Tuning liver pyruvate kinase activity up or down with a new class of allosteric modulators

DOI: 10.1016/j.ejmech.2023.115177

Authors: Amalyn Nain-Perez (University of Gothenburg) , Oscar Nilsson (University of Gothenburg) , Aleksei Lulla (University of Cambridge) , Liliana Håversen (University of Gothenburg; Sahlgrenska University Hospital) , Paul Brear (University of Cambridge) , Sara Liljenberg (University of Gothenburg) , Marko Hyvonen (University of Cambridge) , Jan Borén (University of Gothenburg; Sahlgrenska University Hospital) , Morten Grøtli (University of Gothenburg)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: European Journal Of Medicinal Chemistry , VOL 250

State: Published (Approved)
Published: March 2023
Diamond Proposal Number(s): 18548 , 25402

Abstract: The liver isoform of pyruvate kinase (PKL) has gained interest due to its potential capacity to regulate fatty acid synthesis involved in the progression of non-alcoholic fatty liver disease (NAFLD). Here we describe a novel series of PKL modulators that can either activate or inhibit the enzyme allosterically, from a cryptic site at the interface of two protomers in the tetrameric enzyme. Starting from urolithin D, we designed and synthesised 42 new compounds. The effect of these compounds on PKL enzymatic activity was assessed after incubation with cell lysates obtained from a liver cell line. Pronounced activation of PKL activity, up to 3.8-fold, was observed for several compounds at 10 μM, while other compounds were prominent PKL inhibitors reducing its activity to 81% at best. A structure-activity relationship identified linear-shaped sulfone-sulfonamides as activators and non-linear compounds as inhibitors. Crystal structures revealed the conformations of these modulators, which were used as a reference for designing new modulators.

Journal Keywords: Pyruvate kinase; PKL; Modulation; Enzyme activity; Activation; Inhibition

Diamond Keywords: Liver Disease

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Added On: 07/02/2023 09:53

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)