Identification of two dihydrodipicolinate synthase isoforms from Pseudomonas aeruginosa that differ in allosteric regulation

Rachael E. Impey, Santosh Panjikar, Cody J. Hall, Lucy Bock, J. Mark Sutton, Matthew A. Perugini*, Tatiana P. Soares da Costa

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


Pseudomonas aeruginosa is one of the leading causes of nosocomial infections, accounting for 10% of all hospital-acquired infections. Current antibiotics against P. aeruginosa are becoming increasingly ineffective due to the exponential rise in drug resistance. Thus, there is an urgent need to validate and characterize novel drug targets to guide the development of new classes of antibiotics against this pathogen. One such target is the diaminopimelate (DAP) pathway, which is responsible for the biosynthesis of bacterial cell wall and protein building blocks, namely meso-DAP and lysine. The rate-limiting step of this pathway is catalysed by the enzyme dihydrodipicolinate synthase (DHDPS), typically encoded for in bacteria by a single dapA gene. Here, we show that P. aeruginosa encodes two functional DHDPS enzymes, PaDHDPS1 and PaDHDPS2. Although these isoforms have similar catalytic activities (kcat = 29 s−1 and 44 s−1 for PaDHDPS1 and PaDHDPS2, respectively), they are differentially allosterically regulated by lysine, with only PaDHDPS2 showing inhibition by the end product of the DAP pathway (IC50 = 130 μm). The differences in allostery are attributed to a single amino acid difference in the allosteric binding pocket at position 56. This is the first example of a bacterium that contains multiple bona fide DHDPS enzymes, which differ in allosteric regulation. We speculate that the presence of the two isoforms allows an increase in the metabolic flux through the DAP pathway when required in this clinically important pathogen. Databases: PDB ID: 6P90.

Original languageEnglish
Pages (from-to)386-400
Number of pages15
JournalFEBS Journal
Issue number2
Early online date22 Jul 2019
Publication statusPublished - 5 Aug 2019

Bibliographical note

Funding Information: We thank Prof Juliet Gerrard (The University of Auckland) for providing the dapA and dapB plasmids from E.?coli. TPSC acknowledges the National Health and Medical Research Council of Australia (APP1091976) and Australian Research Council (DE190100806) for fellowship support, and MAP the Australian Research Council for funding support (DP150103313). REI is supported by an Australian Research Training scholarship and acknowledges the British Society for Antimicrobial Chemotherapy for funding support. We acknowledge the use of the MX2 beamline at the Australian Synchrotron and the CSIRO Collaborative Crystallisation Centre (www.csiro/C3; Melbourne, Australia). We also thank the La Trobe University Comprehensive Proteomics Platform for providing infrastructure support.

Open Access: Free to read, but no Open Access licence.

Publisher Copyright: © 2021 Federation of European Biochemical Societies

Citation: Impey, R.E., Panjikar, S., Hall, C.J., Bock, L.J., Sutton, J.M., Perugini, M.A. and Soares da Costa, T.P. (2020), Identification of two dihydrodipicolinate synthase isoforms from Pseudomonas aeruginosa that differ in allosteric regulation. FEBS J, 287: 386-400.



  • 4-hydroxy-tetrahydrodipicolinate synthase
  • allosteric regulation
  • antibiotic resistance
  • diaminopimelate
  • lysine biosynthesis


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