A missing enzyme-rescue metabolite as cause of a rare skeletal dysplasia, 2025, Jacobs et al.

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

Spoiler: Authors

Jacobs, Jean; Lyubenova, Hristiana; Potelle, Sven; Kopp, Johannes; Gerin, Isabelle; Chan, Wing Lee; Rodriguez de los Santos, Miguel; Hülsemann, Wiebke; Mensah, Martin A; Cormier-Daire, Valérie; Joosten, Marieke; Bruggenwirth, Hennie T; Stuurman, Kyra E; Miranda, Valancy; Campeau, Philippe M; Wittler, Lars; Graff, Julie; Mundlos, Stefan; Ibrahim, Daniel M; Van Schaftingen, Emile; Fischer-Zirnsak, Björn; Kornak, Uwe; Ehmke, Nadja; Bommer, Guido T

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 sufficient amounts of this enzyme-rescue metabolite leads to the inactivation of UXS1, impairing the synthesis of specific glycans that are crucial for skeletal development. This provides an explanation for the development of the hereditary skeletal disorder Catel–Manzke syndrome in individuals with TGDS deficiency.

Defects in similar protective layers might contribute to metabolic changes in other diseases that cannot be explained with common concepts in metabolic biochemistry.

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From commentary Rare skeletal condition caused by enzyme’s failure to rescue a catalytic cycle —

The authors have provided strong evidence that the product of TGDS has a role as a rescue metabolite. However, the specific pathway and physiological substrate of TGDS in humans remain uncertain. The role of TGDS in rescue could be a moonlighting role, by which a protein can perform a secondary function.

The concept of a rescue metabolite is not new to biochemistry, although this finding is exceptional because it identifies a case in which a defect in the rescue pathway causes a disease state.

Detecting when an enzyme is inactivated by loss of its cofactor or intermediate is challenging, because the enzyme itself is not modified. Assessing this occurrence requires sophisticated experiments that measure progression through metabolic pathways (metabolic flux). Jacobs et al. did not measure the frequency with which UXS1 is inactivated, but information such as this could be valuable, because it is possible that the apparent failure of such enzymes has been left in place by evolution as a method of regulating metabolic flux.