Wael M. Rabeh
New York University Abu Dhabi, PO Box 129188, Abu Dhabi, UAE
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.
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.