Is Plasmodium falciparum aldolase useful for rational drug design?

• Published in: Acta Leidensia Vol. 60; no. 1; p. 135
• Main Authors: Döbeli, H, Itin, C, Meier, B, Certa, U
• Format: Journal Article
• Language: English
• Published: Netherlands 1991
• Subjects: Amino Acid Sequence; Antimalarials; Base Sequence; Drug Design; Drug Resistance - genetics; Fructose-Bisphosphate Aldolase - antagonists & inhibitors; Fructose-Bisphosphate Aldolase - genetics; Malaria - prevention & control; Molecular Sequence Data; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology
• ISSN: 0065-1362

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.