Design, synthesis and analysis of inhibitors of bacterial aspartate semialdehyde dehydrogenase

authored by

Russell J. Cox, Jennifer S. Gibson, Andrea T. Hadfield

Abstract

Unsaturated and fluorinated analogues of aspartyl-β-phosphate were synthesised as potential inhibitors of the bacterial enzyme aspartate semialdehyde dehydrogenase (ASA-DH). Acetylenic and Z-olefinic analogues showed competitive inhibition, but an E-olefinic analogue was inactive. A monofluoromethylene phosphonate competed poorly, but showed time-dependent inhibition of ASA-DH in the absence of phosphate. Simulated docking procedures were used to rationalise the results. These studies showed that substrate and inhibitor binding are mediated by interaction with two active-site arginine residues, and for likely covalent attachment to the active-site thiol group, electrophilic carbon atoms should be located 4.5 Å, or less, from the thiol.

External Organisation(s)

University of Bristol

Type

Article

Journal

CHEMBIOCHEM

Volume

6

Pages

2255-2260

No. of pages

6

ISSN

1439-4227

Publication date

01.12.2005

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Biochemistry, Molecular Medicine, Molecular Biology, Organic Chemistry

Electronic version(s)

https://doi.org/10.1002/cbic.200500172 (Access: Unknown)