TGDS acts as a “rescue molecule” in sugar metabolism—a previously unknown physiological function of the enzyme deoxy-TDP-D-glucose 4,6-dehydratase described now by researchers in Nature. The recently published study shows that TGDS is essential in a kind of emergency mechanism for the synthesis of UDP-xylose, a component required for building glycosaminoglycans. These long-chain sugar polymers are indispensable for bones, cartilage, and connective tissue. For the first time, the scientists provide a mechanism explaining the development of Catel-Manzke syndrome, a very rare hereditary skeletal disorder caused by homozygous or compound heterozygous pathogenic variants in the TGDS gene.

Functional studies in a range of cell lines and a mouse model revealed that TGDS is tightly linked to the activity of UXS1 (UDP-glucuronate decarboxylase 1). This enzyme catalyzes the conversion of UDP-glucuronate to UDP-xylose, but can occasionally lose an intermediate metabolite and remain in an inactive form. As the researchers discovered, TGDS produces a kind of rescue molecule from UDP-glucose that allows UXS1 to become reactivated, enabling the enzymatic reaction to proceed. Deleterious variants in TGDS, however, prevent the reactivation of UXS1. Malfunction of such molecular rescue systems, like that involving TGDS and UXS1, may also play a role in the pathogenesis of other diseases.