Exploration of inhibitors for diaminopimelate aminotransferase

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 IC50 values 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. (C) 2010 Elsevier Ltd. All rights reserved.