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

• Verfasst von: Urscher, Miriam [VerfasserIn]
• Verfasst von: Alisch, Romy [VerfasserIn]
• Verfasst von: Deponte, Marcel [VerfasserIn]
• Titel: Tight-binding inhibitors efficiently inactivate both reaction centers of monomeric Plasmodium falciparum glyoxalase 1
• Verf.angabe: Miriam Urscher, Swati S. More, Romy Alisch, Robert Vince and Marcel Deponte
• E-Jahr: 2012
• Jahr: 19 May 2012
• Umfang: 11 S.
• Teil: volume:279
• Teil: year:2012
• Teil: number:14
• Teil: pages:2568-2578
• Teil: extent:11
• Fussnoten: Gesehen am 15.10.2018
• Titel Quelle: Enthalten in: Vereinigung der Europäischen Biochemischen GesellschaftenThe FEBS journal
• Ort Quelle: Oxford [u.a.] : Wiley-Blackwell, 2005
• Jahr Quelle: 2012
• Band/Heft Quelle: 279(2012), 14, Seite 2568-2578
• ISSN Quelle: 1742-4658
• DOI: doi:10.1111/j.1742-4658.2012.08640.x
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: allosteric enzyme
• Sach-SW: drug development
• Sach-SW: glyoxalase
• Sach-SW: malaria
• Sach-SW: tight-binding inhibitor
• K10plus-PPN: 158190276X

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 Kiapp 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.