A chemoproteomic portrait of the oncometabolite fumarate

Nat Chem Biol. 2019 Apr;15(4):391-400. doi: 10.1038/s41589-018-0217-y. Epub 2019 Feb 4.

Abstract

Hereditary cancer disorders often provide an important window into novel mechanisms supporting tumor growth. Understanding these mechanisms thus represents a vital goal. Toward this goal, here we report a chemoproteomic map of fumarate, a covalent oncometabolite whose accumulation marks the genetic cancer syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC). We applied a fumarate-competitive chemoproteomic probe in concert with LC-MS/MS to discover new cysteines sensitive to fumarate hydratase (FH) mutation in HLRCC cell models. Analysis of this dataset revealed an unexpected influence of local environment and pH on fumarate reactivity, and enabled the characterization of a novel FH-regulated cysteine residue that lies at a key protein-protein interface in the SWI-SNF tumor-suppressor complex. Our studies provide a powerful resource for understanding the covalent imprint of fumarate on the proteome and lay the foundation for future efforts to exploit this distinct aspect of oncometabolism for cancer diagnosis and therapy.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Chromatography, Liquid / methods
  • Cysteine
  • Fumarates / metabolism*
  • HEK293 Cells
  • Humans
  • Hydrogen-Ion Concentration
  • Leiomyomatosis / genetics
  • Leiomyomatosis / metabolism*
  • Models, Biological
  • Neoplastic Syndromes, Hereditary / genetics
  • Neoplastic Syndromes, Hereditary / metabolism*
  • Proteomics
  • Signal Transduction
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism*
  • Tandem Mass Spectrometry / methods
  • Uterine Neoplasms / genetics
  • Uterine Neoplasms / metabolism*

Substances

  • Fumarates
  • Cysteine

Supplementary concepts

  • Hereditary leiomyomatosis and renal cell cancer