Midway Evaluation in Biochemistry - Yiming Yang Jónatansdóttir

Title of thesis:
Exploring weak metabolic regulation of glycolytic enzymes for drug discovery

Student:
Yiming Yang Jónatansdóttir

Doctoral committee:
Jens Guðmundur Hjörleifsson, Ass. Professor at the faculty of life- and environmental sciences, University of Iceland (supervisor) Óttar Rolfsson, Professor at the faculty of medicine, University of University of Iceland Ronny Helland, PhD, Head of administration, Department of Chemistry, University of Tromsø, Norway. Knut Teigen, PhD, Professor at the department of Biomedicine, University of Bergen, Norway

Abstract:
In a crowded cellular environment, the activity of enzymes is affected not only by substrate binding, but also interactions with effector molecules that contribute to the regulation of metabolic homeostasis. Most metabolite effectors have binding affinities ranging from sub-mM to high-µM, reflecting typical intracellular concentrations. However, the quantification of metabolites is often done in cell lysates such that the local concentration gradients may be overlooked. Under stress, metabolite concentrations inside cells may rise sharply, enhancing the role of weak binders. We assumed that such weakly binding metabolites may partake in metabolic regulations and could be a valuable source of finding new enzyme modulators. In this study, we investigated glucose-6-phosphate isomerase (GPI) and triosephosphate isomerase (TPI), key enzymes in glycolysis, as potential drug targets for cancer therapy. Many cancers rely on glycolysis, making glycolytic enzymes attractive therapeutic targets. Despite implications in tumor growth, GPI and TPI remain underexplored for druggability. Using biochemical and biophysical assays, we screened metabolites for interactions with these enzymes and identified novel weak inhibitors binding at the enzyme active sites, further characterized by X-ray crystallography. Currently, virtual screening is being undertaken in an effort to expand the sampling of chemical space for identifying hits with improved affinities and potencies. The most promising hits will be experimentally tested, and the validated hits will be used for the development of 3D quantitative structure activity relationships (QSAR) models in the hit-to-lead optimization stage. In summary, our recent findings suggest that weak modulation of enzymes could be undervalued and may play a more substantial role in cellular homeostasis than previously appreciated. Our future attention will be directed towards the discovery of enzyme inhibitors with desired properties for drug design