Poster Presentation The 47th Lorne Conference on Protein Structure and Function 2022

Modulation of Mycobacterium tuberculosis isocitrate lyase activities (#101)

Brooke Kwai 1 , Ghader Bashiri 2 , Ivanhoe Leung 3
  1. School of Chemical Sciences, The University of Auckland, Auckland, New Zealand
  2. School of Biological Sciences, The University of Auckland, Auckland, New Zealand
  3. The University of Melbourne, Melbourne, Australia

Mycobacterium tuberculosis isocitrate lyase (ICL) isoforms 1 and 2 are critical metabolic enzymes that enable virulence and survival by acting as gatekeepers at the junction between the glyoxylate shunt and the TCA cycle.1,2,3 Details about the regulation and modulation of ICLs at the protein level is significant, as the direction of carbon flow between these two key metabolite pathways may enable the development of new treatments against tuberculosis.4 Herein, we report our work on the modulation of ICLs from structural and mechanistic perspectives by using X-ray crystallography, NMR spectroscopy, mutagenesis and kinetic studies. Our results provide new fundamental knowledge about the control of the central carbon metabolism in M. tuberculosis.

  1. Bhusal, R., Bashiri, G., Kwai, B., Sperry, J. & Leung, I. Targeting isocitrate lyase for the treatment of latent tuberculosis. Drug Discov. Today, 22, 1008‐1016 (2017)
  2. Bhusal, R., Patel, K., Kwai, B., et al. Development of NMR and thermal shift assays for Mycobacterium tuberculosis isocitrate lyase inhibitors screening. Med. Chem. Commun., 8, 2155‐2163 (2017).
  3. Bhusal, R. P., Jiao, W., Kwai, B. X. C., et al. Acetyl‐CoA‐Mediated Activation of Mycobacterium tuberculosis Isocitrate Lyase 2. Nat Commun., 10, 4639 (2019).
  4. Kwai, B. X. C., Collins, A. J., Middleditch, M. J., et al. Itaconate is a covalent inhibitor of the Mycobacterium tuberculosis isocitrate lyase. RSC Med.Chem., 12, 57‐61 (2020).