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Wrenger C.,Bernhard Nocht Institute for Tropical Medicine | Muller I.B.,Bernhard Nocht Institute for Tropical Medicine | Schifferdecker A.J.,Bernhard Nocht Institute for Tropical Medicine | Jain R.,European Molecular Biology Laboratory Hamburg Outstation | And 2 more authors.
Journal of Molecular Biology | Year: 2011

Aspartate aminotransferases (AspATs; EC 2.6.1.1) catalyze the conversion of aspartate and α-ketoglutarate into oxaloacetate and glutamate and are key enzymes in the nitrogen metabolism of all organisms. Recent findings suggest that the plasmodial enzyme [Plasmodium falciparum aspartate aminotransferase (PfAspAT)] may also play a pivotal role in energy metabolism and in the de novo biosynthesis of pyrimidines. However, while PfAspAT is a potential drug target, the high homology between the active sites of currently available AspAT structures hinders the development of specific inhibitors of these enzymes. In this article, we report the X-ray structure of the PfAspAT homodimer at a resolution of 2.8 Å. While the overall fold is similar to the currently available structures of other AspATs, the structure presented shows a significant divergence in the conformation of the N-terminal residues. Deletion of these divergent PfAspAT N-terminal residues results in a loss of activity for the recombinant protein, and addition of a peptide containing these 13 N-terminal residues results in inhibition both in vitro and in a lysate isolated from cultured parasites, while the activity of human cytosolic AspAT is unaffected. The finding that the divergent N-terminal amino acids of PfAspAT play a role in catalytic activity indicates that specific inhibition of the enzyme may provide a lead for the development of novel compounds in the treatment of malaria. We also report on the localization of PfAspAT to the parasite cytosol and discuss the implications of the role of PfAspAT in the supply of malate to the parasite mitochondria. © 2010 Elsevier Ltd. All rights reserved. Source


Jain R.,European Molecular Biology Laboratory Hamburg Outstation | Jain R.,University of Wisconsin - Madison | Jordanova R.,European Molecular Biology Laboratory Hamburg Outstation | Muller I.B.,Bernhard Nocht Institute for Tropical Medicine | And 2 more authors.
Acta Crystallographica Section F: Structural Biology and Crystallization Communications | Year: 2010

Aspartate aminotransferases (EC 2.6.1.1) catalyse the conversion of aspartate and -ketoglutarate to oxaloacetate and glutamate in a reversible manner. Thus, the aspartate aminotransferase of Plasmodium falciparum (PfAspAT) plays a central role in the transamination of amino acids. Recent findings suggest that PfAspAT may also play a pivotal role in energy metabolism and the de novo biosynthesis of pyrimidines. While therapeutics based upon the inhibition of other proteins in these pathways are already used in the treatment of malaria, the advent of multidrug-resistant strains has limited their efficacy. The presence of PfAspAT in these pathways may offer additional opportunities for the development of novel therapeutics. In order to gain a deeper understanding of the function and role of PfAspAT, it has been expressed and purified to homogeneity. The successful crystallization of PfAspAT, the collection of a 2.8 Å diffraction data set and initial attempts to solve the structure using molecular replacement are reported. © 2010 International Union of Crystallography All rights reserved. Source

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