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==''Mycobacterium tuberculosis'' salicylate synthase (Mbt1)==

==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). MtbI belongs to the MST enzyme family, which consists of structural homologues (Irp9, MenF, EntC, and MtbI) that isomerize chromate to isochorismate. These enzymes are in involved in menaquinone, siderophore, or tryptophan biosynthesis.

[[Image:Pathways.png|500 px|center|thumb|Figure 1: This is the pathway of reactions catilized by wild-type MbtI. Ferrer ''et al.'', 2012]]

==Structure==

[[Image:Active_site_cleft.png|300 px|left|thumb|Figure 2: This shows a single sub unit of MbtI, with the active site cleft located at the lower left hand side of the image.]]

The crystal asymmetric unit was found to contain <scene name='69/694235/3log/1'> four MbtI molecules</scene>, 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 core of the protein is formed by 21 beta-strands folded into a twisted beta-sandwich. The protein's core is then surrounded by 10 alpha helices.

== 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''.

== Function ==

== Relevance ==

== Structural highlights ==

==Mechanism==

A magnesium ion in the active site orients the C1 carboxyl group of chorismate. A lysine residue then serves as a general base for the activation of a water molecule to attack at C2

The catalytic mechanism for conversion of isochorismate to salicylate by MbtI is a sigmatropic, pericyclic mechanism that is pH-dependent. Chromate mutase activity is only observed in the absence of magnesium ion in the active site while salicylate synthase activity is depended on magnesium ion. The active site of MbtI is altered by the removal of the magnesium cofactor causing chromate mutase activity. MbtI has differing binding modes for chromate that leads to different substrate conformations/transition states and resulting in different products.

==Inhibition Studies==

 

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