Modeling of M2‐PYK to show Possible ″Drugable Sights″ in Cancer Cells

Abstract

An important discovery in cancer biology is that the expression of pyruvate kinase M2 (M2‐PYK) as the basis of cancer specific metabolism. M2‐PYK is a protein that catalyzes the last step of glycolysis by transferring the phosphate group from the phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP) resulting in pyruvate and adenosine triphosphate (ATP). During the Warburg effect, tumors show an increased rate of glycolysis, but instead of pyruvate moving to the Krebs cycle, it enters the lactic acid fermentation pathway. The isozyme, M2‐PYK, dissociates from the active tetramer into two inactive dimers. The Olathe North SMART Team (Students Modeling A Research Topic) modeled the M2‐PYK using 3D printing technology to show possible drug binding sites designed to stabilize the tetramer against dissociation. Our mentor provided tools to locate potential “drugable pockets” on the surface of the protein that are created by residues from the two neighboring subunits across the interface. The criteria used to identify a drugable pocket were: 1) the presence of multiple side‐chains that could be ionized to carry a charge that come from each subunit to make up the interface; and 2) a surface that reflects some level of penetration into the protein, i.e. a fissure in the protein's surface when every atom in the protein is rendered by its Van der Waals radius. Supported by a grant from NIH‐SEPA.