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Application of AlDeSense to Stratify Ovarian Cancer Cells Based on Aldehyde Dehydrogenase 1A1 Activity
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Structural and biochemical evidence that ATP inhibits the cancer biomarker human aldehyde dehydrogenase 1A3

Albert Castellví1,2, Raquel Pequerul1, Vito Barracco1

  • 1Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma de Barcelona, 08193 Bellaterra, Cerdanyola del Vallès, Barcelona, Spain.

Communications Biology
|April 14, 2022
PubMed

Insights

High-resolution structures reveal how ATP binds to aldehyde dehydrogenase 1A3 (ALDH1A3), inhibiting its activity. This finding aids in designing new cancer therapies targeting ALDH1A3.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Enzymology

Background:

  • Human aldehyde dehydrogenase (ALDH) is crucial for oxidative stress response and retinoid metabolism, implicated in diseases like cancer, diabetes, and obesity.
  • The ALDH1A3 isoform is a key focus due to its role as a cancer stem cell biomarker and therapeutic target.

Purpose of the Study:

  • To determine the high-resolution three-dimensional structures of ALDH1A3 in its apo form, complexed with NAD+, and complexed with ATP.
  • To elucidate the mechanism of ATP binding and its inhibitory effect on ALDH1A3 activity.

Main Methods:

  • X-ray crystallography was used to obtain high-resolution 3D structures of ALDH1A3.
  • Biochemical assays were performed to assess the inhibitory effects of ATP on ALDH1A3 dehydrogenase and esterase activities.

Main Results:

  • High-resolution structures of ALDH1A3 were determined for the apo-enzyme, NAD+ complex, and ATP complex.
  • ATP binds to the adenosine-binding pocket of the cofactor-binding site, and a polyethylene glycol aldehyde molecule is covalently bound to the active-site cysteine, mimicking a catalytic intermediate.
  • ATP inhibits both dehydrogenase activity (Ki = 0.48 mM, mixed inhibition against NAD+) and esterase activity of ALDH1A3.

Conclusions:

  • The determined ALDH1A3 structures provide a basis for rational drug design of selective inhibitors.
  • ATP binding modulates ALDH1A3 activity based on cellular energy status, potentially impacting metabolic reprogramming in diseases.

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