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Comparative Structural Analysis of Phospholipase A2 and Combinatorial Screening of PLA2 Inhibitors
Sanjay Sharma Timilsina, Sarnim Gurung, Roshan Adhikari, Jignesh Savani, Mayank Agrawal, Vedamurthy A.B., Joy Harris Hoskeri
Pages - 14 - 26     |    Revised - 05-04-2013     |    Published - 30-04-2013
Volume - 7   Issue - 1    |    Publication Date - June 2013  Table of Contents
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KEYWORDS
Phospholipase A2, Antivenom Drugs, Superimposition Studies, Sequence Alignment, Combinatorial Screening, Molecular Docking.
ABSTRACT
Phospholipases A2 (PLA2) enzyme release fatty acids from the second carbon group of glycerol. This particular phospholipase specifically recognizes the Sn-2 acyl bond of phospholipids and catalytically hydrolyzes the bond releasing arachidonic acid and lysophospholipids. PLA2 are commonly found in mammalian tissues as well as in insects and snakes venom. Venoms constitute a rich source of phospholipase A2 (PLA2) enzymes, which show remarkable diversity in their structure and function. In this investigation, we have made an attempt in analyzing the identical active domain in different PLA2 protein structure isolated from different venoms by studying the conserved active pocket residues. The 21 crystal structures of different PLA2 enzymes isolated from venoms of different species were studied and collected from PDB database. Comparative studies to analyse the conserved active site in this protein was carried out by superimposition studies using TOPMATCH server. To validate the superimposition results sequence alignment studies was carried out using T-COFFEE by multiple sequence alignment analysis. This revealed that 9 PLA2 enzymes from different venoms viz., Daboia russellii, Cerrophidion godmani, Dienagkistrodon acutus, Bothrops Neuwied, Agkistrodon contortrix, Naja sagittifera, Bos Taurus, Notechis sentatusscutatus, Apis mellifera showed similarity in their active pocket residues, indicating a single drug can effectively occupy their pocket and inhibit the functions of these nine proteins. Hence, in-silico drug designing studies for antivenom drugs against PLA2 was carried out by combinatorial screening of 18 antivenom compounds by docking with PLA2 molecule using Autodock 3.0 tool. In-silico drug designing studies revealed that among 18 antivenom compounds, Indole was most potent in its action in inhibiting the PLA2 function with inhibition constant of 0.04.
1 Google Scholar 
2 CiteSeerX 
3 refSeek 
4 Scribd 
5 SlideShare 
6 PdfSR 
1 E.A. Dennis. “Diversity of group types, regulation, and function of phospholipaseA2." Journal of Biological Chemistry. Vol 269(18), pp. 13057-13060, May. 1994.
2 Y.H. Pan, T.M. Epstein, M.K. Jain and B.J. Bahnson. "Five coplanar anion binding sites on one face of phospholipase A2: relationship to interface binding". Biochemistry. Vol 40(3), pp. 609–617, Jan. 2001.
3 J.P. Nicolas, Y. Lin, G. Lambeau, F. Ghomashchi, M. Lazdunski and M.H. Gelb. "Localization of structural elements of bee venom phospholipase A2 involved in N-type receptor binding and neurotoxicity". Journal Biological Chemistry. Vol 272(11), pp. 7173-7181, Mar. 1997.
4 R.M. Kini. Venom Phospholipase A2 Enzymes: Structure, Function and Mechanism. England,John Wiley & Sons, Chichester, 1997, pp. 1-511.
5 J. P. Chippaux. Snake bites- appraisal of the global situation. Bulletin of World Health Organization, Vol 76(5), 515-524, May. 1998.
6 L.A. Ferreira., O.B. Henriques, A.A. Andreoni, G.R. Vital, M.M. Campos, G.G. Habermehl, and V.L. de Moraes. “Antivenom and biological effects of ar-turmerone isolated from Curcuma longa (Zingiberaceae)”. Toxicon. 30, pp. 1211–1218, Oct. 1992.
