A missing enzyme-rescue metabolite as cause of a rare skeletal dysplasia
Bibliographic record
Abstract
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 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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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".