Discovery of a vital enzymatic guardian angel

In their search for the cause of the rare Catel-Manzke syndrome, a genetic skeletal disorder, researchers at UCLouvain and Charité have come across a new type of mechanism: the enzyme TGDS, whose function in the human body had previously been unknown, produces the sugar derivative UDP-4-keto-6-deoxyglucose, which rescues a second enzyme from its inactive state. Only with the help of this “guardian angel” is the second enzyme able to produce the building blocks needed for bone formation.

This process appears to be vital at least in mice: animals that cannot produce the enzyme-rescuing molecule are not viable. In people with Catel-Manzke syndrome, TGDS function is not completely lost, but only impaired. The syndrome manifests mainly as short stature, a cleft palate, a too-small lower jaw, congenital heart defects, and malformations of the index fingers.

That enzymes can temporarily lose their function and be reactivated by rescue molecules represents a very unusual concept in the biochemistry of the cell, which is defective in Catel-Manzke syndrome. The fundamental findings are published TODAY at 5 p.m. in the journal Nature.

Article describing this research

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

Jacobs J, Lyubenova H, Potelle S, Kopp J, Gerin I, Chan WL, Rodriguez de los Santos M, Hülsemann W, Mensah MA, Cormier-Daire V, Joosten M, Bruggenwirth HT, Stuurman KE, Miranda V, Campeau PM, Wittler L, Graff J, Mundlos S, Ibrahim DM, Van Schaftingen E, Fischer-Zirnsak B, Kornak U, Ehmke N & Bommer GT

Nature 2025 https://doi.org/10.1038/s41586-025-09397-x

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

Nature 2025