The stereoselective synthesis of aziridine analogues of diaminopimelic acid (DAP) and their interaction with dap epimerase

Christopher M. Diaper, Andrew Sutherland, Bindu Pillai, Michael N G James, Paul Semchuk, John S. Blanchard, John C. Vederas

Research output: Contribution to journalArticle

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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 4 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 14 and DL-azi-DAP 29) were made as pure diastereomers, and both were shown to be irreversible inhibitors of DAP epimerase. LL-Azi-DAP 14 selectively binds to Cys-73 of the enzyme active site whereas DL-azi-DAP 29 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 epimerisation of LL-DAP 1 and meso-DAP 2 by DAP epimerase.

Original languageEnglish (US)
Pages (from-to)4402-4411
Number of pages10
JournalOrganic and Biomolecular Chemistry
Volume3
Issue number24
DOIs
StatePublished - Dec 21 2005

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Diaminopimelic Acid
diaminopimelate epimerase
Racemases and Epimerases
analogs
acids
synthesis
interactions
inhibitors
aziridine
Catalytic Domain
methylene
carboxylic acids
attack
enzymes
Enzymes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)

Cite this

The stereoselective synthesis of aziridine analogues of diaminopimelic acid (DAP) and their interaction with dap epimerase. / Diaper, Christopher M.; Sutherland, Andrew; Pillai, Bindu; James, Michael N G; Semchuk, Paul; Blanchard, John S.; Vederas, John C.

In: Organic and Biomolecular Chemistry, Vol. 3, No. 24, 21.12.2005, p. 4402-4411.

Research output: Contribution to journalArticle

Diaper, Christopher M. ; Sutherland, Andrew ; Pillai, Bindu ; James, Michael N G ; Semchuk, Paul ; Blanchard, John S. ; Vederas, John C. / The stereoselective synthesis of aziridine analogues of diaminopimelic acid (DAP) and their interaction with dap epimerase. In: Organic and Biomolecular Chemistry. 2005 ; Vol. 3, No. 24. pp. 4402-4411.
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