Structure of daidzin, a naturally occurring anti-alcohol-addiction agent, in complex with human mitochondrial aldehyde dehydrogenase.
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.
Lowe
Edward D
ED
Laboratory of Molecular Biophysics, University of Oxford, Rex Richards Building, Oxford OX1 3QU, UK. edl@biop.ox.ac.uk
Gao
Guang-Yao
GY
Johnson
Louise N
LN
Keung
Wing Ming
WM
D000437:Alcoholism / Q000201:enzymology*; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D016739:Behavior, Addictive / Q000201:enzymology*; D001665:Binding Sites; D006224:Cricetinae; D018360:Crystallography, X-Ray; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007529:Isoflavones / Q000737:chemistry* / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology*; D008958:Models, Molecular; D015394:Molecular Structure; D050697:Retinal Dehydrogenase; D013329:Structure-Activity Relationship
D007527:Isoenzymes; D007529:Isoflavones; C013908:daidzin; D000080924:Aldehyde Dehydrogenase 1 Family; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase