Abstract
Glucose consumption and therefore methylglyoxal production of human erythrocytes increase significantly upon infection with malaria parasites. The glyoxalase systems of the host-parasite unit cope with this metabolic challenge by catalyzing the removal of harmful methylglyoxal. Thus, glyoxalase 1 from the malaria parasite Plasmodium falciparum (PfGlo1) could be a promising drug target. However, the enzyme has two different active sites and their simultaneous inactivation is considered challenging. Here, we describe the inactivation of PfGlo1 by two glyoxalase-specific tight-binding inhibitors with nanomolar K i app values and noncompetitive inhibition patterns. The inhibitors do not discriminate between the high-affinity and the high-activity conformations of PfGlo1, but seem to stabilize or trigger a conformational change in analogy with the substrate. In summary, we have characterized the most potent inhibitors of PfGlo1 known to date.
Original language | English (US) |
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Pages (from-to) | 2568-2578 |
Number of pages | 11 |
Journal | FEBS Journal |
Volume | 279 |
Issue number | 14 |
DOIs | |
State | Published - Jul 2012 |
Keywords
- allosteric enzyme
- drug development
- glyoxalase
- malaria
- tight-binding inhibitor