First crystal structures of 1-deoxy-d-xylulose 5-phosphate synthase (DXPS) from Mycobacterium tuberculosis indicate a distinct mechanism of intermediate stabilization

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.

Automated summary

The development of drug resistance highlights the importance of new antibiotics. Most bacteria synthesize isoprenoid precursors through the MEP pathway, making 1-deoxy-d-xylulose 5-phosphate synthase (DXPS) an attractive target. In this study, the DXPS structure of the pathogenic bacteria Mycobacterium tuberculosis was successfully solved using a loop truncation method, revealing differences and new insights into the stabilization mechanism of the enamine intermediate. The findings provide an opportunity for structure-based drug design to develop specific inhibitors for M. tuberculosis DXPS.