title: Is Plasmodium falciparum aldolase useful for rational drug design?
abstract: P. falciparum lacks a functional citric acid cycle. Unlike most tissues of the mammalian host, it is totally dependent on glycolysis for energy generation. A compound which selectively inhibits the parasite's ATP-generating machinery is therefore a potential antimalarial agent. Such a drug may interact in two ways: a) by inhibiting the activity of an enzyme or b) by disturbing the micro-organization of consecutive enzymes in a metabolic pathway. In mammalian tissues the glycolytic pathway involves the cytoskeleton as a matrix to keep phosphofructokinase, aldolase and glyceraldehyde-3-phosphate dehydrogenase in an optimal sterical position for rapid substrate conversion. For instance, these three enzymes bind to the band 3 protein in erythrocytes or to actin in muscle cells. P. falciparum aldolase binds with very high affinity to the band 3 protein of human erythrocyte ghosts. However, the true in vivo site of association is believed to be actin II of P. falciparum. This actin has a sequence element which is almost identical to that of the band 3 aldolase binding site. We therefore suppose that plasmodia exploit a similar matrix organization. If true, the association of these enzymes with the cytoskeleton is a target for novel antimalarials. In contrast to all vertebrate aldolases, P. falciparum and P. berghei aldolases have two neighbouring lysine residues near the carboxy-terminus. We show here that mutagenesis of these basic residues has an effect on the catalytic constants Vmax and KM and moreover, the ability to bind to band 3 is reduced.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Central Research Units, F. Hoffmann-La Roche AG, Basle, Switzerland.
authors.forename: H
authors.initials: H
authors.lastname: Döbeli
authors.forename: C
authors.initials: C
authors.lastname: Itin
authors.forename: B
authors.initials: B
authors.lastname: Meier
authors.forename: U
authors.initials: U
authors.lastname: Certa
mesh_terms: D000595:Amino Acid Sequence; D000962:Antimalarials; D001483:Base Sequence; D015195:Drug Design; D004351:Drug Resistance / Q000235:genetics; D005634:Fructose-Bisphosphate Aldolase / Q000037:antagonists & inhibitors* / Q000235:genetics; D008288:Malaria / Q000517:prevention & control*; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000962:Antimalarials; D005634:Fructose-Bisphosphate Aldolase