Adenylate kinase and GTP:AMP phosphotransferase of the malarial parasite Plasmodium falciparum. Central players in cellular energy metabolism

Mol Biochem Parasitol. 2004 Aug;136(2):211-20. doi: 10.1016/j.molbiopara.2004.04.001.


For coping with energetic and synthetic challenges, parasites require high activities of adenylate kinase (AK; ATP + AMP <==> 2 ADP) and GTP:AMP phosphotransferase (GAK; GTP + AMP <==> GDP + ADP). These enzymes were identified in erythrocytic stages of Plasmodium falciparum. The genes encoding PfAK and PfGAK are located on chromosomes 10 and 4, respectively. Molecular cloning and heterologous expression in E. coli yielded enzymatically active proteins of 28.9 (PfAK) and 28.0 kDa (PfGAK). Recombinant PfAK resembles authentic PfAK in its biochemical characteristics including the possible association with a stabilizing protein and the high specificity for AMP as the mononucleotide substrate. Specificity is less stringent for the triphosphate, with ATP as the best substrate (75 U/mg; kcat = 2160 min(-1) at 25 degrees C). PfAK contains the sequence of the amphiphatic helix that is known to mediate translocation of the cytosolic protein into the mitochondrial intermembrane space. PfGAK exhibits substrate preference for GTP and AMP (100 U/mg; kcat = 2800 min(-1) at 25 degrees C); notably, there is no detectable activity with ATP. In contrast to its human orthologue (AK3), PfGAK contains a zinc finger motif and binds ionic iron. The dinucleoside pentaphosphate compounds AP5A and GP5A inhibited PfAK and PfGAK, respectively, with Ki values of approximately 0.2 microM which is more than 250-fold lower than the KM values determined for the nucleotide substrates. The disubstrate inhibitors are useful for studying the enzymatic mechanism of PfAK and PfGAK as well as their function in adenine nucleotide homeostasis; in addition, the chimeric inhibitors represent interesting lead compounds for developing nucleosides to be used as antiparasitic agents.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenylate Kinase / antagonists & inhibitors
  • Adenylate Kinase / genetics
  • Adenylate Kinase / metabolism*
  • Amino Acid Sequence
  • Animals
  • Antimalarials / pharmacology
  • Base Sequence
  • DNA, Protozoan / genetics
  • Energy Metabolism
  • Enzyme Inhibitors / pharmacology
  • Genes, Protozoan
  • Humans
  • Molecular Sequence Data
  • Nucleoside-Phosphate Kinase / antagonists & inhibitors
  • Nucleoside-Phosphate Kinase / genetics
  • Nucleoside-Phosphate Kinase / metabolism*
  • Plasmodium falciparum / enzymology*
  • Plasmodium falciparum / genetics
  • Plasmodium falciparum / growth & development
  • Plasmodium falciparum / metabolism
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Substrate Specificity


  • Antimalarials
  • DNA, Protozoan
  • Enzyme Inhibitors
  • Recombinant Proteins
  • nucleoside triphosphate-adenylate kinase
  • Adenylate Kinase
  • Nucleoside-Phosphate Kinase