Structural highlights
3pfp is a 2 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Ligands: | , , , , |
| Related: | 2b7o, 3nv8, 3kgf, 3nud, 3nue |
| Gene: | aroG, Rv2178c (Mycobacterium tuberculosis) |
| Activity: | 3-deoxy-7-phosphoheptulonate synthase, with EC number 2.5.1.54 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Function
[O53512_MYCTU] Catalyzes an aldol-like condensation reaction between phosphoenolpyruvate (PEP) and D-erythrose 4-phosphate (E4P) to generate 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAH7P) and inorganic phosphate.[1]
Publication Abstract from PubMed
Tuberculosis remains a serious global health threat, with the emergence of multidrug-resistant strains highlighting the urgent need for novel antituberculosis drugs. The enzyme 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase (DAH7PS) catalyzes the first step of the shikimate pathway for the biosynthesis of aromatic compounds. This pathway has been shown to be essential in Mycobacterium tuberculosis, the pathogen responsible for tuberculosis. DAH7PS catalyzes a condensation reaction between P-enolpyruvate and erythrose 4-phosphate to give 3-deoxy-D-arabino-heptulosonate 7-phosphate. The enzyme reaction mechanism is proposed to include a tetrahedral intermediate, which is formed by attack of an active site water on the central carbon of P-enolpyruvate during the course of the reaction. Molecular modeling of this intermediate into the active site reported in this study shows a configurational preference consistent with water attack from the re face of P-enolpyruvate. Based on this model, we designed and synthesized an inhibitor of DAH7PS that mimics this reaction intermediate. Both enantiomers of this intermediate mimic were potent inhibitors of M. tuberculosis DAH7PS, with inhibitory constants in the nanomolar range. The crystal structure of the DAH7PS-inhibitor complex was solved to 2.35 A. Both the position of the inhibitor and the conformational changes of active site residues observed in this structure correspond closely to the predictions from the intermediate modeling. This structure also identifies a water molecule that is located in the appropriate position to attack the re face of P-enolpyruvate during the course of the reaction, allowing the catalytic mechanism for this enzyme to be clearly defined.
Potent inhibitors of a shikimate pathway enzyme from Mycobacterium tuberculosis: combining mechanism- and modeling-based design.,Reichau S, Jiao W, Walker SR, Hutton RD, Baker EN, Parker EJ J Biol Chem. 2011 May 6;286(18):16197-207. Epub 2011 Mar 15. PMID:21454647[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Webby CJ, Baker HM, Lott JS, Baker EN, Parker EJ. The structure of 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase from Mycobacterium tuberculosis reveals a common catalytic scaffold and ancestry for type I and type II enzymes. J Mol Biol. 2005 Dec 9;354(4):927-39. Epub 2005 Oct 21. PMID:16288916 doi:10.1016/j.jmb.2005.09.093
- ↑ Reichau S, Jiao W, Walker SR, Hutton RD, Baker EN, Parker EJ. Potent inhibitors of a shikimate pathway enzyme from Mycobacterium tuberculosis: combining mechanism- and modeling-based design. J Biol Chem. 2011 May 6;286(18):16197-207. Epub 2011 Mar 15. PMID:21454647 doi:http://dx.doi.org/10.1074/jbc.M110.211649
