Oral Presentation RACI Biomolecular Division Conference 2013

Aldolase Mechanism, Inhibition and Allostery (#43)

Emily Parker 1
  1. Department of Chemistry and Biomolecular Interaction Centre, University of Canterbury, Christchurch, New Zealand

Our studies examine the mechanisms and allosteric regulation of a number of essential biosynthetic enzymes from pathogenic bacteria such as Mycobacterium tuberculosis, Neisseria meningitidis and Campylobacter pylori.  These enzymes catalyse key steps in the production of the aromatic amino acids and leucine, and the sialic acids are key targets for potential antibacterial development.

This talk will outline our progress on understanding the mechanism and complex allosteric response of 3-deoxy-D-arabino-heptulsonate 7-phosphate synthase (DAH7PS), which catalyses the first committed step in the biosynthesis of the aromatic amino acids.  I will also out line our work on the N-acetyl neuraminic acid synthase and on the α-isopropyl malate synthase, which catalyses the first step of leucine biosynthesis .  Our studies have pinpointed features in the active and allosteric sites which have enabled the detailed understanding of mechanism and allow inhibitor development . 

  1. Webby, C. J., Jiao, W., Hutton, R. D., Blackmore, N. J., Baker, H. M., Baker, E. N., Jameson, G. B. & Parker, E. J. (2010). Synergistic allostery, a sophisticated regulatory network for the control of aromatic amino acid biosynthesis in Mycobacterium tuberculosis. J. Biol. Chem. 285, 30567-30576.
  2. Cross, P. J., Allison, T. M., Dobson, R. C. J., Jameson, G. B. & Parker, E. J. (2013) Engineering allosteric control to an unregulated enzyme by transfer of a regulatory domain, Proc Natl Acad Sci USA. 110, 2111-2116. 3.
  3. Reichau, S., Jiao, W.T., Walker, S. R., Hutton, R. D., Baker, E. N. & Parker, E. J. (2011) Potent inhibitors of a shikimate pathway enzyme from Mycobacterium tuberculosis: Combining mechanism- and modeling-based design, J Biol Chem. 286, 16197-16207.
  4. Joseph, D. D. A., Jiao, W. & Parker, E. J. (2013) Arg314 is essential for catalysis by N-acetyl neuraminic acid synthase from Neisseria meningitidis, Biochemistry. 52, 2609-2619.