Details
| Originalsprache | Englisch |
|---|---|
| Seiten (von - bis) | 2255-2260 |
| Seitenumfang | 6 |
| Fachzeitschrift | CHEMBIOCHEM |
| Jahrgang | 6 |
| Ausgabenummer | 12 |
| Publikationsstatus | Veröffentlicht - 1 Dez. 2005 |
| Extern publiziert | Ja |
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.
ASJC Scopus Sachgebiete
- Biochemie, Genetik und Molekularbiologie (insg.)
- Biochemie
- Biochemie, Genetik und Molekularbiologie (insg.)
- Molekularmedizin
- Biochemie, Genetik und Molekularbiologie (insg.)
- Molekularbiologie
- Chemie (insg.)
- Organische Chemie
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in: CHEMBIOCHEM, Jahrgang 6, Nr. 12, 01.12.2005, S. 2255-2260.
Publikation: Beitrag in Fachzeitschrift › Artikel › Forschung › 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 -