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

Nature Structural & Molecular Biology volume 17, pages 159164 (2010) | Download Citation

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.

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Acknowledgements

T.D.H. wishes to thank the staff at the 19-ID beamline facility, especially M. Cuff, N. Duke and S. Ginell. Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source. Argonne is operated by UChicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research, under contract DE-AC02-06CH11357. This work was supported in part by US National Institutes of Health grants AA011982 and AA018123 to T.D.H. and AA11147 to D.M.-R.; S.P.-M. was supported by US National Institutes of Health training fellowship T32-DK064466.

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Affiliations

  1. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

    • Samantha Perez-Miller
    • , Hina Younus
    • , Ram Vanam
    •  & Thomas D Hurley
  2. Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, USA.

    • Che-Hong Chen
    •  & Daria Mochly-Rosen

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Contributions

S.P.-M. performed experiments, data analysis and manuscript preparation; H.Y. performed experiments and helped with data analysis; R.V. performed experiments; C.-H.C. helped with data analysis and manuscript preparation; D.M.-R. initiated the study and helped with study design, data analysis and manuscript preparation; T.D.H. designed the study and performed data analysis, experiments and manuscript preparation.

Competing interests

C.-H.C. and D.M.-R. plan to found a pharmaceutical company based on the activators of aldehyde dehydrogenases. Neither author holds any financial interest at the moment.

Corresponding author

Correspondence to Thomas D Hurley.

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https://doi.org/10.1038/nsmb.1737

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