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Deciphering structure, function and mechanism of Plasmodium IspD homologs from their evolutionary imprints

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Abstract

Malaria is a life-threatening mosquito-borne blood disease caused by infection with Plasmodium parasites. Anti-malarial drug resistance is a global threat to control and eliminate malaria and therefore, it is very important to discover and evaluate new drug targets. The 2-C-methyl-d-erythritol 4-phosphate cytidylyltransferase (IspD) homolog is a second in vivo target for fosmidomycin within isoprenoid biosynthesis in malarial parasites. In the present study, we have deciphered the sequence-structure–function integrity of IspD homologs based on their evolutionary imprints. The function and catalytic mechanism of them were also intensively studied by using sequence-structure homology, molecular modeling, and docking approach. Results of our study indicated that substrate-binding and dimer interface motifs in their structures were extensively conserved and part of them closely related to eubacterial origins. Amino acid substitutions in their coiled-coil regions found to bring a radical change in secondary structural elements, which in turn may change the local structural environment. Arg or Asp was identified as a catalytic site in plasmodium IspD homologs, contributing a direct role in the cytidylyltransferase activity similar to bacterial IspD. Results of molecular docking studies demonstrated how anti-malarial drugs such as fosmidomycin and FR-900098 have competitively interacted with the substrate-binding site of these homologs. As shown by our analysis, species-specific evolutionary imprints in these homologs determine the sequence-structure–function-virulence integrity and binding site alterations in order to confer anti-malarial drug resistance.

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References

  1. World Malaria Report (2017) World Health Organization 2017. ISBN 978-92-4-156552-3. http://www.who.int/malaria/publications/world-malaria-report-2017/en/

  2. Antony HA, Parija SC (2016) Anti-malarial drug resistance: an overview. Trop Parasitol 6:30–41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cui L, Mharakurwa S, Ndiaye D, Rathod PK, Rosenthal PJ (2015) Anti-malarial drug resistance: literature review and activities and findings of the ICEMR network. Am J Trop Med Hyg 93:57–68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Carey MA, Papin JA, Guler JL (2017) Novel Plasmodium falciparum metabolic network reconstruction identifies shifts associated with clinical anti-malarial resistance. BMC Genom 18:543

    Article  CAS  Google Scholar 

  5. Velanker SS, Ray SS, Gokhale RS, Suma S, Balaram H, Balaram P, Murthy MR (1997) Triosephosphate isomerase from Plasmodium falciparum: the crystal structure provides insights into anti-malarial drug design. Structure 5:751–761

    Article  CAS  PubMed  Google Scholar 

  6. Donaldson T, Kim K (2010) Targeting Plasmodium falciparum purine salvage enzymes: A look at structure-based drug development. Infect Disord Drug Targets 10:191–199

    Article  CAS  PubMed  Google Scholar 

  7. Crowther GJ, Napuli AJ, Gilligan JH, Gagaring K, Borboa R, Francek C, Chen Z, Dagostino EF, Stockmyer JB, Wang Y, Rodenbough PP, Castaneda LJ, Leibly DJ, Bhandari J, Gelb MH, Brinker A, Engels IH, Taylor J, Chatterjee AK, Fantauzzi P, Glynne RJ, Van Voorhis WC, Kuhen KL (2011) Identification of inhibitors for putative malaria drug targets among novel anti-malarial compounds. Mol Biochem Parasitol 175:21–29

    Article  CAS  PubMed  Google Scholar 

  8. Singh N, Chevé G, Avery MA, McCurdy CR (2007) Targeting the methyl erythritol phosphate (MEP) pathway for novel anti-malarial, antibacterial and herbicidal drug discovery: inhibition of 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR) enzyme. Curr Pharm Des 13:1161–1177

    Article  CAS  PubMed  Google Scholar 

  9. Lim L, McFadden GI (2010) The evolution, metabolism and functions of the apicoplast. Philos Trans R Soc Lond B Biol Sci 365:749–763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Seeber F, Soldati-Favre D (2010) Metabolic pathways in the apicoplast of apicomplexa. Int Rev Cell Mol Biol 281:161–228

    Article  CAS  PubMed  Google Scholar 

  11. Kuntz L, Tritsch D, Grosdemange-Billiard C, Hemmerlin A, Willem A, Bach TJ, Rohmer M (2005) Isoprenoid biosynthesis as a target for antibacterial and antiparasitic drugs: phosphonohydroxamic acids as inhibitors of deoxyxylulose phosphate reducto-isomerase. Biochem J 386:127–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gräwert T, Groll M, Rohdich F, Bacher A, Eisenreich W (2011) Biochemistry of the non-evalonate isoprenoid pathway. Cell Mol Life Sci 68:3797–3814

