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Tamoxifen, an anticancer drug, is an activator of human aldehyde dehydrogenase 1A1

Javier A Belmont-Díaz1, Luis F Calleja-Castañeda, Belem Yoval-Sánchez

  • 1Departamento de Bioquímica, Instituto Nacional de Cardiología, México D.F, México.

Proteins
|October 31, 2014
PubMed

Insights

Tamoxifen surprisingly activates aldehyde dehydrogenase 1A1 (ALDH1A1), an enzyme crucial for antioxidant response. This discovery offers potential new therapeutic strategies for diseases linked to compromised antioxidant defenses.

Area of Science:

  • Biochemistry
  • Enzymology
  • Pharmacology

Background:

  • Aldehyde dehydrogenase (ALDH) activity modulation is a potential therapeutic strategy for various diseases.
  • Few compounds are known to activate ALDH enzymes.
  • N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide protects against heart ischemia/reperfusion damage.

Purpose of the Study:

  • To identify novel molecules that modulate aldehyde dehydrogenase (ALDH) activity.
  • To investigate the binding and activity modulation of compounds on human aldehyde dehydrogenase class 1A1 (ALDH1A1).

Main Methods:

  • Molecular docking to analyze compound binding to the ALDH1A1 active site.
  • Enzyme activity assays to test the modulatory effects of compounds.
  • Kinetic analysis to determine the mechanism of action.
  • Thermal denaturation and competitive binding assays.

Main Results:

  • Tamoxifen, an estrogen receptor antagonist, significantly increased ALDH1A1 activity and decreased its Km for NAD(+).
  • Tamoxifen demonstrated specificity for ALDH1A1, with no observed effects on ALDH2 or ALDH3A1.
  • Evidence suggests tamoxifen binds to the aldehyde site of ALDH1A1, similar to another known ALDH modulator.
  • Kinetic data indicate tamoxifen may enhance NADH release, potentially overcoming a rate-limiting step.

Conclusions:

  • Tamoxifen is a novel, specific activator of human ALDH1A1.
  • Tamoxifen's mechanism involves binding to the aldehyde site and potentially improving coenzyme release.
  • This finding suggests tamoxifen could enhance antioxidant responses, offering therapeutic potential for related diseases.
Keywords:
ALDH1A1aldehyde dehydrogenaseslipid peroxidation productsoxidative stresstamoxifen

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