Structural biology of glucose-6-phosphate dehydrogenase and small-molecule activators
Bibliographic record
Abstract
Glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme in the pentose phosphate pathway.It's essential for the production of NADPH and glutathione, and the reduction of reactive oxygen species.G6PD exists as inactive monomers and active dimers and tetramers, with its structure and activity sensitive to the presence of its co-factors NADP+ and glucose-6phosphate.G6PD deficiency is one of the most common enzymatic disorders, with over 150 single mutations known to affect enzyme activity.G6PD activity also declines with age and is associated with the accumulation of oxidative DNA damage [1].By contrast, increased G6PD activity has been shown to extend lifespan and healthspan in animal models [2].Overcoming G6PD decline and deficiency with the use of activators may help prevent diseases of ageing and treat hereditary G6PD deficiency.Indeed, novel small molecule activators of G6PD increase the lifespan of worms.Here, we explore the mechanisms by which small molecules activate G6PD using X-ray crystallography, analytical size exclusion chromatography and HDX-MS.It was hypothesised that these molecules stabilise G6PD in its more active tetrameric state.However, we've found that these small molecule activators do not alter the oligomeric state of G6PD in solution.Instead, X-ray crystallography reveals a paradox where the soaking of a small molecule activator into the crystals results into the loss of density for structural NADP+, which is usually associated with reduced G6PD activity [3,4].
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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 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".