Abstract
Phosphoenolpyruvate carboxykinase (PEPCK) is an important catalytic enzyme in helminth parasites that catalyses a reverse reaction forming oxaloacetate from phosphoenolpyruvate. Because of its functional significance, present work was undertaken to construct and validate the 3D structure of PEPCK in Schistosoma mansoni. The 3D model protein was generated based on the known crystal structure of rat cytosolic PEPCK as template using Modeller 9v10 software. The resulting models were assessed by Procheck, Anolea, ProSA-web, and Errat. We have also identified all the pockets and voids on the best model protein to provide a detailed delineation of all atoms participating in their formation using CASTp server and to dock with best fitted ligand (guanosine diphosphate, GDP) using AutoDock 4.2. The model protein showed reliable structure with Ramachandran plot: 90.2 % core region, 9.1 % allow, 0.8 % generously allowed and 0.0 % disallowed region amino acid distributions. GDP was found to be docked in its active site, which formed a single H-bond with ASN 524 residue of model protein. Characterisation of PEPCK model protein has also been done to know its various biochemical natures. Therefore, the model structure could prove useful in further functional characterization and may be used to target and design drugs against S. mansoni.
Similar content being viewed by others
References
Al Lazikani B, Jung J, Xiang Z, Honig B (2001) Protein structure prediction. Curr Opin Chem Biol 5:51–56
Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ (1990) Basic local alignment search tool. J Mol Biol 215(3):403–410
Asahi H, Osman A, Cook RM, LoVerde PT, Stadecker MJ (2000) Schistosoma mansoni phosphoenolpyruvate carboxykinase, a novel egg antigen: immunological properties of the recombinant protein and identification of a T-cell epitope. Infect Immun 68(6):3385–3393
Banerjee AK, Arora N, Murty USN (2009) Structural model of the Plasmodium falciparum thioredoxin reductase: a novel target for antimalarial drugs. J Vector Borne Dis 46:171–183
Barrett J (2009) Forty years of helminth biochemistry. Parasitology 136:633–1642
Berriman M, Haas BJ, LoVerde PT, Wilson RA, Dillon GP, Cerqueira GC, Mashiyama ST, Al-Lazikani B, Andrade LF, Ashton PD, Aslett MA, Bartholomeu DC, Blandin G, Caffrey CR, Coghlan A, Coulson R, Day TA, Delcher A, DeMarco R, Djikeng A, Eyre T, Gamble JA, Ghedin E, Gu Y, Hertz-Fowler C, Hirai H, Hirai Y, Houston R, Ivens A, Johnston DA, Lacerda D, Macedo CD, McVeigh P, Ning Z, Oliveira G, Overington JP, Parkhill J, Pertea M, Pierce RJ, Protasio AV, Quail MA, Rajandream MA, Rogers J, Sajid M, Salzberg SL, Stanke M, Tivey AR, White O, Williams DL, Wortman J, Wu W, Zamanian M, Zerlotini A, Fraser-Liggett CM, Barrell BG, El-Sayed NM (2009) The genome of the blood fluke Schistosoma mansoni. Nature 460(7253):352–358
Binkowski TA, Naghibzadeh S, Liang J (2003) CASTp: computed atlas of surface topography of proteins. Nucl Acids Res 31(13):3352–3355
Bueding E (1950) Effect of drugs on metabolism and enzyme systems of parasites. J Parasitol 36(3):201–210
Bundy DA (1994) Immuno-epidemiology of intestinal helminthic infection. The global burden of intestinal nematode disease. Trans R Soc Trop Med Hyg 88(3):259–261
Cavasotto CN, Phatak SS (2009) Homology modeling in drug discovery: current trends and applications. Drug Discov Today 14(13/14):676–683
Chirac P, Torreele E (2006) Global framework on essential health R&D. Lancet 367(9522):1560–1561
Dundas J, Ouyang Z, Tseng J, Binkowski A, Turpaz Y, Liang J (2006) CASTp: computed atlas of surface topography of proteins with structural and topographical mapping of functionally annotated residues. Nucl Acid Res 34:W116–W118
Elsliger MA, Deacon AM, Godzik A, Lesley SA, Wooley J, Wuthrich K, Wilson IA (2010) The JCSG high-throughput structural biology pipeline. Acta Crystallogr F66:1137–1142
Eswar N, Eramian D, Webb B, Shen M, Sali A (2008) Protein structure modeling with Modeller. Methods Mol Biol 426(1):145–159
Fiser A, Do RK, Sali A (2000) Modeling of loops in protein structures. Prot Sci 9:1753–1773
Fiser A, Feig M, Brooks CL, Sali A (2002) Evolution and physics in comparative protein structure modeling. Acc Chem Res 35:413–421
Gasteiger E, Gattiker A, Hoogland C, Ivanyi I, Appel RD, Bairoch A (2003) ExPASy: the proteomics server for in-depth protein knowledge and analysis. Nucl Acids Res 31(13):3784–3788
Geary TG, Winterrowd CA, Alexander-Bowman SJ, Favreau MA, Nulf SC, Klein RD (1993) Ascaris suum: cloning of a cDNA encoding phosphoenolpyruvate carboxykinase. Exp Parasitol 77:155–161
Guruprasad K, Reddy BV, Pandit MW (1990) Correlation between stability of a protein and its dipeptide composition: a novel approach for predicting in vivo stability of a protein from its primary sequence. Protein Eng 4(2):155–161
Hotez PJ (2008) Forgotten people and forgotten diseases: the neglected tropical diseases and their impact on global health and development. ASM Press, Washington, DC
Khan HN, Rashid H, Kulsoom S (2011) Homology modeling of γ-aminobutyrate-aminotransferase, a pyridoxal phosphate-dependent enzyme of Homo sapiens: molecular modeling approach to rational drug design against epilepsy. Afr J Biotechnol 10(31):5916–5926
