Structural and mechanistic studies on eukaryotic UDP-galactopyranose mutases
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Bibliographic record
Abstract
Galactofuranose (Galf) is the five membered ring form of galactose. It is found on the cell wall and surface of many pathogens including Mycobacterium tuberculosis, Aspergillus fumigatus, Leishmania major, and Trypanosoma cruzi. Galf has been implicated in pathogenesis in these organisms; thus the biosynthetic pathway of Galf is a target for drug design. Galf is synthesized by the enzyme UDP-galactopyranose mutase (UGM), which converts UDP-galactopyranose (UDP-Galp) to UDP-galactofuranose (UDP-Galf). Solving the mechanism and structure of UGMs will aid in the development of specific inhibitors against these enzymes. Herein we present the detailed functional analysis of UGMs from A. fumigatus, T. cruzi, and L. major. The mechamism and structure these eukaryotic UGMs were examined by steady-state kinetics, rapid-reaction kinetics, trapping of reaction intermediates, fluorescence anisotropy, and X-ray crystallography. The mechanism first involves reduction of the required flavin by NADPH, followed by UDP-Galp binding and subsequent SN2 attack by the flavin on galactose displacing UDP to form a flavin N5-C1 galactose adduct. Next, the galactose ring opens forming an iminium ion allowing isomerization to occur. Lastly, the product is released and UGM is available to bind another substrate or be reoxidized by molecular oxygen. The three-dimensional structure of A. fumigatus UGM was solved using X-ray crystallography in four conformations: oxidized in complex with sulfate ions, reduced, reduced in complex with UDP, and reduced in complex with UDP-Galp, giving valuable information on the unique features of eukaryotic UGMs including features important for oligomerization and for substrate binding. The novel mechanism and structure provide valuable information for the development of specific inhibitors of eukaryotic UGMs.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 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 it