Friday, February 22, 2019

A chemoproteomic portrait of the oncometabolite fumarate

Rhushikesh A. Kulkarni, Daniel W. Bak, Darmood Wei, Sarah E. Bergholtz, Chloe A. Briney, Jonathan H. Shrimp, Aktan Alpsoy, Abigail L. Thorpe, Arissa E. Bavari, Daniel R. Crooks, Michaella Levy, Laurence Florens, Michael P. Washburn, Norma Frizzell, Emily C. Dykhuizen, Eranthie Weerapana, W. Marston Linehan & Jordan L. Meier

Nature Chemical Biology, 2019
DOI: 10.1038/s41589-018-0217-y

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.

Identification of a cell-active chikungunya virus nsP2 protease inhibitor using a covalent fragment-based screening approach

Eric M. Merten  and John D. Sears  and Tina M. Leisner  and P. Brian Hardy  and Anirban Ghoshal  and Mohammad Anwar Hossain  and Kesatebrhan...