2005 Alfred Bader Award Lecture Diaminopimelate and lysine biosynthesis - An antimicrobial target in bacteria
Bibliographic record
Abstract
The development of bacterial resistance to current antibiotic therapy has stimulated the search for novel antimicrobial agents. The essential peptidoglycan cell wall layer in bacteria is the site of action of many current drugs, such as β-lactams and vancomycin. It is also a target for a number of very potent bacterially produced antibiotic peptides, such as nisin A and lacticin 3147, both of which are highly posttranslationally modified lantibiotics that act by binding to lipid II, the peptidoglycan precursor. Another set of potential targets for antibiotic development are the bacterial enzymes that make precursors for lipid II and peptidoglycan, for example, those in the pathway to diamino pimelic acid (DAP) and its metabolic product, L-lysine. Among these, DAP epimerase is a unique nonpyridoxal phosphate (PLP) dependent enzyme that appears to use two active site thiols (Cys73 and Cys217) as a base and an acid to depro tonate the α-hydrogen of LL-DAP or meso-DAP from one side and reprotonate from the other. This process cannot be easily duplicated in the absence of the enzyme. A primary goal of our work was to generate inhibitors of DAP epi merase that would accurately mimic the natural substrates (meso-DAP and LL-DAP) in the enzyme active site and, through crystallographic analysis, provide insight into mechanism and substrate specificity. A series of aziridine-containing DAP analogs were chemically synthesized and tested as inhibitors of DAP epimerase from Haemophilus influenzae. Two diastereomers of 2-(4-amino-4-carboxybutyl)aziridine-2-carboxylic acid (AziDAP) act as rapid irreversible inactivators of DAP epimerase; the AziDAP analog of LL-DAP reacts selectively with the sulfhydryl of Cys73, whereas the corresponding analog of meso-DAP reacts with Cys217. AziDAP isomers are too unstable to be useful antibiotics. However, mass spectral and X-ray crystallographic analyses of the inactivated enzymes confirm that the thiol attacks the methylene group of the aziridine with concomitant ring opening to give a DAP analog bound in the active site. Further crystallographic analyses should yield useful mechanistic insights.Key words: enzyme mechanism, enzyme inhibition, antibiotics, aziridines, amino acids.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.003 | 0.002 |
| Insufficient payload (model declined to judge) | 0.076 | 0.034 |
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".