Friend or Foe? Unravelling the allosteric interactions between two enzymes from <em>Mycobacterium tuberculosis</em> — ASN Events
  1. Schedule
  2. Session Five - Poster Session A including Refreshments
  3. Friend or Foe? Unravelling the allosteric interactions between two enzymes from Mycobacterium tuberculosis

Friend or Foe? Unravelling the allosteric interactions between two enzymes from Mycobacterium tuberculosis (#151)

Nicola J Blackmore 1 , Emily J Parker 1 , Ali R Nazmi 1
  1. University of Canterbury, Ilam, NZ, New Zealand

3-Deoxy-D-arbino-heptulosonate 7-phosphate synthase (DAH7PS) catalyses the first committed step of aromatic amino acid biosynthesis and consequently is usually tightly feedback regulated by the end products of the pathway Trp, Phe and Tyr. Another critical enzyme of the pathway is chorismate mutase (CM), which directs the metabolite chorismate toward the synthesis of Tyr and Phe.

Mycobacterium tuberculosis DAH7PS (MtuDAH7PS) is only regulated by binary or ternary combinations of the aromatic amino acids that include Trp with either Phe or Tyr and is completely inhibited by all three aromatic amino acids.1,2 Crystallographic studies of MtuDAH7PS reveal three distinct allosteric binding sites, but no significant conformational changes associated with inhibitor binding to account for the observed inhibition.1,2

MtuDAH7PS also forms a hetero-octomeric complex with MtuCM causing a dramatic increasing CM activity by 100 fold.3Furthermore, complex formation bestows the unregulated MtuCM with regulatory sensitivity to Phe and Tyr.3 We have investigated the impact that complex formation has on MtuDAH7PS activity and regulation. We have also shown that the allosteric binding sites of MtuDAH7PS are directly responsible for the acquired regulation of MtuCM activity. Additionally we have shown that Phe binding to MtuDAH7PS promotes complex dissociation, providing important insight into the mechanisms of inhibitory signal transmission in this large complex.

  1. Blackmore, N. J. et al. Three sites and you are out: Ternary synergistic allostery controls aromatic amino acid biosynthesis in Mycobacterium tuberculosis. J. Mol. Biol. 425, 1582-1592 (2013).
  2. Webby, C. J. et al. Synergistic allostery: a sophisticated regulatory network for the control of aromatic amino acid biosynthesis in Mycobacterium tuberculosis. J. Biol. Chem. 285, 30567-30576 (2010).
  3. Sasso, S. et al. Structure and function of a complex between chorismate mutase and DAHP synthase: efficiency boost for the junior partner. Embo Journal 28, 2128-2142 (2009).