Structure of Daidzin, a Naturally Occurring Anti-Alcohol-Addiction Agent, in Complex with Human Mitochondrial Aldehyde DehydrogenaseJ. Med. Chem.,
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 Å 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.
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