Biochemical and structural characterization of the apicoplast dihydrolipoamide dehydrogenase of Plasmodium falciparum

Biosci Rep. 2015 Jan 14;35(1):e00171. doi: 10.1042/BSR20140150.


PDC (pyruvate dehydrogenase complex) is a multi-enzyme complex comprising an E1 (pyruvate decarboxylase), an E2 (dihydrolipomide acetyltransferase) and an E3 (dihydrolipoamide dehydrogenase). PDC catalyses the decarboxylation of pyruvate and forms acetyl-CoA and NADH. In the human malaria parasite Plasmodium falciparum, the single PDC is located exclusively in the apicoplast. Plasmodium PDC is essential for parasite survival in the mosquito vector and for late liver stage development in the human host, suggesting its suitability as a target for intervention strategies against malaria. Here, PfaE3 (P. falciparum apicoplast E3) was recombinantly expressed and characterized. Biochemical parameters were comparable with those determined for E3 from other organisms. A homology model for PfaE3 reveals an extra anti-parallel β-strand at the position where human E3BP (E3-binding protein) interacts with E3; a parasite-specific feature that may be exploitable for drug discovery against PDC. To assess the biological role of Pfae3, it was deleted from P. falciparum and although the mutants are viable, they displayed a highly synchronous growth phenotype during intra-erythrocytic development. The mutants also showed changes in the expression of some mitochondrial and antioxidant proteins suggesting that deletion of Pfae3 impacts on the parasite's metabolic function with downstream effects on the parasite's redox homoeostasis and cell cycle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apicoplasts / chemistry
  • Apicoplasts / enzymology*
  • Crystallography, X-Ray
  • Dihydrolipoamide Dehydrogenase / chemistry*
  • Dihydrolipoamide Dehydrogenase / isolation & purification
  • Humans
  • Malaria, Falciparum / microbiology*
  • Models, Molecular
  • Plasmodium falciparum / chemistry
  • Plasmodium falciparum / enzymology*
  • Protein Conformation
  • Protein Multimerization
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / isolation & purification


  • Recombinant Proteins
  • Dihydrolipoamide Dehydrogenase