The stereoselective synthesis of aziridine analogues of diaminopimelic acid (DAP) and their interaction with dap epimerase.
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.
Diaper
Christopher M
CM
Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada, T6G 2G2.
Sutherland
Andrew
A
Pillai
Bindu
B
James
Michael N G
MN
Semchuk
Paul
P
Blanchard
John S
JS
Vederas
John C
JC
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
D001388:Aziridines; C033132:aziridine; D003960:Diaminopimelic Acid; D000591:Amino Acid Isomerases; C042032:diaminopimelate epimerase; D003545:Cysteine