Human Fructose Metabolism and D-Glycerate Kinase Deficiency

• Applicant: Professor Dr. Jörn Oliver Sass
• Subject Area: Biochemistry
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558545467

D-fructose is an abundant carbohydrate in the human diet, both as a monosaccharide and as a component of the table sugar sucrose. The best known metabolic pathway of human fructose catabolism proceeds in the cytosol via fructose-1-phosphate, which is cleaved into dihydroxyacetone phosphate and D-glyceraldehyde. Following phosphorylation of the latter metabolite, both compounds can enter glycolysis. In contrast, mitochondrial fructose metabolism has attracted limited attention so far, although evidence for its existence is available for decades and its impairment has been linked to D-glyceric aciduria due to D-glycerate kinase deficiency, a rare inborn error of human metabolism, whose molecular basis we have first described 14 years ago. The proposed project will use various human-derived cell lines and the nematode Caenorhabditis elegans for a better understanding of the mitochondrial contributions to fructose metabolism. Does fructose provide an important part of the energy supply of certain cells or is its role rather that of inducing structural changes and mediating fructose toxicity? Is this possibly different in cells of intestinal, hepatic or pancreatic origin? What are molecular implications and possibly secondary consequences of genetic deficiency of D-glycerate kinase due to mutations in GLYCTK? Will D-fructose and D-glyceraldehyde promote the formation of 2-phospho-D-glycerate in the mitochondria of human-derived cells? Will proteomics studies help with the identification of the transport mechanism that enables 2-phospho-D-glycerate to leave the mitochondrion for further metabolism? The proposed project shall not only contribute to a better understanding of D-glyceric aciduria as a rare genetic metabolic disorder in the human, but shall also be relevant for a better recognition of the role of fructose in pathomechanisms underlying common diseases that prompt major public health concerns.

• DFG Programme: Research Grants