Exploration of inhibitors for diaminopimelate aminotransferase

  • Fan C
  • Clay M
  • Deyholos M
 et al. 
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Abstract

Bacteria and higher plants make l-lysine from diaminopimelic acid (DAP). In mammals l-lysine is an essential amino acid that must be acquired from the diet as the biosynthetic pathway is absent for this key constituent of proteins. Recently, ll-diaminopimelate aminotransferase (ll-DAP-AT), a pyridoxal-5′-phosphate (PLP)-dependent enzyme, was reported to catalyze a key step in the route to l-lysine in plants and Chlamydia. Specific inhibitors of this enzyme could thus potentially serve as herbicides or antibiotics that are non-toxic to mammals. In this work, 29,201 inhibitors were screened against ll-DAP-AT and the IC50values were determined for the top 46 compounds. An aryl hydrazide and rhodanine derivatives were further modified to generate 20 analogues that were also tested against ll-DAP-AT. These analogues provide additional structure-activity relationships (SAR) that are useful in guiding further design of inhibitors. © 2010 Elsevier Ltd. All rights reserved.

Author-supplied keywords

  • Aminotransferase
  • Arabidopsis thaliana
  • Chlamydia
  • Diaminopimelate (DAP)
  • Enzyme inhibition
  • Lysine biosynthesis
  • Pyridoxal-5′-phosphate (PLP)

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Authors

  • Chenguang Fan

  • Matthew D. Clay

  • Michael K. Deyholos

  • John C. Vederas

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