title: Tight-binding inhibitors efficiently inactivate both reaction centers of monomeric Plasmodium falciparum glyoxalase 1.
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.
authors.affiliation: Department of Parasitology, Ruprecht-Karls University, Heidelberg, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Urscher
authors.forename: Swati S
authors.initials: SS
authors.lastname: More
authors.forename: Romy
authors.initials: R
authors.lastname: Alisch
authors.forename: Robert
authors.initials: R
authors.lastname: Vince
authors.forename: Marcel
authors.initials: M
authors.lastname: Deponte
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D006790:Host-Parasite Interactions; D006801:Humans; D007700:Kinetics; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000502:physiology; D011485:Protein Binding; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011765:Pyruvaldehyde / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D011765:Pyruvaldehyde; D007791:Lactoylglutathione Lyase