A missing enzyme-rescue metabolite as cause of a rare skeletal dysplasia.

ABSTRACT: Living cells depend on an intricate network of chemical reactions catalysed by enzymes, which sometimes make mistakes that lead to their inactivation. Here we report a metabolite-based mechanism for preserving enzyme function in an unfavourable environment. We found that the enzyme TGDS produces UDP-4-keto-6-deoxyglucose, a mimic of the reaction intermediate of the enzyme UXS1, which regenerates the essential cofactor NAD⁺ within the catalytic pocket of UXS1 by completing its catalytic cycle. Thus, the production of an 'enzyme-rescue metabolite' by TGDS represents a mechanism for maintaining the activity of an enzyme in a subcellular compartment where NAD⁺ is scarce. Using a combination of in vitro and in vivo studies, we demonstrate that the inability to produce suff

SUBMITTER: Jacobs J 

PROVIDER: S-EPMC12488480 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature