Serendipitous Identification of a Covalent Activator of Liver Pyruvate Kinase. (9th November 2022)

• Record Type: Journal Article
• Authors: Battisti, Umberto Maria; Gao, Chunxia; Nilsson, Oscar; Akladios, Fady; Lulla, Aleksei; Bogucka, Agnieszka; Nain‐Perez, Amalyn; Håversen, Liliana; Kim, Woonghee; Boren, Jan; Hyvönen, Marko; Uhlen, Mathias; Mardinoglu, Adil; Grøtli, Morten
• Is Part Of: Chembiochem. Volume 24:Number 1(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-11-09
• Subjects: covalent activators -- enzymes -- ligand design -- PKL -- structure-activity relationships; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.202200339
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: Enzymes are effective biological catalysts that accelerate almost all metabolic reactions in living organisms. Synthetic modulators of enzymes are useful tools for the study of enzymatic reactions and can provide starting points for the design of new drugs. Here, we report on the discovery of a class of biologically active compounds that covalently modifies lysine residues in human liver pyruvate kinase (PKL), leading to allosteric activation of the enzyme (EC50 =0.29 μM). Surprisingly, the allosteric activation control point resides on the lysine residue K282 present in the catalytic site of PKL. These findings were confirmed by structural data, MS/MS experiments, and molecular modelling studies. Altogether, our study provides a molecular basis for the activation mechanism and establishes a framework for further development of human liver pyruvate kinase covalent activators. Abstract : MS/MS experiments and molecular modelling studies identified a mechanism by which a lysine residue in the active site of human liver pyruvate kinase (PKL) can be targeted by benzo[ d ]isothiazole‐1, 1‐dioxide derivatives, resulting in the covalent activation of PKL. This previously unknown mechanism holds promise for further development of PKL activators.