title: Exploration of inhibitors for diaminopimelate aminotransferase.
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 IC(50) 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.
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Fan
authors.affiliation: St. Mary's University College, 14500 Bannister Road SE, Calgary, Alberta, Canada T2X 1Z4.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Clay
authors.affiliation: Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2E9.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Deyholos
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2.
authors.forename: John C
authors.initials: JC
authors.lastname: Vederas
mesh_terms: D003960:Diaminopimelic Acid / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D012236:Rhodanine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000637:Transaminases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006834:Hydrazines; D003960:Diaminopimelic Acid; D012236:Rhodanine; D000637:Transaminases