    Article  CAS  PubMed  Google Scholar 

  13. Odom AR, Van Voorhis WC (2010) Functional genetic analysis of the Plasmodium falciparum deoxyxylulose 5-phosphate reductoisomerase gene. Mol Biochem Parasitol 170:108–111

    Article  CAS  PubMed  Google Scholar 

  14. Wiesner J, Ziemann C, Hintz M, Reichenberg A, Ortmann R, Schlitzer M, Fuhst R, Timmesfeld N, Vilcinskas A, Jomaa H (2016) FR-900098, an anti-malarial development candidate that inhibits the non-mevalonate isoprenoid biosynthesis pathway, shows no evidence of acute toxicity and genotoxicity. Virulence 7:718–728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jomaa H, Wiesner J, Sanderbrand S, Altincicek B, Weidemeyer C, Hintz M, Türbachova I, Eberl M, Zeidler J, Lichtenthaler HK, Soldati D, Beck E (1999) Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as anti-malarial drugs. Science 285:1573–1576

    Article  CAS  PubMed  Google Scholar 

  16. Wiesner J, Hintz M, Altincicek B, Sanderbrand S, Weidemeyer C, Beck E, Jomaa H (2000) Plasmodium falciparum: detection of the deoxyxylulose 5-phosphate reductoisomerase activity. Exp Parasitol 96:182–186

    Article  CAS  PubMed  Google Scholar 

  17. Zhang B, Watts KM, Hodge D, Kemp LM, Hunstad DA, Hicks LM, Odom AR (2011) A second target of the anti-malarial and antibacterial agent fosmidomycin revealed by cellular metabolic profiling. Biochem 50:3570–3577

    Article  CAS  Google Scholar 

  18. Botté CY, Dubar F, McFadden GI, Maréchal E, Biot C (2012) Plasmodium falciparum apicoplast drugs: targets or off-targets? Chem Rev 112:1269–1283

    Article  CAS  PubMed  Google Scholar 

  19. Imlay LS, Armstrong CM, Masters MC, Li T, Price KE, Edwards RL, Mann KM, Li LX, Stallings CL, Berry NG, O’Neill PM, Odom AR (2015) Plasmodium IspD (2-C-methyl-d-erythritol 4-phosphate cytidyltransferase), an essential and druggable anti-malarial target. ACS Infect Dis 1:157–167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gabrielsen M, Rohdich F, Eisenreich W, Grawert T, Hecht S, Bacher A, Hunter WN (2004) Biosynthesis of isoprenoids: a bifunctional IspDF enzyme from Campylobacter jejuni. Eur J Biochem 271:3028–3035

    Article  CAS  PubMed  Google Scholar 

  21. Kemp LE, Bond CS, Hunter WN (2003) Structure of a tetragonal crystal form of Escherichia coli 2-C-methyl-d-erythritol 4-phosphate cytidylyltransferase. Acta Crystallogr Sect D 59:607–610

    Article  CAS  Google Scholar 

  22. Behnen J, Köster H, Neudert G, Craan T, Heine A, Klebe G (2012) Experimental and computational active site mapping as a starting point to fragment-based lead discovery. ChemMedChem 7:248–261

    Article  CAS  PubMed  Google Scholar 

  23. Baur S, Marles-Wright J, Buckenmaier S, Lewis RJ, Vollmer W (2009) Synthesis of CDP-activated ribitol for teichoic acid precursors in Streptococcus pneumoniae. J Bacteriol 191:1200–1210

    Article  CAS  PubMed  Google Scholar 

  24. Gabrielsen M, Kaiser J, Rohdich F, Eisenreich W, Laupitz R, Bacher A, Bond CS, Hunter WN (2006) The crystal structure of a plant 2C-methyl-d-erythritol 4-phosphate cytidylyltransferase exhibits a distinct quaternary structure compared to bacterial homologues and a possible role in feedback regulation for cytidine monophosphate. FEBS J 273:1065–1073

    Article  CAS  PubMed  Google Scholar 

  25. Björkelid C, Bergfors T, Henriksson LM, Stern AL, Unge T, Mowbray SL, Jones TA (2011) Structural and functional studies of mycobacterial IspD enzymes. Acta Crystallogr D Biol Crystallogr 67:403–414

