Nature chemical biology · 2019
A chemoproteomic portrait of the oncometabolite fumarate.
СтатьяResearch Support, N.I.H., IntramuralПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Kulkarni Rhushikesh A, Bak Daniel W, Wei Darmood, Bergholtz Sarah E, Briney Chloe A, Shrimp Jonathan H, Alpsoy Aktan, Thorpe Abigail L, Bavari Arissa E, Crooks Daniel R, Levy Michaella, Florens Laurence, Washburn Michael P, Frizzell Norma, Dykhuizen Emily C, Weerapana Eranthie, Linehan W Marston, Meier Jordan L
Аннотация
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.