Structural Evidence for Isoform-Selective Allosteric Inhibition of Lactate Dehydrogenase A
Anders Friberg, Hartmut Rehwinkel, Duy Nguyen, Vera Pütter, Maria Quanz, Jörg Weiske, Uwe Eberspächer, Iring Heisler, Gernot Langer
Abstract
Lactate dehydrogenase A (LDHA) is frequently overexpressed in tumors, thereby sustaining high glycolysis rates, tumor growth, and chemoresistance. High-throughput screening resulted in the identification of phthalimide and dibenzofuran derivatives as novel lactate dehydrogenase inhibitors, selectively inhibiting the activity of the LDHA isoenzyme. Cocrystallization experiments confirmed target engagement in addition to demonstrating binding to a novel allosteric binding site present in all four LDHA subunits of the LDH5 homotetramer.
Topics & Concepts
HomotetramerAllosteric regulationLactate dehydrogenaseLactate dehydrogenase ABiochemistryGlycolysisChemistryDehydrogenaseBiologyEnzymeProtein subunitGeneCancer, Hypoxia, and MetabolismMetabolomics and Mass Spectrometry StudiesMedical Imaging Techniques and Applications