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Design, Synthesis and Analysis of Inhibitors of Bacterial Aspartate Semialdehyde Dehydrogenase
Author(s) -
Cox Russell J.,
Gibson Jennifer S.,
Hadfield Andrea T.
Publication year - 2005
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200500172
Subject(s) - electrophile , chemistry , phosphonate , active site , stereochemistry , thiol , covalent bond , dehydrogenase , enzyme , docking (animal) , substrate (aquarium) , non competitive inhibition , arginine , binding site , phosphate , biochemistry , organic chemistry , amino acid , biology , catalysis , medicine , ecology , nursing
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.