2-(4-Amino-4-carboxybutyl)aziridine-2-carboxylic acid. A potent irreversible inhibitor of diaminopimelic acid epimerase. Spontaneous formation from .alpha.-(halomethyl)diaminopimelic acids

2-(4-Amino-4-carboxybutyl)aziridine-2-carboxylic acid (3) (aziridino-DAP) was identified as the product of spontaneous hydrolysis of alpha-(halomethyl)diaminopimelic acids (alpha-halomethyl-DAPs) 2a-c. Under physiological conditions, 3 is an extremely potent irreversible inhibitor of the bacterial e...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1990-08, Vol.33 (8), p.2157-2162
Main Authors: Gerhart, Fritz, Higgins, William, Tardif, Chantal, Ducep, Jean Bernard
Format: Article
Language:English
Subjects:
Amino Acid Isomerases
Amino Acids, Diamino
Aziridines - pharmacology
Chemical Phenomena
Chemistry
Diaminopimelic Acid - analogs & derivatives
Escherichia coli - enzymology
Hydrolysis
Isomerases - antagonists & inhibitors
Kinetics
Racemases and Epimerases - antagonists & inhibitors
Thermodynamics
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Summary:2-(4-Amino-4-carboxybutyl)aziridine-2-carboxylic acid (3) (aziridino-DAP) was identified as the product of spontaneous hydrolysis of alpha-(halomethyl)diaminopimelic acids (alpha-halomethyl-DAPs) 2a-c. Under physiological conditions, 3 is an extremely potent irreversible inhibitor of the bacterial enzyme diaminopimelic acid epimerase (DAP-epimerase; EC 5.1.1.7). This unusual mode of action of an alpha-halomethyl amino acid with a non-pyridoxal enzyme is investigated. Synthesis and characterization of 2a-c and 3, kinetics of spontaneous formation of 3 from alpha-halomethyl-DAPs, and kinetics of enzyme inhibition by both 3 and by alpha-halomethyl-DAPs are reported.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00170a018