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

• DOI: 10.1038/s41598-022-11205-9
• Publication Date: 2022-05-04T10:04:08Z
• Authors: Robin M. Gierse; Rick Oerlemans; Eswar R. Reddem; Victor O. Gawriljuk; Alaa Alhayek; Dominik Baitinger; Harald Jakobi; Bernd Laber; Gudrun Lange; Anna K. H. Hirsch; Matthew R. Groves
• Keywords: ddc:500; Science; Anti-Bacterial Agents: pharmacology; Transferases/metabolism; Article; Anti-Bacterial Agents/pharmacology; 03 medical and health sciences; Transferases; Mycobacterium tuberculosis/metabolism; Animals; X-ray crystallography; Pentosephosphates; 0303 health sciences; Binding Sites; Transferases: metabolism; Q; R; 500; 600; Mycobacterium tuberculosis; Mycobacterium tuberculosis: metabolism; Anti-Bacterial Agents; Enzymes; 3. Good health; 1-deoxylulose 5-phosphate; Enzyme mechanisms; info:eu-repo/classification/ddc/600; Medicine; Molecular modelling; Structural biology

AbstractThe 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.