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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. (2007)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, England.

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.

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The structural formulae of (a) triclosan and (b) (E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-­(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-ylacrylamide (compound 29) produced using the program ISIS/Draw.
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fig1: The structural formulae of (a) triclosan and (b) (E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-­(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-ylacrylamide (compound 29) produced using the program ISIS/Draw.

Mentions: Recent studies have revealed that it may be possible to control apicomplexan parasite infections by targeting processes that reside in their apicoplast organelle, which contains over 500 different proteins responsible for carrying out a number of key metabolic pathways (Waller et al., 1998 ▶; Zuther et al., 1999 ▶). This organelle is thought to have arisen through the process of secondary endosymbiosis. Thus, the apicomplexan progenitor endocytosed an ancient alga which contained a cyanobacterial-derived plastid obtained in a previous primary endosymbiotic event. Consistent with this, analysis of the genes encoding the enzymes of apicoplast-located pathways suggests that they are closely related to those found in prokaryotes and the chloroplasts of plants (Zuther et al., 1999 ▶; Fast et al., 2001 ▶; Kohler et al., 1997 ▶). For example, in apicomplexan parasites the fatty-acid biosynthesis pathway resembles the type II fatty-acid synthase that is found in bacteria and plant chloroplasts and in which each catalytic step of the pathway is encoded on a separate polypeptide (Magnuson et al., 1993 ▶), rather than the type I FAS found in man (Smith, 2003 ▶). Enoyl acyl carrier protein reductase (ENR) carries out one of two reductive steps in the type II FAS pathway and has been shown to be the target of several families of antimicrobial compounds, including the diazaborines (Baldock et al., 1996 ▶), aminopyridine-based inhibitors (Payne et al., 2002 ▶; Seefeld et al., 2003 ▶) and triclosan (Levy et al., 1999 ▶; Fig. 1 ▶), a biocide which is found in many household formulations such as toothpastes, soaps, mouthwashes and plastics (Bhargava & Leonard, 1996 ▶).


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. (2007)

The structural formulae of (a) triclosan and (b) (E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-­(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-ylacrylamide (compound 29) produced using the program ISIS/Draw.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2483495&req=5

fig1: The structural formulae of (a) triclosan and (b) (E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-­(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-ylacrylamide (compound 29) produced using the program ISIS/Draw.
Mentions: Recent studies have revealed that it may be possible to control apicomplexan parasite infections by targeting processes that reside in their apicoplast organelle, which contains over 500 different proteins responsible for carrying out a number of key metabolic pathways (Waller et al., 1998 ▶; Zuther et al., 1999 ▶). This organelle is thought to have arisen through the process of secondary endosymbiosis. Thus, the apicomplexan progenitor endocytosed an ancient alga which contained a cyanobacterial-derived plastid obtained in a previous primary endosymbiotic event. Consistent with this, analysis of the genes encoding the enzymes of apicoplast-located pathways suggests that they are closely related to those found in prokaryotes and the chloroplasts of plants (Zuther et al., 1999 ▶; Fast et al., 2001 ▶; Kohler et al., 1997 ▶). For example, in apicomplexan parasites the fatty-acid biosynthesis pathway resembles the type II fatty-acid synthase that is found in bacteria and plant chloroplasts and in which each catalytic step of the pathway is encoded on a separate polypeptide (Magnuson et al., 1993 ▶), rather than the type I FAS found in man (Smith, 2003 ▶). Enoyl acyl carrier protein reductase (ENR) carries out one of two reductive steps in the type II FAS pathway and has been shown to be the target of several families of antimicrobial compounds, including the diazaborines (Baldock et al., 1996 ▶), aminopyridine-based inhibitors (Payne et al., 2002 ▶; Seefeld et al., 2003 ▶) and triclosan (Levy et al., 1999 ▶; Fig. 1 ▶), a biocide which is found in many household formulations such as toothpastes, soaps, mouthwashes and plastics (Bhargava & Leonard, 1996 ▶).

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, England.

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.

Show MeSH
Related in: MedlinePlus