The objective is to better understand those molecular events involved in the initiation of glucose catabolism in neoplastic tissues. The major focus will be on the enzyme hexokinase, which plays a central role in animal cell growth by providing precursors for both energy metabolism and for the biosynthesis of nucleic acids. Progress to date has shown that hexokinase is markedly elevated in many tumors, that it is bound to a receptor protein in the outer mitochondrial membrane, and that the bound form of the enzyme can support high rates of glucose catabolism. The mitochondrial form of hexokinase and its receptor protein have been purified to near-homogeneity.
Specific aims are six-fold: 1. Characterization of purified tumor mitochondrial hexokinase in order to define clearly its similarities to and differences from those forms of hexokinase found in normal glucose-utilizing tissues. 2. Characterization of the purified receptor protein to establish its specificity in binding hexokinase and to determine whether it covalently modifies the enzyme. 3. Identification of those regions of the receptor by protein which recognize and bind tumor hexokinase. 4. Identification of the intracellular site of synthesis of the receptor protein. (Is it mitochondrial or cytoplasmic?) 5. Assessment of the capacity of the receptor protein to provide bound hexokinase with """"""""preferred access"""""""" to ATP synthesized in the inner mitochondrial compartment. 6. Assessment of the relationship of mitochondrial binding of hexokinase to the elevated rates of glucose catabolism and nucleic acid synthesis observed in many tumors. The research is necessary and fundamental to our understanding of glucose catabolism in normal and neoplastic tissues and may offer new insights into effective chemotherapeutic approaches.
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