title: The stereoselective synthesis of aziridine analogues of diaminopimelic acid (DAP) and their interaction with dap epimerase.
abstract: Aziridine analogues of diaminopimelic acid (DAP) have been prepared stereoselectively for the first time and evaluated as inhibitors of DAP epimerase. (2R,3S,3'S)-3-(3'-Aminopropane)aziridine-2,3'-dicarboxylate was synthesised and shown to be a reversible inhibitor of DAP epimerase with an IC(50) value of 2.88 mM. (2S,4S)- and (2S,4R)-2-(4-Amino-4-carboxybutyl)aziridine-2-carboxylic acid (ll-azi-DAP and dl-azi-DAP ) were made as pure diastereomers, and both were shown to be irreversible inhibitors of DAP epimerase. ll-Azi-DAP selectively binds to Cys-73 of the enzyme active site whereas dl-azi-DAP binds to Cys-217 via attack of sulfhydryl on the methylene of the inhibitor aziridine ring. These observations are consistent with the two base mechanism proposed for the epimerization of ll-DAP and meso-DAP by DAP epimerase.
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada, T6G 2G2.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Diaper
authors.forename: Andrew
authors.initials: A
authors.lastname: Sutherland
authors.forename: Bindu
authors.initials: B
authors.lastname: Pillai
authors.forename: Michael N G
authors.initials: MN
authors.lastname: James
authors.forename: Paul
authors.initials: P
authors.lastname: Semchuk
authors.forename: John S
authors.initials: JS
authors.lastname: Blanchard
authors.forename: John C
authors.initials: JC
authors.lastname: Vederas
mesh_terms: D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001388:Aziridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D003960:Diaminopimelic Acid / Q000737:chemistry* / Q000378:metabolism*; D007536:Isomerism; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D013237:Stereoisomerism
chemical_list: D001388:Aziridines; C033132:aziridine; D003960:Diaminopimelic Acid; D000591:Amino Acid Isomerases; C042032:diaminopimelate epimerase; D003545:Cysteine