CRYSTAL-STRUCTURE OF FRUCTOSE-1,6-BISPHOSPHATE ALDOLASE FROM THE HUMAN MALARIA PARASITE PLASMODIUM-FALCIPARUM

The structure of the glycolytic enzyme class I fructose-1,6-bisphospha te aldolase from the human malaria parasite Plasmodium falciparum has been determined by X-ray crystallography. Homotetrameric P. falciparum aldolase (PfALDO) crystallizes in space group P3(2)21 with one 80 kDa dimer per asymmetric unit. The final refined PfALDO model has an R-fa ctor of 0.239 and an R-free of 0.329 with respect to data from 8 to 3. 0 Angstrom resolution. PfALDO is potentially a target for antimalarial drug design as the intraerythrocytic merozoite lifestage of P. falcip arum is completely dependent upon glycolysis for its ATP production. T hus, inhibitors directed against the glycolytic enzymes in P. falcipar um may be effective in killing the parasite. The structure of PfALDO i s compared with the previously determined structure of human aldolase in order to determine possible targets for the structure-based design of selective PfALDO ligands. The salient structural differences includ e a hydrophobic pocket on the surface of PfALDO, which results from so me amino acid changes and a single residue deletion compared with huma n aldolase, and the overall quaternary structure of the PfALDO tetrame r, which buries less surface area than human aldolase.