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Nat Chem Biol. 2019 Feb 4. doi: 10.1038/s41589-018-0217-y. [Epub ahead of print]

A chemoproteomic portrait of the oncometabolite fumarate.

Author information

1
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MA, USA.
2
Department of Chemistry, Boston College, Chestnut Hill, MA, USA.
3
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MA, USA.
4
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN, USA.
5
Stowers Institute for Medical Research, Kansas City, MI, USA.
6
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KA, USA.
7
Department of Pharmacology, Physiology and Neuroscience, School of Medicine, University of South Carolina, Columbia, SC, USA.
8
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MA, USA. jordan.meier@nih.gov.

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.

PMID:
30718813
DOI:
10.1038/s41589-018-0217-y

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