Structure of daidzin, a naturally occurring anti-alcohol-addiction agent, in complex with human mitochondrial aldehyde dehydrogenase.

Abstract	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.
Authors	Edward D Lowe, Guang-Yao Gao, Louise N Johnson, Wing Ming Keung
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 51 Issue 15 Pg. 4482-7 (Aug 14 2008) ISSN: 1520-4804 [Electronic] United States
PMID	18613661 (Publication Type: Journal Article)
Chemical References	Isoenzymes Isoflavones daidzin Aldehyde Dehydrogenase 1 Family ALDH2 protein, human Aldehyde Dehydrogenase Aldehyde Dehydrogenase, Mitochondrial ALDH1A1 protein, human Retinal Dehydrogenase
Topics	Alcoholism (enzymology) Aldehyde Dehydrogenase (antagonists & inhibitors, metabolism) Aldehyde Dehydrogenase 1 Family Aldehyde Dehydrogenase, Mitochondrial Animals Behavior, Addictive (enzymology) Binding Sites Cricetinae Crystallography, X-Ray Humans Isoenzymes (antagonists & inhibitors, metabolism) Isoflavones (chemistry, pharmacology) Mitochondria (drug effects, enzymology) Models, Molecular Molecular Structure Retinal Dehydrogenase Structure-Activity Relationship

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