Understanding the metabolic fate of the rescue metabolite UDP-4-keto-6-deoxyglucose

Delrée, Pauline
(2026)

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Details

Supervisors
Bommer, Guido
Faculty
Faculté de pharmacie et des sciences biomédicales
Degree label
Master [120] en sciences biomédicales, à finalité approfondie
Abstract
enThe endoplasmic reticulum (ER) lumen contains hexose-6-phosphate dehydrogenase (H6PD), a bifunctional enzyme that catalyzes the oxidation of glucose-6-phosphate and related hexose-6-phosphates, followed by hydrolysis of the resulting lactone. By using both NAD⁺ and NADP⁺ as cofactors, H6PD establishes a distinct redox environment within the ER. This activity lowers luminal NAD⁺ levels, leading to a hostile environment for the NAD⁺ dependent enzyme UDP-xylose synthase 1 (UXS1): This enzyme occasionally loses its cofactor and is converted in an NADH-bound inactive form. With low ER NAD+ concentrations, it cannot regain its activity by cofactor replacement thereby limiting UDP-xylose production and glycosaminoglycan (GAG) synthesis. Our laboratory previously showed that TGDS produces UDP-4-keto-6-deoxyglucose, a metabolite capable of restoring UXS1 activity. In the presented master thesis, I attempted to further characterise the metabolic fate of UDP-4-keto-6-deoxyglucose using a combination of genetic, molecular biology and biochemical approaches.