    Article  CAS  PubMed  Google Scholar 

  26. Gabrielsen M, Bond CS, Hallyburton I, Hecht S, Bacher A, Eisenreich W, Rohdich F, Hunter WN (2004) Hexameric assembly of the bifunctional methylerythritol 2,4-cyclodiphosphate synthase and protein-protein associations in the deoxy-xylulose-dependent pathway of isoprenoid precursor biosynthesis. J Biol Chem 279:52753–52761

    Article  CAS  PubMed  Google Scholar 

  27. Witschel MC, Höffken HW, Seet M, Parra L, Mietzner T, Thater F, Niggeweg R, Röhl F, Illarionov B, Rohdich F, Kaiser J, Fischer M, Bacher A, Diederich F (2011) Inhibitors of the herbicidal target IspD: allosteric site binding. Angew Chem Int Ed Engl 50:7931–7935

    Article  CAS  PubMed  Google Scholar 

  28. Obiol-Pardo C, Cordero A, Rubio-Martinez J, Imperial S (2010) Homology modeling of Mycobacterium tuberculosis 2C-methyl-d-erythritol-4-phosphate cytidylyltransferase, the third enzyme in the MEP pathway for isoprenoid biosynthesis. J Mol Model 16:1061–1073

    Article  CAS  PubMed  Google Scholar 

  29. Letunic I, Doerks T, Bork P (2011) SMART 7: recent updates to the protein domain annotation resource. Nucl Acids Res 40:D302–D305

    Article  CAS  PubMed  Google Scholar 

  30. Hall TA (1999) BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucl Acids Symp Ser 41:95–98

    CAS  Google Scholar 

  31. Rohdich F, Wungsintaweekul J, Fellermeier M, Sagner S, Herz S, Kis K, Eisenreich W, Bacher A, Zenk MH (1999) Cytidine 5′-triphosphate-dependent biosynthesis of isoprenoids: YgbP protein of Escherichia coli catalyzes the formation of 4-diphosphocytidyl-2-C-methylerythritol. Proc Natl Acad Sci USA 96:11758–11763

    Article  CAS  PubMed  Google Scholar 

  32. Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucl Acids Res 25:3389–3402

    Article  CAS  PubMed  Google Scholar 

  33. Thompson JD, Higgins DG, Gibson TJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, positions-specific gap penalties and weight matrix choice. Nucl Acids Res 22:4673–4680

    Article  CAS  PubMed  Google Scholar 

  34. de Castro E, Sigrist CJ, Gattiker A, Bulliard V, Langendijk-Genevaux PS, Gasteiger E, Bairoch A, Hulo N (2006) ScanProsite: detection of PROSITE signature matches and ProRule-associated functional and structural residues in proteins. Nucl Acids Res 34:W362–W365

    Article  CAS  PubMed  Google Scholar 

  35. Bailey TL, Elkan C (1994) Fitting a mixture model by expectation maximization to discover motifs in biopolymers. Proceedings of the second international conference on intelligent systems for molecular biology. AAAI Press, Menlo Park, p 28–36

    Google Scholar 

  36. Marchler-Bauer A, Lu S, Anderson JB, Chitsaz F, Derbyshire MK, DeWeese-Scott C, Fong JH, Geer LY, Geer RC, Gonzales NR, Gwadz M, Hurwitz DI, Jackson JD, Ke Z, Lanczycki CJ, Lu F, Marchler GH, Mullokandov M, Omelchenko MV, Robertson CL, Song JS, Thanki N, Yamashita RA, Zhang D, Zhang N, Zheng C, Bryant SH (2011) CDD: a conserved domain database for the functional annotation of proteins. Nucl Acids Res 39:D225–D229

    Article  CAS  PubMed  Google Scholar 

  37. Foth BJ, Ralph SA, Tonkin CJ, Struck NS, Fraunholz M, Roos DS, Cowman AF, McFadden GI (2003) Dissecting apicoplast targeting in the malaria parasite Plasmodium falciparum. Science 299:705–708

    Article  CAS  PubMed  Google Scholar 

  38. Zuegge J, Ralph S, Schmuker M, McFadden GI, Schneider G (2001) Deciphering apicoplast targeting signals - feature extraction from nuclear-encoded precursors of Plasmodium falciparum apicoplast proteins. Gene 280:19–26

