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Journal of Bacteriology, September 2006, p. 6081-6091, Vol. 188, No. 17
0021-9193/06/$08.00+0     doi:10.1128/JB.00338-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Structure of MbtI from Mycobacterium tuberculosis, the First Enzyme in the Biosynthesis of the Siderophore Mycobactin, Reveals It To Be a Salicylate Synthase

Anthony J. Harrison,1,2 Minmin Yu,4 Therés Gårdenborg,1,2,{dagger} Martin Middleditch,2 Rochelle J. Ramsay,1,2 Edward N. Baker,1,2,3 and J. Shaun Lott1,2*

Centre for Molecular Biodiscovery,1 School of Biological Sciences,2 Department of Chemistry, University of Auckland, Auckland, New Zealand,3 Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 947204

Received 9 March 2006/ Accepted 21 June 2006

The ability to acquire iron from the extracellular environment is a key determinant of pathogenicity in mycobacteria. Mycobacterium tuberculosis acquires iron exclusively via the siderophore mycobactin T, the biosynthesis of which depends on the production of salicylate from chorismate. Salicylate production in other bacteria is either a two-step process involving an isochorismate synthase (chorismate isomerase) and a pyruvate lyase, as observed for Pseudomonas aeruginosa, or a single-step conversion catalyzed by a salicylate synthase, as with Yersinia enterocolitica. Here we present the structure of the enzyme MbtI (Rv2386c) from M. tuberculosis, solved by multiwavelength anomalous diffraction at a resolution of 1.8 Å, and biochemical evidence that it is the salicylate synthase necessary for mycobactin biosynthesis. The enzyme is critically dependent on Mg2+ for activity and produces salicylate via an isochorismate intermediate. MbtI is structurally similar to salicylate synthase (Irp9) from Y. enterocolitica and the large subunit of anthranilate synthase (TrpE) and shares the overall architecture of other chorismate-utilizing enzymes, such as the related aminodeoxychorismate synthase PabB. Like Irp9, but unlike TrpE or PabB, MbtI is neither regulated by nor structurally stabilized by bound tryptophan. The structure of MbtI is the starting point for the design of inhibitors of siderophore biosynthesis, which may make useful lead compounds for the production of new antituberculosis drugs, given the strong dependence of pathogenesis on iron acquisition in M. tuberculosis.

* Corresponding author. Mailing address: School of Biological Sciences, University of Auckland, Private Bag 92-019, Auckland 1020, New Zealand. Phone: 64-9-373-7599. Fax: 64-9-373-7414. E-mail: s.lott{at}auckland.ac.nz.

{dagger} Present address: IBG, Uppsala Biomedicinska Center, Uppsala University, Box 592, S-75124 Uppsala, Sweden.

Journal of Bacteriology, September 2006, p. 6081-6091, Vol. 188, No. 17
0021-9193/06/$08.00+0     doi:10.1128/JB.00338-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Van Lanen, S. G., Lin, S., Shen, B. (2008). Biosynthesis of the enediyne antitumor antibiotic C-1027 involves a new branching point in chorismate metabolism. Proc. Natl. Acad. Sci. USA 105: 494-499 [Abstract] [Full Text]  
  • Miethke, M., Marahiel, M. A. (2007). Siderophore-Based Iron Acquisition and Pathogen Control. Microbiol. Mol. Biol. Rev. 71: 413-451 [Abstract] [Full Text]  
  • Strawn, M. A., Marr, S. K., Inoue, K., Inada, N., Zubieta, C., Wildermuth, M. C. (2007). Arabidopsis Isochorismate Synthase Functional in Pathogen-induced Salicylate Biosynthesis Exhibits Properties Consistent with a Role in Diverse Stress Responses. J. Biol. Chem. 282: 5919-5933 [Abstract] [Full Text]  


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