| Autor: |
Lowe ED; Laboratory of Molecular Biophysics, University of Oxford, Rex Richards Building, Oxford OX1 3QU, UK. edl@biop.ox.ac.uk, Gao GY, Johnson LN, Keung WM |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2008 Aug 14; Vol. 51 (15), pp. 4482-7. Date of Electronic Publication: 2008 Jul 10. |
| DOI: |
10.1021/jm800488j |
| Abstrakt: |
The ALDH2*2 gene encoding the inactive variant form of mitochondrial aldehyde dehydrogenase (ALDH2) protects nearly all carriers of this gene from alcoholism. Inhibition of ALDH2 has hence become a possible strategy to treat alcoholism. The natural product 7-O-glucosyl-4'-hydroxyisoflavone (daidzin), isolated from the kudzu vine ( Peruraria lobata), is a specific inhibitor of ALDH2 and suppresses ethanol consumption. Daidzin is the active principle in a herbal remedy for "alcohol addiction" and provides a lead for the design of improved ALDH2. The structure of daidzin/ALDH2 in complex at 2.4 A resolution shows the isoflavone moiety of daidzin binding close to the aldehyde substrate-binding site in a hydrophobic cleft and the glucosyl function binding to a hydrophobic patch immediately outside the isoflavone-binding pocket. These observations provide an explanation for both the specificity and affinity of daidzin (IC50 =80 nM) and the affinity of analogues with different substituents at the glucosyl position. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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