    Article  CAS  PubMed  Google Scholar 

  39. Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG (1997) The ClustalX windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucl Acids Res 25:4876–4882

    Article  CAS  PubMed  Google Scholar 

  40. Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S (2011) MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 28:2731–2739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gasteiger E, Hoogland C, Gattiker A, Duvaud S, Wilkins MR, Appel RD, Bairoch A (2005) Protein Identification and Analysis Tools on the ExPASy Server; (In) John M. Walker (ed): The proteomics protocols handbook. Humana Press, New York, p 571–607

    Chapter  Google Scholar 

  42. Geourjon C, Deleage G (1995) SOPMA: significant improvements in protein secondary structure prediction by consensus prediction from multiple alignments. Comput Appl Biosci 11:681–684

    CAS  PubMed  Google Scholar 

  43. Söding J (2005) Protein homology detection by HMM-HMM comparison. Bioinformatics 21:951–960

    Article  PubMed  Google Scholar 

  44. Biasini M, Bienert S, Waterhouse A, Arnold K, Studer G, Schmidt T, Kiefer F, Cassarino TG, Bertoni M, Bordoli L, Schwede T (2014) SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res 42:W252–W258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Roy A, Kucukural A, Zhang Y (2010) I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc 5:725–738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Xu D, Zhang Y (2011) Improving the physical realism and structural accuracy of protein models by a two-step atomic-level energy minimization. Biophys 101:2525–2534

    CAS  Google Scholar 

  47. Sumathi K, Ananthalakshmi P, Roshan MN, Sekar K (2006) 3dSS: 3D structural superposition. Nucleic Acids Res 34:W128–W132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Krissinel E, Henrick K (2004) Secondary-structure matching (SSM), a new tool for fast protein structure alignment in three dimensions. Acta Crystallogr D Biol Crystallogr 60:2256–2268

    Article  CAS  PubMed  Google Scholar 

  49. Ashkenazy H, Erez E, Martz E, Pupko T, Ben-Tal N (2010) ConSurf 2010: calculating evolutionary conservation in sequence and structure of proteins and nucleic acids. Nucl Acids Res 38:W529–W533

    Article  CAS  PubMed  Google Scholar 

  50. Laskowski RA, Watson JD, Thornton JM (2005) ProFunc: a server for predicting protein function from 3D structure. Nucleic Acids Res 33:W89–W93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wass MN, Kelley LA, Sternberg MJ (2010) 3DLigandSite: predicting ligand-binding sites using similar structures. Nucl Acids Res 38:W469–W473

    Article  CAS  PubMed  Google Scholar 

  52. Roy A, Yang J, Zhang Y (2012) COFACTOR: An accurate comparative algorithm for structure-based protein function annotation. Nucleic Acids Res 40:W471–W487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lee HS, Zhang Y (2012) BSP-SLIM: A blind low-resolution ligand-protein docking approach using theoretically predicted protein structures. Proteins 80:93–110

    Article  CAS  PubMed  Google Scholar 

  54. Balamurugan B, Roshan Md MNA, Shaahul BH, Sumathi K, Senthilkumar R, Udayakumar A, Venkatesh KHB, Kalaivani M, Sowmiya G, Sivasankari P, Saravanan S, Vasuki CR, Gopalakrishnan K, Selvakumar KN, Jaikumar M, Brindha T, Daliah M, Sekar K (2007) PSAP: protein structure analysis package. J Appl Crystallogr 40:773–777

    Article  CAS  Google Scholar 

  55. Wallace AC, Laskowski RA, Thornton JM (1995) LIGPLOT: A program to generate schematic diagrams of protein-ligand interactions. Prot Eng 8:127–134

    Article  CAS  Google Scholar 

  56. Han LY, Lin HH, Li ZR, Zheng CJ, Cao ZW, Xie B, Chen YZ (2006) PEARLS: program for energetic analysis of receptor-ligand system. J Chem Inf Model 46:445–450

    Article  CAS  PubMed  Google Scholar 

  57. Yeh I, Hanekamp T, Tsoka S, Karp PD, Altman RB (2004) Computational analysis of Plasmodium falciparum metabolism: organizing genomic information to facilitate drug discovery. Genome Res 14:917–924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Furnham N, Garavelli JS, Apweiler R, Thornton JM (2005) Missing in action: enzyme functional annotations in biological databases. Nature Chem Biol 5:521–525

