Details
| Original language | English |
|---|---|
| Pages (from-to) | 2255-2260 |
| Number of pages | 6 |
| Journal | CHEMBIOCHEM |
| Volume | 6 |
| Issue number | 12 |
| Publication status | Published - 1 Dec 2005 |
| Externally published | Yes |
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.
Keywords
- Enzymes, Inhibitors, Phosphonates, Simulated docking, Synthesis design
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Medicine
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Biology
- Chemistry(all)
- Organic Chemistry
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In: CHEMBIOCHEM, Vol. 6, No. 12, 01.12.2005, p. 2255-2260.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Design, synthesis and analysis of inhibitors of bacterial aspartate semialdehyde dehydrogenase
AU - Cox, Russell J.
AU - Gibson, Jennifer S.
AU - Hadfield, Andrea T.
PY - 2005/12/1
Y1 - 2005/12/1
N2 - 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.
AB - 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.
KW - Enzymes
KW - Inhibitors
KW - Phosphonates
KW - Simulated docking
KW - Synthesis design
UR - http://www.scopus.com/inward/record.url?scp=33846571051&partnerID=8YFLogxK
U2 - 10.1002/cbic.200500172
DO - 10.1002/cbic.200500172
M3 - Article
C2 - 16261551
AN - SCOPUS:33846571051
VL - 6
SP - 2255
EP - 2260
JO - CHEMBIOCHEM
JF - CHEMBIOCHEM
SN - 1439-4227
IS - 12
ER -