Studies of Toxoplasma gondii and Plasmodium falciparum enoyl acyl carrier protein reductase and implications for the development of antiparasitic agents.
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.
Muench
Stephen P
SP
The Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, England.
Prigge
Sean T
ST
McLeod
Rima
R
Rafferty
John B
JB
Kirisits
Michael J
MJ
Roberts
Craig W
CW
Mui
Ernest J
EJ
Rice
David W
DW
D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000737:chemistry; D000977:Antiparasitic Agents / Q000737:chemistry*; D001051:Apoenzymes / Q000737:chemistry; D001426:Bacterial Proteins / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009243:NAD / Q000737:chemistry; D010940:Plant Proteins / Q000737:chemistry; D010963:Plasmodium falciparum / Q000201:enzymology*; D011487:Protein Conformation; D016415:Sequence Alignment; D013045:Species Specificity; D014122:Toxoplasma / Q000201:enzymology*; D014260:Triclosan / Q000737:chemistry; D014867:Water / Q000737:chemistry
D000962:Antimalarials; D000977:Antiparasitic Agents; D001051:Apoenzymes; D001426:Bacterial Proteins; D010940:Plant Proteins; D014867:Water; D009243:NAD; D014260:Triclosan; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)