7 A. Argiolas and J.J. Pisano. "Facilitation of phospholipase A2 activity by mastoparans, a new class of mast cell degranulating peptides from wasp venom". Journal of Biological Chemistry. Vol 258(22), pp. 13697-13702, Nov. 1983.
8 Z. Mallat, G. Lambeau, A. Tedgui. "Lipoprotein-Associated and Secreted Phospholipases A2 in Cardiovascular Disease: Roles as Biological Effectors and Biomarkers". Circulation. Vol 122(21), pp. 2183-2200. Nov. 2010.
9 D. De Luca, A. Minucci, P. Cogo, E.D. Capoluongo, G. Conti, D. Pietrini, V.P. Carnielli, and M.Piastra. "Secretory phospholipase A pathway during pediatric acute respiratory distress syndrome: a preliminary study". Pediatric Critical CareMediciine. Vol 12(1), 20-24, Jan. 2011.
10 W.R. Henderson, R.C. Oslund, J.G. Bollinger, X. Ye, Y.T. Tien, J. Xue, and M.H. Gelb. "Blockade of Human Group X Secreted Phospholipase A2 (GX-sPLA2)-induced Airway Inflammation and Hyperresponsiveness in a Mouse Asthma Model by a Selective GX-sPLA2 Inhibitor". Journal of Biological Chemistry, Vol 286(32), 28049–28055, Aug. 2011.
11 Y. Wei, S.P. Epstein, S. Fukuoka, N.P. Birmingham, X.M. Li, and P.A. Asbell. "sPLA2-IIa Amplifies Ocular Surface Inflammation in the Experimental Dry Eye (DE) BALB/c Mouse Model". Investigative Opthalmology and Visual Science. Vol 52(7), pp. 4780–4788, Jul. 2011.
12 M.J. Sippl and M. Wiederstein. “A note on difficult structure alignment problems”.Bioinformatics. Vol 24(3), pp. 426-427, Jan. 2008.
13 C. Notredame, D.G. Higgins and J. Heringa. “T-Coffee: A novel method for fast and accurate multiple sequence alignment”. Journal of Molecular Biology. Vol 302(1), pp. 205-217, Sep.2000.
14 A.W. Schüttelkopf and D.M.Van Aalten. “PRODRG: a tool for high-throughput crystallography of protein-ligand complexes”. Acta Crystallographica Section D Biological Crystallography. Vol 60(8), pp. 1355-1363, Aug. 2004.
15 R. Bhat, Y. Xue and S. Berg. “Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418”. Journal of Biological Chemistry. Vol 278(46), pp.45937–45945, Aug 2003.
16 A.K. Ghose and G.M. Crippen. “Atomic physicochemical parameters for three-dimensionalstructure-directed quantitative structure–activity relationships 2. Modeling dispersive and hydrophobic interactions”. Journal of Chemical Information Computer Sciences. Vol 27(1), pp.21-35, Feb. 1987.
17 T.A. Binkowski, S. Naghibzadeg and J. Liang. “ CASTp computed atlas of surface topography of proteins”. Nucleic Acid Research. Vol 31(13), pp. 3352–3355, Jul. 2003.
18 J. Gasteiger and M. Marsili. “Iterative partial equalization of orbital electronegativity - a rapid access to atomic charges”. Tetrahedron. Vol 36(22), pp. 3219-3288, Mar. 1980.
19 T. Reya and H. Clevers. ” Wnt signalling in stem cells and cancer”. Nature. Vol 434(7035), pp.843-850, Apr. 2005.
Mr. Sanjay Sharma Timilsina
The Oxford College of Science, - India
sanjaytimilsina@gmail.com
Mr. Sarnim Gurung
The Oxford College of Science, - India
Mr. Roshan Adhikari
Dept. of Biotechnology The Oxford College of Science, - India
Miss Jignesh Savani
Dept. of Biotechnology, The Oxford College of Science, - India
Mr. Mayank Agrawal
Dept. of Biotechnology The Oxford College of Science, - India
Dr. Vedamurthy A.B.
The Oxford College of Science, - India
Dr. Joy Harris Hoskeri
The Oxford College of Science - India