The metabolism of glucose is essential for most cells to survive and to thrive. Yet, the need for glucose is often cell-specific, and the metabolic pathways that use glucose are differently regulated due to the existence of several versions of the enzymes catalysing the critical steps of glycolysis.
Glucose phosphorylation by hexokinases (five different enzymes) is one of these critical steps. The rate of glucose utilisation has to be adjusted to the needs for downstream metabolites (ATP, pyruvate, acetyl-CoA, serine). Accordingly, hexokinases are feed-back inhibited by glucose-6-phosphate, but in a surprising way this inhibition is not yet fully understood: it is a sophisticated feature implicating the binding of glucose-6-phosphate to an allosteric site.
With her lab, Maria Veiga-da-Cunha and Emile Van Schaftingen collaborate to understand the impact of defects in the regulation of hexokinases present in inborn errors of metabolism. These can either be due to mutations in hexokinase itself or in other enzymes (including metabolite repair enzymes) or transporters that impact the production of metabolites affecting the regulation of hexokinases.
To address these questions they use two strategies : 1) an in vitro approach, where they produce and study the enzymatic properties of the recombinant enzymes and 2) a physiological one that uses cell and mouse models that mimic the enzymatic defects that are studied by metabolic analysis.
Through understanding the pathophysiological mechanism of still enigmatic inborn errors of metabolism, the Veiga-da-Cunha lab seeks to provide new treatments for the patients.