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Diethylaminobenzaldehyde is a covalent, irreversible inactivator of ALDH7A1

Min Luo1, Kent S Gates1, Michael T Henzl2

  • 1†Department of Chemistry, University of Missouri-Columbia, Columbia, Missouri 65211, United States.

ACS Chemical Biology
|January 3, 2015
PubMed

Insights

Aldehyde dehydrogenases (ALDHs) are linked to cancer stem cells and drug resistance. This study reveals that 4-diethylaminobenzaldehyde (DEAB) irreversibly inactivates ALDH7A1, forming a covalent acyl-enzyme, challenging previous assumptions.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Aldehyde dehydrogenases (ALDHs) are increasingly recognized for their role in cancer stem cells.
  • ALDH overexpression is associated with resistance to cancer therapeutics.
  • Understanding ALDH inhibition mechanisms is crucial for developing new cancer treatments.

Purpose of the Study:

  • To determine the crystal structure of an aldehyde dehydrogenase in complex with the inhibitor 4-diethylaminobenzaldehyde (DEAB).
  • To elucidate the mechanism of DEAB inhibition on ALDH7A1.
  • To challenge the established understanding of DEAB as a reversible inhibitor.

Main Methods:

  • X-ray crystallography to obtain the structure of ALDH7A1 complexed with DEAB.
  • Biochemical assays to investigate the inhibitory activity and mechanism of DEAB.
  • Mass spectrometry to identify covalent adducts.

Main Results:

  • The first crystal structure of an aldehyde dehydrogenase complexed with DEAB was determined.
  • DEAB was shown to irreversibly inactivate ALDH7A1.
  • A stable, covalent acyl-enzyme intermediate was identified as the product of DEAB inactivation.

Conclusions:

  • DEAB acts as an irreversible inhibitor of ALDH7A1, not a reversible one as previously believed.
  • The formation of a covalent acyl-enzyme species underlies the irreversible inactivation mechanism.
  • These findings necessitate a re-evaluation of DEAB's utility and mechanism in targeting ALDHs for cancer therapy.

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