title: Selective inhibition of Plasmodium falciparum aldolase by a tubulin derived peptide and identification of the binding site.
abstract: Aldolase of the human malaria parasite Plasmodium falciparum (PfAldo) may be a potential target for the development of novel antimalarial drugs. Using in vitro mutagenesis we analyzed the function of the carboxy-terminus of the recombinant enzyme. Deletion of the carboxy-terminus of PfAldo confirmed its critical role in catalysis; exchange of conserved residues minimally affected enzyme activity. We exchanged a pair of parasite specific lysine residues with corresponding amino acids of the host. These mutant enzymes exhibited an increased catalytic activity and reduced binding to erythrocyte band 3 protein. Homologous peptides of human band 3 protein and P. falciparum alpha-tubulin were competitive inhibitors of PfAldo. Selective inhibition of PfAldo by the alpha-tubulin peptide depends on the presence of tandem lysine residues and the fine structure of the inhibitor peptide. Our data support the concept of a matrix organisation of glycolytic enzymes in Plasmodium falciparum.
authors.affiliation: Department PRT, F. Hoffmann-La Roche, Ltd., Basel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Itin
authors.forename: Y
authors.initials: Y
authors.lastname: Burki
authors.forename: U
authors.initials: U
authors.lastname: Certa
authors.forename: H
authors.initials: H
authors.lastname: Döbeli
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000378:metabolism; D001665:Binding Sites; D002384:Catalysis; D017124:Conserved Sequence; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005634:Fructose-Bisphosphate Aldolase / Q000037:antagonists & inhibitors* / Q000235:genetics; D008239:Lysine / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001457:Anion Exchange Protein 1, Erythrocyte; D016326:Extracellular Matrix Proteins; D010446:Peptide Fragments; D014404:Tubulin; D005634:Fructose-Bisphosphate Aldolase; D008239:Lysine