Dimerization of inositol monophosphatase Mycobacterium tuberculosis SuhB is not constitutive, but induced by binding of the activator Mg²⁺

Background. The cell wall of Mycobacterium tuberculosis contains a wide range of phosphatidyl inositol-based glycolipids that play critical structural roles and, in part, govern pathogen-host interactions. Synthesis of phosphatidyl inositol is dependent on free myo-inositol, generated through dephosphorylation of myo-inositol-1-phosphate by inositol monophosphatase (IMPase). Human IMPase, the putative target of lithium therapy, has been studied extensively, but the function of four IMPase-like genes in M. tuberculosis is unclear. Results. We determined the crystal structure, to 2.6 Å resolution, of the IMPase M. tuberculosis SuhB in the apo form, and analysed self-assembly by analytical ultracentrifugation. Contrary to the paradigm of constitutive dimerization of IMPases, SuhB is predominantly monomeric in the absence of the physiological activator Mg²⁺, in spite of a conserved fold and apparent dimerization in the crystal. However, Mg²⁺ concentrations that result in enzymatic activation of SuhB decisively promote dimerization, with the inhibitor Li⁺ amplifying the effect of Mg²⁺, but failing to induce dimerization on its own. Conclusion. The correlation of Mg ²⁺-driven enzymatic activity with dimerization suggests that catalytic activity is linked to the dimer form. Current models of lithium inhibition of IMPases posit that Li⁺ competes for one of three catalytic Mg²⁺ sites in the active site, stabilized by a mobile loop at the dimer interface. Our data suggest that Mg²⁺/Li ⁺-induced ordering of this loop may promote dimerization by expanding the dimer interface of SuhB. The dynamic nature of the monomer-dimer equilibrium may also explain the extended concentration range over which Mg ²⁺ maintains SuhB activity.