title: Structural studies on Mycobacterium tuberculosis DXR in complex with the antibiotic FR-900098.
abstract: A number of pathogens, including the causative agents of tuberculosis and malaria, synthesize the essential isoprenoid precursor isopentenyl diphosphate via the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway rather than the classical mevalonate pathway that is found in humans. As part of a structure-based drug-discovery program against tuberculosis, DXR, the enzyme that carries out the second step in the MEP pathway, has been investigated. This enzyme is the target for the antibiotic fosmidomycin and its active acetyl derivative FR-900098. The structure of DXR from Mycobacterium tuberculosis in complex with FR-900098, manganese and the NADPH cofactor has been solved and refined. This is a new crystal form that diffracts to a higher resolution than any other DXR complex reported to date. Comparisons with other ternary complexes show that the conformation is that of the enzyme in an active state: the active-site flap is well defined and the cofactor-binding domain has a conformation that brings the NADPH into the active site in a manner suitable for catalysis. The substrate-binding site is highly conserved in a number of pathogens that use this pathway, so any new inhibitor that is designed for the M. tuberculosis enzyme is likely to exhibit broad-spectrum activity.
authors.affiliation: Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden.
authors.forename: Christofer
authors.initials: C
authors.lastname: Björkelid
authors.forename: Terese
authors.initials: T
authors.lastname: Bergfors
authors.forename: Torsten
authors.initials: T
authors.lastname: Unge
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Mowbray
authors.forename: T Alwyn
authors.initials: TA
authors.lastname: Jones
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000737:chemistry* / Q000378:metabolism*; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D004896:Erythritol / Q000031:analogs & derivatives / Q000378:metabolism; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008345:Manganese / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000201:enzymology*; D009249:NADP / Q000737:chemistry / Q000378:metabolism; D010088:Oxidoreductases / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D016415:Sequence Alignment; D013403:Sugar Phosphates / Q000378:metabolism
chemical_list: C114232:2-C-methylerythritol 4-phosphate; D000900:Anti-Bacterial Agents; D009097:Multienzyme Complexes; D013403:Sugar Phosphates; D005578:Fosfomycin; D008345:Manganese; D009249:NADP; C024639:3-(N-acetyl-N-hydroxy)aminopropylphosphonic acid; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases; D004896:Erythritol