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Studies of Toxoplasma gondii and Plasmodium falciparum enoyl acyl carrier protein reductase and implications for the development of antiparasitic agents.

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Muench SP, Prigge ST, McLeod R, Rafferty JB, Kirisits MJ, Roberts CW, Mui EJ, Rice DW
OpenAccess logo Acta Crystallogr D Biol Crystallogr 63 328-38 (2007)
Related entries: 2o2s, 2o50

Cited: 30 times
EuropePMC logo PMID: 17327670

Abstract

Recent studies have demonstrated that submicromolar concentrations of the biocide triclosan arrest the growth of the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii and inhibit the activity of the apicomplexan enoyl acyl carrier protein reductase (ENR). The crystal structures of T. gondii and P. falciparum ENR in complex with NAD(+) and triclosan and of T. gondii ENR in an apo form have been solved to 2.6, 2.2 and 2.8 A, respectively. The structures of T. gondii ENR have revealed that, as in its bacterial and plant homologues, a loop region which flanks the active site becomes ordered upon inhibitor binding, resulting in the slow tight binding of triclosan. In addition, the T. gondii ENR-triclosan complex reveals the folding of a hydrophilic insert common to the apicomplexan family that flanks the substrate-binding domain and is disordered in all other reported apicomplexan ENR structures. Structural comparison of the apicomplexan ENR structures with their bacterial and plant counterparts has revealed that although the active sites of the parasite enzymes are broadly similar to those of their bacterial counterparts, there are a number of important differences within the drug-binding pocket that reduce the packing interactions formed with several inhibitors in the apicomplexan ENR enzymes. Together with other significant structural differences, this provides a possible explanation of the lower affinity of the parasite ENR enzyme family for aminopyridine-based inhibitors, suggesting that an effective antiparasitic agent may well be distinct from equivalent antimicrobials.

Reviews - 2o2y mentioned but not cited (1)

  1. The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases-Part III: In-Silico Molecular Docking Investigations. Ogungbe IV, Setzer WN. Molecules 21 E1389 (2016)

Articles - 2o2y mentioned but not cited (5)

  1. Studies of Toxoplasma gondii and Plasmodium falciparum enoyl acyl carrier protein reductase and implications for the development of antiparasitic agents. Muench SP, Prigge ST, McLeod R, Rafferty JB, Kirisits MJ, Roberts CW, Mui EJ, Rice DW. Acta Crystallogr D Biol Crystallogr 63 328-338 (2007)
  2. Novel type II fatty acid biosynthesis (FAS II) inhibitors as multistage antimalarial agents. Schrader FC, Glinca S, Sattler JM, Dahse HM, Afanador GA, Prigge ST, Lanzer M, Mueller AK, Klebe G, Schlitzer M. ChemMedChem 8 442-461 (2013)
  3. Celastrol inhibits Plasmodium falciparum enoyl-acyl carrier protein reductase. Tallorin LC, Durrant JD, Nguyen QG, McCammon JA, Burkart MD. Bioorg Med Chem 22 6053-6061 (2014)
  4. Dynamics of Plasmodium falciparum enoyl-ACP reductase and implications on drug discovery. Lindert S, McCammon JA. Protein Sci 21 1734-1745 (2012)
  5. How Diverse Are the Protein-Bound Conformations of Small-Molecule Drugs and Cofactors? Friedrich NO, Simsir M, Kirchmair J. Front Chem 6 68 (2018)


Reviews citing this publication (4)

  1. Make it or take it: fatty acid metabolism of apicomplexan parasites. Mazumdar J, Striepen B. Eukaryot Cell 6 1727-1735 (2007)
  2. Applications of structure-based design to antibacterial drug discovery. Cain R, Narramore S, McPhillie M, Simmons K, Fishwick CW. Bioorg Chem 55 69-76 (2014)
  3. Screening for small molecule inhibitors of Toxoplasma gondii. Kortagere S. Expert Opin Drug Discov 7 1193-1206 (2012)
  4. Structural biology of plasmodial proteins. Gayathri P, Balaram H, Murthy MR. Curr Opin Struct Biol 17 744-754 (2007)

Articles citing this publication (20)

