family and then in the venoms of consisting of an identical zinc-dependent motif HEX- Elapidae family. A limited study has been done on the XHXXGXXH and of a methionine turn [8]. Matrixin, astacin reprolysin subfamily in the venoms of Atractaspididae and serralysin are other parts of metzincin family [9]. A family. The protein sequences deposited for reprolysin zincin-like fold is common in SVMPs so that Zn2+ ion takes subfamily in Viperinae family venoms are accounted to be a major role in the catalysis of the hydrolysis of internal, more than in the venoms of Crotalinae family. It suggests the alpha-peptide bonds in a polypeptide chain. One or two advantages of using SVMPs from Viperinae family showing metal ions hold the water molecule (as a nucleophile) and a vital importance in therapeutic and medical applications. Brevilysin H6, acutolysin, bilitoxin, leucolysin, *Address correspondence to this author at the Department of Bioinformatics, jararhagin, bothrolysin, bothropasin, adamalysin, atrolysin A, School of Life Sciences, Bharathidasan University, Tiruchirappalli-620024, atroxase, basilysin, horrilysin, ruberlysin, trimerelysin, Tamil Nadu, India; Tel: +91-431-2407071; Fax:+91-431-2407045; E-mail: [email protected] russellysin, cobrin, najalysin and catrocollastatin are some 1875-6298/14 $58.00+.00 © 2014 Bentham Science Publishers Structural, Functional and Therapeutic Aspects of Snake Venom Metalloproteinases Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1 29 Fig. (1). Dispersion of snake venom metalloproteinases in Colubroidea superfamily. The above figure is represented the total number of species reported for the metalloproteinases and the below figure represents the total number protein sequence entries available in Pfam version 26.0 for Colubroidea superfamily. examples of SVMPs molecular diversity available in reprolysin subfamily has four different conserved domains: a MEROPS database [11]. Twenty eight structures of rep- reprolysin catalytic domain, a disintegrin domain, a rep- rolysin subfamily and 2 structures of ADAMs cysteine-rich rolysin family propeptide domain and an ADAMs cysteine- subfamily include with ligands have been deposited in the rich domain. A reprolysin is a main catalytic enzyme domain protein data bank (PDB) to date. Thus, overwhelming bioin- involving in Zn2+ ion binding and peptide cleavage activity. formatics resources, crystallographic structural information Disintegrin is a small domain typically with an Arg-Gly-Asp and literature records for SVMPs family of enzymes are recognition sequence on a disintegrin-loop that inhibits collectively support the identification, designing and platelet aggregation via integrin binding. Reprolysin family development of therapeutic compounds or peptides from the propeptide domain is the propeptide for members of snake venom sources. peptidase family M12B. The propeptide contains a sequence motif similar to the "cysteine switch" of the matrixins [13- 2. FUNCTIONAL DOMAINS 15]. The last domain, adamalysin (ADAMs), is membrane- bound zinc containing metalloproteinase, which is con- SVMPs are classified into three types (P-I to P-III) based sidered to be crucial modulators of physiological and patho- on their conserved domain architecture [5, 12]. M12B 30 Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1 P. Chellapandi (A) (B) Fig. (2). Topological view of conserved domains identified in metalloproteinase of G. halys (2a) and WebLogo representation of the conserved functional motifs identified across the peptidase M12B family (2b). physiological processes [16]. The residues that are important the molecule [22, 23]. Such multiple functional motifs in the for stabilizing domains architecture are strictly conserved metalloproteinase of G. halys may influence its binding cleft throughout the primary structure among SVMPs [17]. orientation on bacterial membrane proteins. Reprolysin, disintegrin and ADAM cysteine-rich domains are common in the PDB structures with accession 3. STRUCTURAL EVALUATION number of 3K7L, 3DSL, 3HDB, 2ERQ, 2DW0 and 2E3X To elucidate their molecular structure and function, and other available PDB structures have only a reprolysin crystallographic studies have been carried out for the venoms domain. In addition to these domains, a reprolysin M12B of Naja atra, Bothrops moojeni, B. asper, B. jararaca, A. propeptide domain is predicted in the metalloproteinase of acutus, Crotalus adamanteus, C. atrox, Trimeresurus flavo- Gloydius halys (Agkistrodon halys) venom (Fig. 2a). We viridis, T. mucrosquamatus and Daboia russellii siamensis identified consensus motif HEXXHXUGUXHU and a bulky (Table 1). In general, SVMPs are structurally related to the hydrophobic core in the binding packets. Conserved domains mammalian membrane-bound ADAMs and other bacterial in those sequences were searched out with SMART 7.0 reprolysin subfamilies [24]. server [18] and NCBI-conserved domain database [19]. Catalytic site residue, Glu335 and 3 actives site residues, 3.1. Adamalysin II His334, His338 and His344, are located in a catalytic reprolysin domain of metalloproteinase from G. halys venom. The first crystallographic structure of adamalysin II In contrast, two highly conserved characteristic sequences from the snake venom of C. adamanteus was determined His142-Glu143-X-X-His146-X-X-Gly149-X-X-His152 and by Gomis-Ruth et al. [13]. Adamalysin II is mostly multi- Cys162-Ile163-Met164 are identified in acutolysin C [20]. domain protein, an ellipsoidal molecule with a shallow The sequentially conserved motifs