Abstract
Histone lysine methyltransferase (HKMT) are histone-modifying enzymes that catalyze the transfer of methyl groups to lysine and arginine residues of histone protein. HKMTs have been involved in transcriptional regulation of various proteins in organisms. Malaria parasite also has HKMT, which plays a major role in parasite development and pathogenesis and also in regulation of various biological process and pathways. Our aim is to study fundamental biology of key molecules involved in the survival of Plasmodium falciparum and use these to develop efficient synthetic peptides and chemical compounds. As a first step in this direction, we computationally predicted the three-dimensional structure of HKMT of P. falciparum (PfHKMT) by using iterative threading assembly refinement. The PfHKMT three-dimensional model was validated using PROCHECK and docked with known HKMT inhibitor Bix01294 using Autodock. Our initial results are encouraging and indicate that structural analysis of PfHKMT could be important in developing novel synthetic molecules against malaria.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abu-Farha M, Lambert JP, Al-Madhoun AS, Elisma F, Skerjanc IS, Figeys D (2008) The tale of two domains: proteomics and genomics analysis of SMYD2, a new histone methyltransferase. Mol Cell Proteomics 7:560–572
Bernstein BE, Meissner A, Lander ES (2007) The mammalian epigenome. Cell 128:669–681
Chookajorn T, Dzikowski R, Frank M, Li F, Jiwani AZ, Hartl DL, Deitsch KW (2007a) Epigenetic memory at malaria virulence genes. Proc Natl Acad Sci USA 104:899–902
Chookajorn T, Dzikowski R, Frank M, Li F, Jiwani AZ, Hartl DL, Deitsch KW (2007b) Epigenetics memory at malaria virulence genes. Proc Natl Acad Sci USA 104:899–902
Cowman AF, Berry D, Baum J (2012) The cellular and molecular basis for malaria parasites invasion of the human red blood cell. J Cell Biol 198:961–971
Cui L, Miao J, Furuya T, Li X, Su X, Cui L (2007) PfGCN5 mediated histone H3 acetylation plays a key role in gene expression in Plasmodium falciparum. Eukaryot Cell 6:1219–1227
Cui L, Fan Q, Cui L, Miao J (2008) Histone lysine methyltransferases and demethylases in Plasmodium falciparum. Int J Parasitol 38:1083–1097
Duraisingh MT, Voss TS, Marty AJ, Duffy MF, Good RT, Thompson JK, Freitas-Junior LH, Scherf A, Crabb BS, Cowman AF (2005) Heterochromatin silencing and locus repositioning linked to regulation of virulence genes in Plasmodium falciparum. Cell 121:13–24
Fan Q, Miao J, Cui L, Cui L (2009) Characterization of PRMT1 from Plasmodium falciparum. Biochem J 421:107–118
Feng Q, Wang H, Ng HH, Erdjument-Bromage H, Tempst P, Struhl K, Zhang Y (2002) Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain. Curr Biol 12:1052–1058
Frank M, Dzikowski R, Costantini D, Amulic B, Berdougo E, Deitch K (2006) Strict pairing of var promoters and introns is required for var gene silencing in the malaria parasite Plasmodium falciparum. J Biol Chem 281:9942–9952
Freitas-Junior LH, Hernandez-Rivas R, Ralph SA, Montiel-Condado D, Ruvalcaba-Salazar OK, Rojas-Meza AP, Mancio-Silva L, Leal-Silvestre RJ, Gontijo AM, Shorte S, Scherf A (2005) Telomeric heterochromatin propagation and histone acetylation control mutually exclusive expression of antigenic variation genes in malaria parasites. Cell 121:25–36
Geer LY, Domrachev M, Lipman DJ, Bryant SH (2002) CDART: protein homology by domain architecture. Genome Res 12:1619–16123
Gelato KA, Fischle W (2008) Role of histone modifications in defining chromatin structure and function. Biol Chem 389:353–363
Johns DT (1999) Protein secondary structure prediction based on position-specific scoring matrices. J Mol Biol 292:195–202
