Journal
CHEMBIOCHEM
Volume 6, Issue 12, Pages 2255-2260Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.200500172
Keywords
enzymes; inhibitors; phosphonates; simulated docking; synthesis design
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Unsaturated and fluorinated analogues of aspartyl-beta-phosphate were synthesised as potential inhibitors of the bacterial enzyme aspartate semialdehyde dehydrogenose (ASA-DH). Acetylenic and Z-olefinic analogues showed competitive inhibition, but an E-oleflnic 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 angstrom, or less, from the thiol.
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