Research summary

Molecular Structure and regulatory role of dual-function hexokinases:

In addition to their catalytic function in glycolysis, hexokinases are involved in glucose sensing and glucose-dependent signal transduction in eukaryotic cells from yeast to man. The hexokinase isoenzyme ScHxk2 of the fermentative yeast Saccharomyces cerevisiae translocates to the nucleus when glucose is abundantly available to contribute to the repression of genes that encode enzymes of alternative catabolic pathways (glucose repression). The structural, catalytic and regulatory properties of this hexokinase depend on the state of phosphorylation of two of its amino acid residues. Despite fundamental metabolic differences, the unique hexokinase KlHxk1 (Rag5p) is required for glucose repression in the non-fermentative yeast Kluyveromyces lactis, and the establishment of fructose repression in the methylotrophic yeast Hansenula polymorpha is specifically dependent on the hexokinase HpHxk1. By contrast to the situation in various somatic cells, the hexokinases in human spermatozoa lack the N-terminal porin-binding domain which allows their somatic counterparts to interact with the outer mitochondrial membrane. Current work is focused on the exploration of structure-to-function relations of eukaryotic hexokinases and on the identification of protein kinases and phosphoprotein phosphatases that regulate their functionality by covalent modifications.