A109: The Warburg Effect and Human Hexokinase 2 in Cancer Metabolism and Apoptosis.
1New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
Cancer utilizes glucose at elevated levels to support its growth and proliferation, historically known as Warburg effect. Targeting glucose metabolism in cancer cells to limit its growth will enhance patients survival rate. Hexokinase catalyzes glucose phosphorylation, and is a major step in regulation of glycolysis. Four isozymes are present in human with Hexokinase 2 (HK2) being the most active and specifically expressed in verity of different cancers. In addition, gene expression profiling experiments of different types of cancer showed high expression levels of HK2, and various biological studies highlighted the importance of HK2 in tumor metastasis making it an ideal target to characterize cancer metabolism and for the development of new class of cancer therapeutics.
To characterize HK2s structural fold and its interaction with the mitochondria, different constructs of HK2 were expressed and characterized using X-ray crystallography, thermodynamic stability, chemical unfolding, enzyme kinetics, and structural modeling.
We solved the crystal structure of human HK2 in complex with glucose and glucose-6-phosphate (PDB code: 2NZT), where it is a homodimer with catalytically active N- and C-terminal domains linked by a seven-turn helix. Through biochemical and biophysical characterization of HK2, we found that the N-terminal domain not only catalyzes a reaction but it thermodynamically stabilities the entire enzyme, where deletion of the N-terminal helix altered the stability and catalytic activity of the full-length enzyme. Also, conformation of the N-terminal active site but not C-terminal is important in stabilizing the enzyme.
Understanding the structural and molecular mechanisms of human HK2 in cancer metabolism and apoptosis will accelerate the design and development of new class of cancer therapeutics. Different biological studies have shown the importance in HK2 as a therapeutical target for the design and development of new therapeutics that is safe with high efficacy. However, this is the first biochemical study that highlights the structural role of HK2 in inhibiting cancer metabolism. Study the structure and mechanism of HK2 will accelerate the discovery and design of the new anticancer therapeutics.