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 A, 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.