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Mycobacterium tuberculosis salicylate synthase (Mbt1)
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You may include any references to papers as in: the use of JSmol in Proteopedia [1] or to the article describing Jmol [2] to the rescue.
Introduction
Mycobacterim tuberculosis salicylate synthase (MtbI) is a highly promiscuous enzyme that has four distinct activities: isochorismate synthase (IS), isochorismate pyruvate lyase (IPL), salicylate synthase (SS) and chromate mutate (CM).
Structure
The crystal asymmetric unit was found to contain four MbtI molecules, however crystal packing and size exclusion chromatography data suggest a monomeric enzyme. There are no significant structural changes between the four monomers excepts from the localized differences in the active site. The overall molecular structure consist of a polypeptide of 450 residues that forms one large single domain with a similar fold to other chromate-utilizing enzymes. The fold consists of two alpha/deta subdomains, each forming a large antiparallel beta sheet with helices packed around the outside of the two beta sheets that form the core.
Function
Disease
The salicylate synthase activity of MbtI produces salicylate from chorismate through an isochorismate intermediate. This reaction is Mg dependent. Chorismate is then used in the biosyntheses of Mycobactin T, the siderophore of M. tuberculosis. The siderophore sequesters iron, covering pathogenesis of M. tuberculosis.
Relevance
Structural highlights
Inhibition Studies
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References
1. Chi G1, Manos-Turvey A, O'Connor PD, Johnston JM, Evans GL, Baker EN, Payne RJ, Lott JS, Bulloch EM. 2012. Implications of binding mode and active site flexibility for inhibitor potency against the salicylate synthase from Mycobacterium tuberculosis. Biochemistry 51(24):4868-79. doi: 10.1021/bi3002067
2. Ferrer S1, Martí S, Moliner V, Tuñón I, Bertrán J. 2012 Understanding the different activities of highly promiscuous MbtI by computational methods. Phys Chem Chem Phys. 14(10):3482-9. doi: 10.1039/c2cp23149b.
3. Harrison AJ1, Yu M, Gårdenborg T, Middleditch M, Ramsay RJ, Baker EN, Lott JS. 2006. The structure of MbtI from Mycobacterium tuberculosis, the first enzyme in the biosynthesis of the siderophore mycobactin, reveals it to be a salicylate synthase. J Bacteriol. 188(17):6081-91.
4. Manos-Turvey A1, Cergol KM, Salam NK, Bulloch EM, Chi G, Pang A, Britton WJ, West NP, Baker EN, Lott JS, Payne RJ. 2012. Synthesis and evaluation of M. tuberculosis salicylate synthase (MbtI) inhibitors designed to probe plasticity in the active site. Org Biomol Chem 10(46):9223-36. doi: 10.1039/c2ob26736e.
5. Zwahlen J1, Kolappan S, Zhou R, Kisker C, Tonge PJ. 2007. Structure and mechanism of MbtI, the salicylate synthase from Mycobacterium tuberculosis. Biochemistry. 46(4):954-64.
