Studies with Guanidinium- and Amidinium-Based Inhibitors Suggest Minimal Stabilization of Allylic Carbocation Intermediates by Dehydrosqualene and Squalene Synthases
Bibliographic record
Abstract
Dehydrosqualene and squalene synthases catalyze the redox neutral and the reductive, head-to-head dimerization of farnesyl diphosphate, respectively. In each case, the reaction is thought to proceed via an initial dissociation of farnesyl diphosphate to form an allylic carbocation-pyrophosphate ion pair. This work describes the synthesis and testing of inhibitors in which a guanidinium or amidinium moiety is flanked by a phosphonylphosphinate group and a hydrocarbon tail. These functional groups bear a planar, delocalized, positive charge and therefore should act as excellent mimics of an allylic carbocation. An inhibitor bearing a neutral urea moiety was also prepared as a control. The positively charged inhibitors acted as competitive inhibitors against Staphylococcus aureus dehydrosqualene synthase with K i values in the low micromolar range. Surprisingly, the neutral urea inhibitor was the most potent of the three. Similar trends were seen with the first half reaction of human squalene synthase. One interpretation of these results is that the active sites of these enzymes do not directly stabilize the allylic carbocation via electrostatic or π-cation interactions. Instead, it is likely that the enzymes use tight binding to the pyrophosphate and lipid moieties to promote catalysis and that electrostatic stabilization of the carbocation is provided by the bound pyrophosphate product. An alternate possibility is that these inhibitors cannot bind to the “ionization FPP-binding site” of the enzyme and only bind to the “nonionizing FPP-binding site”. In either case, all reported attempts to generate potent inhibitors with cationic FPP analogues have been unsuccessful to date.
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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) | 0.001 | 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".