Inhibition of <i>Neisseria meningitidis</i> Sialic Acid Synthase by a Tetrahedral Intermediate Analogue<sup>,</sup>
Bibliographic record
Abstract
The Neisseria meningitidis sialic acid synthase (NeuB) catalyzes the metal-dependent condensation of N-acetylmannosamine (ManNAc) and phosphoenolpyruvate (PEP) to generate N-acetylneuraminic acid (NeuAc or sialic acid). N. meningitidis is a causative agent of meningitis and produces a capsular polysaccharide comprised of polysialic acid. This allows it to evade the immune system of the host by an act of molecular mimicry. This work describes the synthesis and characterization of the first potent inhibitor of sialic acid synthase. The inhibitor is a stable deoxy analogue of the tetrahedral intermediate presumed to form in the NeuB reaction and was synthesized as a mixture of stereoisomers at the key tetrahedral center. Inhibition studies demonstrate that one stereoisomer binds more tightly than the other and that the more potent isomer binds with micromolar affinity. An X-ray crystallographic analysis of the NeuB.inhibitor.Mn(2+) complex solved to a resolution of 1.75 A shows that the more tightly bound stereoisomer bears a (2R)-configuration. This suggests that the tetrahedral intermediate formed in the NeuB reaction also bears a (2R)-configuration. This analysis is consistent with a mechanism whereby the active site metal plays at least two roles during catalysis. First, it serves as an electrostatic catalyst and activates the aldehyde of ManNAc for attack by the alkene of PEP. Second, it serves as a source of nucleophilic water and delivers it to the si face of the oxocarbenium intermediate to generate a tetrahedral intermediate with a (2R)-configuration.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 | 0.000 | 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 source (direct Gemma or distilled Codex), 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".