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Thiopurine intolerance-causing mutations in NUDT15 induce temperature-dependent destabilization of the catalytic site

Petr Man1, Milan Fábry2, Irena Sieglová3

  • 1Institute of Microbiology, Academy of Sciences of the Czech Republic, Videnska 1083, Prague 4 142 20, Czech Republic; Faculty of Science, Charles University, Hlavova 2030/8, Prague 2 128 43, Czech Republic.

Biochimica Et Biophysica Acta. Proteins and Proteomics
|January 15, 2019
PubMed

Insights

Germline NUDT15 mutations, causing thiopurine intolerance, destabilize the enzyme

Area of Science:

  • Biochemistry
  • Pharmacogenetics
  • Structural Biology

Background:

  • Germline mutations in NUDT15 are linked to thiopurine intolerance in leukemia and autoimmune disease treatments.
  • These mutations impair NUDT15 hydrolase enzymatic activity by reducing protein stability in vivo.

Purpose of the Study:

  • To investigate the structural basis of NUDT15 protein destabilization caused by R139C and V18I mutations.
  • To understand the role of ligands in stabilizing the native state of NUDT15 mutants.

Main Methods:

  • Thermolysin-based proteolysis.
  • Hydrogen-deuterium exchange mass spectrometry (HDX-MS).

Main Results:

  • Both R139C and V18I NUDT15 mutants showed destabilization of the catalytic site, exacerbated by higher temperatures.
  • This structural perturbation occurred despite the mutations being at different protein locations.
  • NUDT15 reaction products stabilized the mutant proteins, restoring native conformations.

Conclusions:

  • Structural insights reveal how NUDT15 pharmacogenetic variants lead to thiopurine intolerance.
  • Ligand binding is crucial for stabilizing the native state of NUDT15 mutants.
  • Findings may inform personalized chemotherapy strategies by considering NUDT15 structure-activity relationships.
Keywords:
H/D exchangeNUDT15Pharmacogenomic variantsStructural mass spectrometryThiopurine metabolism

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