Tight-binding inhibitors efficiently inactivate both reaction centers of monomeric Plasmodium falciparum glyoxalase 1

Miriam Urscher, Swati S. More, Romy Alisch, Robert Vince, Marcel Deponte

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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 languageEnglish (US)
Pages (from-to)2568-2578
Number of pages11
JournalFEBS Journal
Volume279
Issue number14
DOIs
StatePublished - Jul 2012

Keywords

  • allosteric enzyme
  • drug development
  • glyoxalase
  • malaria
  • tight-binding inhibitor

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