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Updated: Oct 12, 2025

Anaerobic Protein Purification and Kinetic Analysis via Oxygen Electrode for Studying DesB Dioxygenase Activity and Inhibition
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Structural basis of binding and inhibition of ornithine decarboxylase by 1-amino-oxy-3-aminopropane

X Edward Zhou1, Kelly Suino-Powell1, Chad R Schultz2

  • 1Department of Structural Biology, Van Andel Institute, Grand Rapids, Michigan 49503, U.S.A.

The Biochemical Journal
|November 19, 2021
PubMed

Insights

The enzyme ornithine decarboxylase (ODC) is crucial for cell proliferation. A potent inhibitor, 1-amino-oxy-3-aminopropane (APA), forms a stable covalent bond with ODC

Area of Science:

  • Biochemistry
  • Enzymology
  • Structural Biology

Background:

  • Ornithine decarboxylase (ODC) is the rate-limiting enzyme in polyamine synthesis.
  • Polyamines are essential for cell proliferation and are implicated in hyperproliferative diseases like cancer.
  • Current pharmaceutical strategies target ODC for therapeutic intervention.

Purpose of the Study:

  • To elucidate the precise binding mechanism of the potent ODC inhibitor 1-amino-oxy-3-aminopropane (APA).
  • To investigate the structural basis for APA's high inhibitory potency against ODC.
  • To identify novel structural scaffolds for developing improved ODC inhibitors.

Main Methods:

  • X-ray crystallography to determine the structures of ODC-APA and ODC-PLP-citrate complexes.
  • Mass spectrometry to confirm the covalent interaction between APA and the cofactor pyridoxal 5-phosphate (PLP) in solution.
  • Structural analysis of enzyme-inhibitor and enzyme-substrate-analog interactions.

Main Results:

  • A novel crystal structure revealed a covalent oxime linkage between APA and PLP within the ODC active site.
  • Mass spectrometry confirmed this stable covalent adduct in solution.
  • The covalent APA-PLP adduct forms extensive interactions with ODC, explaining its potent and irreversible inhibition.
  • A separate structure showed citrate binding in the ornithine substrate-binding pocket.

Conclusions:

  • APA inhibits ODC via a stable covalent adduct with its cofactor PLP, not through competitive binding alone.
  • This covalent mechanism underlies APA's exceptional potency as an ODC inhibitor.
  • The determined structures offer valuable insights and scaffolds for designing next-generation ODC-targeted therapeutics for cancer and infectious diseases.
Keywords:
crystallographyornithine decarboxylasepolyamines

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