    Article  CAS  Google Scholar 

  59. Tonkin CJ, Foth BJ, Ralph SA, Struck N, Cowman AF, McFadden GI (2008) Evolution of malaria parasite plastid targeting sequences. Proc Natl Acad Sci USA 105:4781–4785

    Article  PubMed  Google Scholar 

  60. Ralph SA, Foth BJ, Hall N, McFadden GI (2004) Evolutionary pressures on apicoplast transit peptides. Mol Biol Evol 21:2183–2194

    Article  CAS  PubMed  Google Scholar 

  61. Morgan RO, Martin-Almedina S, Garcia M, Jhoncon-Kooyip J, Fernandez MP (2006) Deciphering function and mechanism of calcium-binding proteins from their evolutionary imprints. Biochim Biophys Acta 1763:1238–1249

    Article  CAS  PubMed  Google Scholar 

  62. Shi W, Feng J, Zhang M, Lai X, Xu S, Zhang X, Wang H (2007) Biosynthesis of isoprenoids: characterization of a functionally active recombinant 2-C-methyl-d-erythritol 4-phosphate cytidyltransferase (IspD) from Mycobacterium tuberculosis H37Rv. Biochem Mol Biol 40:911–920

    Google Scholar 

  63. Eoh H, Brown AC, Buetow L, Hunter WN, Parish T, Kaur D, Brennan PJ, Crick DC (2007) Characterization of the Mycobacterium tuberculosis 4-diphosphocytidyl-2-C-methyl-d-erythritol synthase: potential for drug development. J Bacteriol 189:8922–8927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Richard SB, Lillo AM, Tetzlaff CN, Bowman ME, Noel JP, Cane DE (2004) Kinetic analysis of Escherichia coli 2-C-methyl-d-erythritol-4-phosphate cytidyltransferase, wild type and mutants, reveals roles of active site amino acids. Biochem 43:12189–12197

    Article  CAS  Google Scholar 

  65. Tiana G, Shakhnovich BE, Dokholyan NV, Shakhnovich EI (2004) Imprint of evolution on protein structures. Proc Natl Acad Sci USA 101:2846–2851

    Article  CAS  PubMed  Google Scholar 

  66. Richard SB, Bowman ME, Kwiatkowski W, Kang I, Chow C, Lillo AM, Cane DE, Noel JP (2001) Structure of 4-diphosphocytidyl-2-C-methylerythritol synthetase involved in mevalonate-independent isoprenoid biosynthesis. Nature Struct Biol 8:641–648

    Article  CAS  PubMed  Google Scholar 

  67. Gerlt JA, Babbitt PC (2001) Divergent evolution of enzymatic function: mechanistically diverse superfamilies and functionally distinct suprafamilies. Annu Rev Biochem 70:209–246

    Article  CAS  PubMed  Google Scholar 

  68. Saab-Rincón G, Olvera L, Olvera M, Rudiño-Piñera E, Benites E, Soberón X, Morett E (2012) Evolutionary walk between (β/α)(8) barrels: catalytic migration from triosephosphate isomerase to thiamin phosphate synthase. J Mol Biol 416:255–270

    Article  CAS  PubMed  Google Scholar 

  69. Huet J, Rucktooa P, Clantin B, Azarkan M, Looze Y, Villeret V, Wintjens R (2008) X-ray structure of papaya chitinase reveals the substrate binding mode of glycosyl hydrolase family 19 chitinases. Biochem 47:8283–8291

    Article  CAS  Google Scholar 

  70. Udaya Prakash NA, Jayanthi M, Sabarinathan R, Kangueane P, Mathew L, Sekar K (2010) Evolution, homology conservation, and identification of unique sequence signatures in GH19 family chitinases. J Mol Evol 70:466–478

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The first author would like to thank Prof. Hemalatha Balaram, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India for her outstanding guidance, suggestions, and comments on the present work. The JNCASR visiting-fellowship scheme (JNC/F&E/VF.0102 (LS-01)/2012-715) is duly acknowledged for financial support.

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  1. Molecular Systems Engineering Lab, Department of Bioinformatics, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India

    P. Chellapandi, R. Prathiviraj & A. Prisilla

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Chellapandi, P., Prathiviraj, R. & Prisilla, A. Deciphering structure, function and mechanism of Plasmodium IspD homologs from their evolutionary imprints. J Comput Aided Mol Des 33, 419–436 (2019). https://doi.org/10.1007/s10822-019-00191-2

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