Hexokinase 2 and Carbohydrate Metabolism: A Multifaceted Metabolic Hub

Hexokinase 2 (Hxk2p) is a key enzyme in glucose metabolism but also acts as a central regulator linking glucose-dependent signaling with cellular physiology in Saccharomyces cerevisiae. Beyond its catalytic function in glycolysis, Hxk2p acts as a regulator of carbon catabolite repression, influencing the expression of genes required for the utilization of alternative carbon sources and mitochondrial activity. Accumulating evidence indicates that deletion of HXK2 triggers a systemic, multidirectional reprogramming of cellular metabolism and physiology that mimics calorie restriction conditions even in nutrient-rich environments. This widespread metabolic reconfiguration involves a fundamental shift from a rapid fermentative mode to an energy-efficient respiratory state, including the redistribution of carbon flux between glycolysis, the pentose phosphate pathway, and respiration. These changes are associated with alterations in ATP homeostasis, biosynthetic capacity, redox balance, and proteostasis. Crucially, because of its implications in genomic regulation, the absence of Hxk2p induces global transcriptional remodelling, whereby the expression of genes involved in respiratory and alternative carbon source metabolism is derepressed, while the expression of glycolytic and biosynthetic genes is downregulated. Ultimately, these pleiotropic adaptations work synergistically, affecting cellular fitness and increasing cell reproductive potential. Therefore, Hxk2p integrates metabolic and signaling pathways that link carbon source utilization with cellular growth, cell cycle, energy homeostasis, and stress responses. This review summarizes current knowledge on Hxk2p function in carbohydrate metabolism, with particular emphasis on its regulatory roles and their implications for gene expression, cellular physiology, and proliferation capacity.