Laskowski RA, MacArthur MW, Thornton JM (2001) PROCHECK: validation of protein structure coordinates. In: Rossmann MG, Arnold E (eds) International tables of crystallography, volume F. Crystallography of biological macromolecules. Kluwer Academic Publishers, Dordrecht, pp 722–725
Lopez-Rubio JJ, Gontijo AM, Nunes MC, Issar N, Rivas RH, Scherf A (2007) 5’ flanking region of var genes nucleate histone modification patterns linked to phenotypic inheritance of virulence traits in malaria parasites. Mol Microbiol 66:1296–1305
Lopez-Rubio JJ, Mancio-Silva L, Scherf A (2009) Genome-wide analysis of heterochromatin associates clonally variant gene regulation with perinuclear repressive centers in malaria parasites. Cell Host Microbe 5:179–190
Malmquist NA, Moss TA, Scherf A, Fuchter MJ (2012) Small molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms in Plasmodium falciparum. Proc Natl Acad Sci USA 109:16708–16713
Miao J, Fan Q, Cui L, Li J, Li J, Cui L (2006) The malaria parasite Plasmodium falciparum histones: organization, expression, and acetylation. Gene 369:53–65
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
Ng HH, Feng Q, Wang H, Erdjument-Bromage H, Tempst P, Zhang Y, Struhl K (2002) Lysine methylation within the globular domain of histone H3 by Dot1 is important for telomeric silencing and Sir protein association. Genes Dev 16:1518–1527
Qian C, Wang X, Manzur K, SN FarooqA, Zeng L, Wang R, Zhou MM (2006) Structural insight of the specificity and catalysis of a viral histone H3 lysine 27 methyltransferase. J Mol Biol 359:86–96
Roy A, Kucukural A, Zhang Y (2010) I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc 5:725–738
Sautel CF, Cannella D, Bastien O, Kieffer S, Aldebert D, Garin J, Tardieux I, Belrhali H, Hakimi MA (2007) SET8-mediated methylations of histone H4 lysine 20 mark silent heterochromatic domains in apicomplexan genomes. Mol Cell Biol 27:5711–5724
Sawan C, Herceg Z (2010) Histone modifications and cancer. In: Ushijima T, Herceg Z (eds) Epigenetics and cancer, part A, volume 70. Advances in genetics. Academic Press, Boston, pp 57–85
Volz JC, Carvalho TG, Ralph SA, Gilson P, Thompson J, Tonkin CJ, Langer C, Crabb BS, Cowman AF (2010) Potential epigenetic regulatory proteins localise to distinct nuclear sub-compartments in Plasmodium falciparum. Int J Parasitol 40:109–121
Volz JC, Bartfai R, Petter M, Langer C, Josling GA, Tsuboi T, Schwach F, Baum F, Rayner JC, Stunnenberg HG, Duffy MF, Cowman AF (2012) PfSET10, a Plasmodium falciparum methyltransferase, maintains the active var gene in a poised state during parasite division. Cell Host Microbe 11:7–18
Voss TS, Healer AJ, Marty AJ, Duffy MF, Thompson JK, Beeson JG, Reeder JC, Crabb BS, Cowman AF (2006) A var gene promoter controls allelic exclusion of virulence genes in Plasmodium falciparum malaria. Nature 439:1004–1008
Acknowledgments
Authors would like to thank National Institute of Immunology, New Delhi and Shiv Nadar University, Uttar Pradesh for providing the resources to conduct these studies. S.S. is a recipient of the IYBA Award from Department of Biotechnology (DBT). M.S. is supported by DBT project. P.D. is supported by a research fellowship from Shiv Nadar University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflict of interest
The authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sharma, M., Dhiman, C., Dangi, P. et al. Designing synthetic drugs against Plasmodium falciparum: a computational study of histone-lysine N-methyltransferase (PfHKMT). Syst Synth Biol 8, 155–160 (2014). https://doi.org/10.1007/s11693-014-9144-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11693-014-9144-8