Kherraz K, Kherraz K, Kameli A (2011) Homology modeling of ferredoxin–nitrite reductase from Arabidopsis thaliana. Bioinformation 6(3):115–119
Knudsen GM, Medzihradszky KF, Lim KC, Hansell E, McKerrow JH (2005) Proteomic analysis of Schistosoma mansoni cercarial secretions. Mol Cell Proteomics 4:1862–1875
Laskowski RA (2009) PDBsum new things. Nucl Acid Res 37:D355–D359
Laskowski RA, MacArthur MW, Moss DS, Thornton JM (1993) PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Crystallogr 26(2):283–291
Laskowski RA, Rullmann JAC, MacArthur MW, Kaptein R, Thornton JM (1996) AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR. J Biomol NMR 8(4):477–486
Mansour TE (2002) Chemotherapeutic targets in parasites contemporary strategies. Cambridge University Press, Cambridge, pp 156–187
McKellar QA, Jackson F (2004) Veterinary anthelmintics: old and new. Trends Parasitol 20:456–461
Melo F, Feytmans E (1998) Assessing protein structures with a non-local atomic interaction energy. J Mol Biol 277:1141–1152
Melo F, Devos D, Depiereux E, Feytmans E (1997) ANOLEA: a www server to assess protein structures. In: Proceedings of the international conference on intelligent systems for molecular biology, vol 5, pp 187–190
Morris AL, MacArthur MW, Hutchinson EG, Thornton JM (1992) Stereochemical quality of protein structure coordinates. Proteins 2(4):345–364
Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm and empirical binding free energy function. J Comput Chem 19:1639–1662
Omura S, Miyadera H, Ui H, Shiomi Z, Yamaguchi Y, Masuma R, Nagamitsu T, Takano D, Sunazuka T, Harder A, Kolbl H, Namikoshii M, Miyoshi H, Sakamoto K, Kita K (2001) An anthelmintic compound, nafuredin, shows selective inhibition of complex I in helminth mitochondria. Proc Natl Acad Sci USA 98:60–62
Rohrer SP, Saz HJ, Nowak T (1986) Purification and characterization of phosphoenolpyruvate carboxykinase from the parasitic helminth Ascaris suum. J Biol Chem 261(28):13049–13055
Roy B, Swargiary A (2009) Anthelmintic efficacy of ethanolic shoot extract of Alpinia nigra on tegumental enzymes of Fasciolopsis buski, a giant intestinal parasite. J Parasit Dis 33:48–53
Roy B, Swargiary A, Syiem D, Tandon V (2010) Potentilla fulgens (Family Rosaceae), a medicinal plant of Northeast India: a natural anthelmintic? J Parasit Dis 34:83–88
Russell RB, Barton GJ (1992) Multiple protein sequence alignment from tertiary structure comparison: assignment of global and residue confidence levels. Proteins 14:309–323
Sali A, Blundell TL (1993) Comparative protein modeling by satisfaction of spatial restraints. J Mol Biol 234:779–815
Sharma P, Bhattacharya A (2012) 3-D structure prediction of aquaporin-2, virtual screening and in silico docking studies of gold and silver derivatives, used as potent inhibitors. Int J Pharma Pharm Sci 4(1):574–579
Sippl MJ (1993) Recognition of errors in three-dimensional structures of proteins. Proteins 17:355–362
Somvanshi P, Singh V (2008) Homology modeling and prediction of catalytic amino acid in the neurotoxin from Indian cobra (Naja naja). Open Bioinfor J 2:97–102
Sullivan SM, Holyoak T (2007) Structures of rat cytosolic PEPCK: insight into the mechanism of phosphorylation and decarboxylation of oxaloacetic acid. Biochemistry 46(35):10078–10088
Sumathi K, Ananthalakshmi P, Roshan MNA, Sekar K (2006) 3dSS: 3D structural superposition. Nucl Acids Res 34:w128–w132
Swargiary A, Roy B (2011) Kinetics of Acetylcholinesterase inhibition in Fasciolopsis buski and Raillietina echinobothrida by shoot extract of Alpinia nigra, an indigenous medicinal plant. Med Plants 3(2):145–150
Verma AK, Swargiary A, Prasad SB, Arjun J (2012) Homology modeling of phosphoenolpyruvate carboxykinase of Ascaris suum. J Pharm Res 5(2):1248–1255
Vokral I, Krizova V, Lamka J, Kubicek V, Szotakova B, Varady B, Nobilis M, Skalova L (2010) Effect of flubendazole on biotransformation enzymes activities in Haemonchus contortus. Open Parasitol J 4:24–28
Wallace AC, Laskowski RA, Thornton JM (1996) LIGPLOT: a program to generate schematic diagrams of protein–ligand interactions. Protein Eng 8:127–134
WHO (2002) WHO traditional medicine strategy 2002–2005. WHO/EDM/TRM/2002.1. 61 pp
WHO (2010) Report on neglected tropical diseases: working to overcome the global impact of neglected tropical diseases? ISBN 978 92 4 1564090 (NLM Classification: WC 680)
Wiederstein M, Sippl MJ (2007) ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucl Acids Res 35:w407–w410
Acknowledgments
This study was supported by the Rajiv Gandhi National Fellowship to AS. The authors are also thankful to Tezpur University for organizing and providing complete training of Modeller 9v10 software.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Swargiary, A., Verma, A.K. & Sarma, K. Homology modeling and docking studies of phosphoenolpyruvate carboxykinase in Schistosoma mansoni . Med Chem Res 22, 2870–2878 (2013). https://doi.org/10.1007/s00044-012-0289-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-012-0289-2