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Tight‐binding inhibitors efficiently inactivate both reaction centers of monomeric Plasmodium falciparum glyoxalase 1
Author(s) -
Urscher Miriam,
More Swati S.,
Alisch Romy,
Vince Robert,
Deponte Marcel
Publication year - 2012
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2012.08640.x
Subject(s) - plasmodium falciparum , chemistry , lactoylglutathione lyase , monomer , combinatorial chemistry , biochemistry , stereochemistry , methylglyoxal , biology , malaria , enzyme , immunology , organic chemistry , polymer
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 ( Pf Glo1) 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 Pf Glo1 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 Pf Glo1, but seem to stabilize or trigger a conformational change in analogy with the substrate. In summary, we have characterized the most potent inhibitors of Pf Glo1 known to date.