2Y1C

X-ray structure of 1-deoxy-D-xylulose 5-phosphate reductoisomerase, DXR, Rv2870c, from Mycobacterium tuberculosis, in complex with manganese.

Summary for 2Y1C

• Entry DOI: 10.2210/pdb2y1c/pdb
• Related: 2Y1D 2Y1E 2Y1F 2Y1G
• Descriptor: 1-DEOXY-D-XYLULOSE 5-PHOSPHATE REDUCTOISOMERASE, MANGANESE (II) ION (3 entities in total)
• Functional Keywords: oxidoreductase, doxp/mep pathway
• Biological source: MYCOBACTERIUM TUBERCULOSIS
• Total number of polymer chains: 2
• Total formula weight: 83511.82

Authors

Henriksson, L.M.,Larsson, A.M.S.,Bergfors, T.,Bjorkelid, C.,Unge, T.,Mowbray, S.L.,Jones, T.A. (deposition date: 2010-12-08, release date: 2011-06-29, Last modification date: 2023-12-20)

Primary citation

Andaloussi, M.,Henriksson, L.M.,Wieckowska, A.,Lindh, M.,Bjorkelid, C.,Larsson, A.M.S.,Iyer, H.,Srinivasa, B.R.,Bergfors, T.,Unge, T.,Mowbray, S.L.,Larhed, M.,Jones, T.A.,Karlen, A.
Design, Synthesis and X-Ray Crystallographic Studies of Alpha-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium Tuberculosis 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase
J.Med.Chem, 54:4964-, 2011

PubMed Abstract: The natural antibiotic fosmidomycin acts via inhibition of 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. Fosmidomycin is active on Mycobacterium tuberculosis DXR (MtDXR), but it lacks antibacterial activity probably because of poor uptake. α-Aryl substituted fosmidomycin analogues have more favorable physicochemical properties and are also more active in inhibiting malaria parasite growth. We have solved crystal structures of MtDXR in complex with 3,4-dichlorophenyl substituted fosmidomycin analogues; these show important differences compared to our previously described forsmidomycin-DXR complex. Our best inhibitor has an IC(50) = 0.15 μM on MtDXR but still lacked activity in a mycobacterial growth assay (MIC > 32 μg/mL). The combined results, however, provide insights into how DXR accommodates the new inhibitors and serve as an excellent starting point for the design of other novel and more potent inhibitors, particularly against pathogens where uptake is less of a problem, such as the malaria parasite.

PubMed: 21678907
DOI: 10.1021/JM2000085

Experimental method

X-RAY DIFFRACTION (1.9 Å)