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Selective peroxynitrite-mediated protein nitration catalyzed by glyoxalase domain containing protein 4

Sarah Wright1, Vu C Dang1, Sami Hussain1

  • 1Nitrase Therapeutics, Brisbane, CA 94005.

Proceedings of the National Academy of Sciences of the United States of America
|February 2, 2026
PubMed

Insights

Researchers discovered that glyoxalase domain-containing protein 4 (GLOD4) is an enzyme that selectively nitrates tyrosine residues on proteins. A key target is alpha-synuclein, implicated in Parkinson's disease.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Enzymology

Background:

  • Tyrosine nitration is a post-translational modification implicated in various disease pathologies.
  • While often considered a non-specific chemical process, the selectivity of protein nitration suggests potential enzymatic involvement.

Purpose of the Study:

  • To identify enzymes responsible for selective protein tyrosine nitration.
  • To investigate the role of glyoxalase domain-containing protein 4 (GLOD4) in protein nitration.

Main Methods:

  • In vitro enzymatic assays to assess GLOD4 activity.
  • Cellular studies to observe GLOD4-mediated nitration in vivo.
  • Murine models to study synuclein pathology and GLOD4 function.

Main Results:

  • GLOD4 was identified as an enzyme catalyzing selective protein tyrosine nitration.
  • Alpha-synuclein (α-syn) was identified as a primary in vivo target of GLOD4-mediated nitration.
  • GLOD4-mediated nitration of α-syn was confirmed in vitro, in cells, and in a mouse model.

Conclusions:

  • GLOD4 possesses enzymatic activity for selective protein tyrosine nitration.
  • GLOD4-mediated nitration of α-syn provides a novel mechanistic link to Parkinson's disease pathogenesis.
  • This discovery opens avenues for understanding and potentially treating diseases involving protein nitration, including Parkinson's disease, cancer, and autoimmunity.
Keywords:
3-nitrotyrosinealpha-synucleinglyoxalase domain containing protein 4 (GLOD4)nitrasestyrosine nitration

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