Inhibiting dihydrodipicolinate synthase across species: Towards specificity for pathogens?
Graphical abstract
Inhibitors of dihydrodipicolinate synthase (DHDPS), a key enzyme in lysine biosynthesis and an important antibiotic target, display significant species-specificity.
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Acknowledgments
This work was funded in part by the Australian Research Council (LX0776388 and DP0770888) and in part by the Royal Society of New Zealand Marsden Fund (contract UOC303).
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2018, Protein Expression and PurificationCitation Excerpt :DHDPS is the product of an essential bacterial gene, and thus is a promising target for antibiotic development [5,7,9,15]. Accordingly, several studies have recently set out to characterize the structure, function and regulation of this unexploited antibiotic target [5,6,10–13,16–27]. DHDPS is the product of the dapA gene [5,9,31].
Structural Determinants Defining the Allosteric Inhibition of an Essential Antibiotic Target
2016, StructureCitation Excerpt :Functionally, DHDPS catalyzes the condensation of pyruvate and (S)-aspartate semialdehyde (ASA) to form the heterocyclic product, hydroxytetrahydrodipicolinic acid (Figure 1). Not surprisingly, traditional DHDPS inhibition strategies have focused on developing small molecules with analogy to these substrates and/or products (Boughton et al., 2008; Hutton et al., 2003, 2007; Laber et al., 1992; Mitsakos et al., 2008; Turner et al., 2005a, 2005b). The most potent substrate-analog inhibitor discovered to date is dipicolinic acid N-oxide, which has a half-maximal inhibitory concentration (IC50) value of 0.8 mM (Couper et al., 1994).
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2012, Studies in Natural Products ChemistryLC-MS and NMR characterization of the purple chromophore formed in the o-aminobenzaldehyde assay of dihydrodipicolinate synthase
2011, Bioorganic and Medicinal ChemistryCitation Excerpt :Lysine is a constituent of the cell wall in Gram-positive bacteria (for example, the pathogenic bacterium Staphylococcus aureus) while the cell wall of Gram-negative bacteria such as Escherichia coli contains meso-DAP.4 Inhibitors of the DAP pathway are being investigated as a potential new class of antibiotics.5–10 Two assays commonly employed to measure the activity of DHDPS are the coupled assay and the o-aminobenzaldehyde (o-ABA) assay.
New insights into the mechanism of dihydrodipicolinate synthase using isothermal titration calorimetry
2010, BiochimieCitation Excerpt :These changes to the tertiary and quaternary structure observed upon allosteric effector binding [14] have lead to a number of plausible mechanisms to explain the propagation of the allosteric binding signal to the active site including (i) signal transmission through the Tyr106/Tyr107 hydrophobic stack, via the proton relay, to Tyr133 which is intimately involved in proton exchange during Schiff-base formation and transamination [12], (ii) disruption of a water channel which connects the allosteric lysine binding site to the active site thereby impeding Schiff-base formation and that (iii) binding of (S)-lysine at the allosteric cleft may change the conformational dynamics available to the enzyme and favour stabilisation of a less catalytically competent conformer or prevent binding or reaction of the (S)-ASA substrate [23]. We have a long standing interest in the structure, function and mechanism of this enzyme, which serves as an important, validated antibiotic target [24,25]. In this paper, we examine the substrate binding thermodynamics of the DHDPS enzymes from E. coli via ITC.