  1. Targeting the Lipid Metabolic Pathways for the Treatment of Malaria. Ben Mamoun C, Prigge ST, Vial H. Drug Dev Res 71 44-55 (2010)
  2. Identification and development of novel inhibitors of Toxoplasma gondii enoyl reductase. Tipparaju SK, Muench SP, Mui EJ, Ruzheinikov SN, Lu JZ, Hutson SL, Kirisits MJ, Prigge ST, Roberts CW, Henriquez FL, Kozikowski AP, Rice DW, McLeod RL. J Med Chem 53 6287-6300 (2010)
  3. Potential of lichen secondary metabolites against Plasmodium liver stage parasites with FAS-II as the potential target. Lauinger IL, Vivas L, Perozzo R, Stairiker C, Tarun A, Zloh M, Zhang X, Xu H, Tonge PJ, Franzblau SG, Pham DH, Esguerra CV, Crawford AD, Maes L, Tasdemir D. J Nat Prod 76 1064-1070 (2013)
  4. Subcellular localization and dynamics of a digalactolipid-like epitope in Toxoplasma gondii. Botté C, Saïdani N, Mondragon R, Mondragón M, Isaac G, Mui E, McLeod R, Dubremetz JF, Vial H, Welti R, Cesbron-Delauw MF, Mercier C, Maréchal E. J Lipid Res 49 746-762 (2008)
  5. Apicoplast fatty acid synthesis is essential for pellicle formation at the end of cytokinesis in Toxoplasma gondii. Martins-Duarte ÉS, Carias M, Vommaro R, Surolia N, de Souza W. J Cell Sci 129 3320-3331 (2016)
  6. Type I and type II fatty acid biosynthesis in Eimeria tenella: enoyl reductase activity and structure. Lu JZ, Muench SP, Allary M, Campbell S, Roberts CW, Mui E, McLeod RL, Rice DW, Prigge ST. Parasitology 134 1949-1962 (2007)
  7. X-ray crystallographic analysis of the complexes of enoyl acyl carrier protein reductase of Plasmodium falciparum with triclosan variants to elucidate the importance of different functional groups in enzyme inhibition. Maity K, Bhargav SP, Sankaran B, Surolia N, Surolia A, Suguna K. IUBMB Life 62 467-476 (2010)
  8. Inhibiting enoyl-ACP reductase (FabI) across pathogenic microorganisms by linear sesquiterpene lactones from Anthemis auriculata. Karioti A, Skaltsa H, Zhang X, Tonge PJ, Perozzo R, Kaiser M, Franzblau SG, Tasdemir D. Phytomedicine 15 1125-1129 (2008)
  9. Modification of triclosan scaffold in search of improved inhibitors for enoyl-acyl carrier protein (ACP) reductase in Toxoplasma gondii. Stec J, Fomovska A, Afanador GA, Muench SP, Zhou Y, Lai BS, El Bissati K, Hickman MR, Lee PJ, Leed SE, Auschwitz JM, Sommervile C, Woods S, Roberts CW, Rice D, Prigge ST, McLeod R, Kozikowski AP. ChemMedChem 8 1138-1160 (2013)
  10. Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites. McPhillie MJ, Zhou Y, Hickman MR, Gordon JA, Weber CR, Li Q, Lee PJ, Amporndanai K, Johnson RM, Darby H, Woods S, Li ZH, Priestley RS, Ristroph KD, Biering SB, El Bissati K, Hwang S, Hakim FE, Dovgin SM, Lykins JD, Roberts L, Hargrave K, Cong H, Sinai AP, Muench SP, Dubey JP, Prud'homme RK, Lorenzi HA, Biagini GA, Moreno SN, Roberts CW, Antonyuk SV, Fishwick CWG, McLeod R. Front Cell Infect Microbiol 10 203 (2020)
  11. Separation and purification of Toxoplasma gondii tachyzoites from in vitro and in vivo culture systems. Wu L, Chen SX, Jiang XG, Fu XL, Shen YJ, Cao JP. Exp Parasitol 130 91-94 (2012)
  12. Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase. Cheng G, Muench SP, Zhou Y, Afanador GA, Mui EJ, Fomovska A, Lai BS, Prigge ST, Woods S, Roberts CW, Hickman MR, Lee PJ, Leed SE, Auschwitz JM, Rice DW, McLeod R. Bioorg Med Chem Lett 23 2035-2043 (2013)
  13. Functional expression of Francisella tularensis FabH and FabI, potential antibacterial targets. Wen L, Chmielowski JN, Bohn KC, Huang JK, Timsina YN, Kodali P, Pathak AK. Protein Expr Purif 65 83-91 (2009)
  14. An update on the rapid advances in malaria parasite cell biology. Coppens I, Sullivan DJ, Prigge ST. Trends Parasitol 26 305-310 (2010)
  15. Letter Development of a triclosan scaffold which allows for adaptations on both the A- and B-ring for transport peptides. Muench SP, Stec J, Zhou Y, Afanador GA, McPhillie MJ, Hickman MR, Lee PJ, Leed SE, Auschwitz JM, Prigge ST, Rice DW, McLeod R. Bioorg Med Chem Lett 23 3551-3555 (2013)
  16. Discrimination of potent inhibitors of Toxoplasma gondii enoyl-acyl carrier protein reductase by a thermal shift assay. Afanador GA, Muench SP, McPhillie M, Fomovska A, Schön A, Zhou Y, Cheng G, Stec J, Freundlich JS, Shieh HM, Anderson JW, Jacobus DP, Fidock DA, Kozikowski AP, Fishwick CW, Rice DW, Freire E, McLeod R, Prigge ST. Biochemistry 52 9155-9166 (2013)
  17. Effect of substrate binding loop mutations on the structure, kinetics, and inhibition of enoyl acyl carrier protein reductase from Plasmodium falciparum. Maity K, Banerjee T, Prabakaran N, Surolia N, Surolia A, Suguna K. IUBMB Life 63 30-41 (2011)
  18. The genome of a Bacteroidetes inhabitant of the human gut encodes a structurally distinct enoyl-acyl carrier protein reductase (FabI). Radka CD, Frank MW, Yao J, Seetharaman J, Miller DJ, Rock CO. J Biol Chem 295 7635-7652 (2020)
  19. Drug Repurposing Based on Protozoan Proteome: In Vitro Evaluation of In Silico Screened Compounds against Toxoplasma gondii. Cajazeiro DC, Toledo PPM, de Sousa NF, Scotti MT, Reimão JQ. Pharmaceutics 14 1634 (2022)
  20. Preliminary investigations of the effect of lipophilic analogues of the active metabolite of isoniazid toward bacterial and plasmodial strains. Delaine T, Bernardes-Génisson V, Quémard A, Constant P, Cosledan F, Meunier B, Bernadou J. Chem Biol Drug Des 79 1001-1006 (2012)


Related citations provided by authors (1)

  1. Expression, purification and crystallization of the Plasmodium falciparum enoyl reductase.. Muench SP, Rafferty JB, McLeod R, Rice DW, Prigge ST Acta Crystallogr D Biol Crystallogr 59 1246-8 (2003)

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