First crystal structures of 1-deoxy-D-xylulose 5-phosphate synthase (DXPS) from Mycobacterium tuberculosis indicate a distinct mechanism of intermediate stabilization.
Gierse, R.M., Oerlemans, R., Reddem, E.R., Gawriljuk, V.O., Alhayek, A., Baitinger, D., Jakobi, H., Laber, B., Lange, G., Hirsch, A.K.H., Groves, M.R.(2022) Sci Rep 12: 7221-7221
- PubMed: 35508530 
- DOI: https://doi.org/10.1038/s41598-022-11205-9
- Primary Citation of Related Structures:  
7A9G, 7A9H - PubMed 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.
Organizational Affiliation: 
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI), Campus Building E 8.1, 66123, Saarbrücken, Germany.