ArticleScientific reports2022
First crystal structures of 1-deoxy-D-xylulose 5-phosphate synthase (DXPS) from Mycobacterium tuberculosis indicate a distinct mechanism of intermediate stabilization.
Article in Scientific reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 20 citations in OpenAlex.
- Aromatic Residues in Mobile Regions Distal to the Active Site Support the Closed Conformation ofBiochemistry · 2026Article
- X-ray Co-crystal Structure of a Novel Pseudomonas aeruginosa DXPS Inhibitor Reveals an Unusual Allosteric Binding Pocket.Research square · 2026Article
- Identification of Natural-Product Inhibitors of the 2ACS medicinal chemistry letters · 2026Article
- Combination Therapy with Azithromycin andMicroorganisms · 2025Article
- Aromatic residues in mobile regions distal to the active site support the closed conformation ofbioRxiv : the preprint server for biology · 2025Article
- Studying Target-Engagement of Anti-Infectives by Solvent-Induced Protein Precipitation and Quantitative Mass Spectrometry.ACS infectious diseases · 2024Article
- Cryo-EM structure of 1-deoxy-D-xylulose 5-phosphate synthase DXPS from Plasmodium falciparum reveals a distinct N-terminal domain.Nature communications · 2024Article
- Evaluation of ketoclomazone and its analogues as inhibitors of 1-deoxy-d-xylulose 5-phosphate synthases and other thiamine diphosphate (ThDP)-dependent enzymes.RSC medicinal chemistry · 2024Article
- Potent Inhibition ofACS infectious diseases · 2024Article
- Disruption of an Active Site Network Leads to Activation of C2α-Lactylthiamin Diphosphate on the Antibacterial Target 1-Deoxy-d-xylulose-5-phosphate Synthase.Biochemistry · 2024Article
- Antibacterial Target DXP Synthase Catalyzes the Cleavage of d-Xylulose 5-Phosphate: a Study of Ketose Phosphate Binding and Ketol Transfer Reaction.Biochemistry · 2022Article
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
Abstract
The development of drug resistance by Mycobacterium tuberculosis and other pathogenic bacteria emphasizes the need for new antibiotics. Unlike animals, most bacteria synthesize isoprenoid precursors through the MEP pathway. 1-Deoxy-D-xylulose 5-phosphate synthase (DXPS) catalyzes the first reaction of the MEP pathway and is an attractive target for the development of new antibiotics. We report here the successful use of a loop truncation to crystallize and solve the first DXPS structures of a pathogen, namely M. tuberculosis (MtDXPS). The main difference found to other DXPS structures is in the active site where a highly coordinated water was found, showing a new mechanism for the enamine-intermediate stabilization. Unlike other DXPS structures, a "fork-like" motif could be identified in the enamine structure, using a different residue for the interaction with the cofactor, potentially leading to a decrease in the stability of the intermediate. In addition, electron density suggesting a phosphate group could be found close to the active site, provides new evidence for the D-GAP binding site. These results provide the opportunity to improve or develop new inhibitors specific for MtDXPS through structure-based drug design.
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