Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant

Samantha Perez-Miller, Hina Younus, Ram Vanam, Che Hong Chen, Daria Mochly-Rosen, Thomas Hurley

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

In approximately one billion people, a point mutation inactivates a key detoxifying enzyme, aldehyde dehydrogenase (ALDH2). This mitochondrial enzyme metabolizes toxic biogenic and environmental aldehydes, including the endogenously produced 4-hydroxynonenal (4HNE) and the environmental pollutant acrolein, and also bioactivates nitroglycerin. ALDH2 is best known, however, for its role in ethanol metabolism. The accumulation of acetaldehyde following the consumption of even a single alcoholic beverage leads to the Asian alcohol-induced flushing syndrome in ALDH2*2 homozygotes. The ALDH2*2 allele is semidominant, and heterozygotic individuals show a similar but less severe phenotype. We recently identified a small molecule, Alda-1, that activates wild-type ALDH2 and restores near-wild-type activity to ALDH2*2. The structures of Alda-1 bound to ALDH2 and ALDH2*2 reveal how Alda-1 activates the wild-type enzyme and how it restores the activity of ALDH2*2 by acting as a structural chaperone.

Original languageEnglish
Pages (from-to)159-164
Number of pages6
JournalNature Structural and Molecular Biology
Volume17
Issue number2
DOIs
StatePublished - Feb 2010

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Aldehyde Dehydrogenase
Enzymes
Acrolein
Alcoholic Beverages
Environmental Pollutants
Acetaldehyde
Poisons
Nitroglycerin
Homozygote
Point Mutation
Aldehydes
Ethanol
Alleles
Alcohols
Phenotype

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant. / Perez-Miller, Samantha; Younus, Hina; Vanam, Ram; Chen, Che Hong; Mochly-Rosen, Daria; Hurley, Thomas.

In: Nature Structural and Molecular Biology, Vol. 17, No. 2, 02.2010, p. 159-164.

Research output: Contribution to journalArticle

Perez-Miller, Samantha ; Younus, Hina ; Vanam, Ram ; Chen, Che Hong ; Mochly-Rosen, Daria ; Hurley, Thomas. / Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant. In: Nature Structural and Molecular Biology. 2010 ; Vol. 17, No. 2. pp. 159-164.
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