Activated Thiol Sepharose‐based proteomic approach to quantify reversible protein oxidation

Xu, Yang; Andrade, Joshua; Ueberheide, Beatrix; Neel, Benjamin G.

doi:10.1096/fj.201900693r

Cited by 3 publications

(2 citation statements)

References 55 publications

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“…3d-e), consistent with previous observations of FHregulated changes in redox homeostasis. [9][10][25][26] Our studies, together with the literature, are consistent with a model in which FH inactivation causes a dependence on enzymes involved in glycolytic metabolism and the enzymatic production of reducing equivalents, 26 only the latter of which is reversed by re-introduction of functional FH activity.…”

Section: Performingsupporting

confidence: 88%

Heterogeneous adaptation of cysteine reactivity to a covalent oncometabolite

Perez

Bak

Bergholtz

et al. 2020

Journal of Biological Chemistry

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An important context in which metabolism influences tumorigenesis is the genetic cancer syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a disease in which mutation of the TCA cycle enzyme fumarate hydratase (FH) causes hyperaccumulation of fumarate. This electrophilic oncometabolite can alter gene activity at the level of transcription, via reversible inhibition of epigenetic dioxygenases, as well as posttranslationally, via covalent modification of cysteine residues. To better understand the potential for metabolites to influence posttranslational modifications important to tumorigenesis and cancer cell growth, here we report a chemoproteomic analysis of a kidney-derived HLRCC cell line. Using a general reactivity probe, we generated a dataset of proteomic cysteine residues sensitive to the reduction in fumarate levels caused by genetic re-introduction of active FH into HLRCC cell lines. This revealed a broad upregulation of cysteine reactivity upon FH rescue, which evidence suggests is caused by an approximately equal proportion of transcriptional and posttranslational modification-mediated regulation. Gene ontology analysis highlighted several new targets and pathways potentially modulated by FH mutation. Comparison of the new dataset to prior studies highlights considerable heterogeneity in the adaptive response of cysteine-containing proteins in different models of HLRCC. This is consistent with emerging studies indicating the existence of cell and tissue-specific cysteine-omes, further emphasizing the need for characterization of diverse models. Our analysis provides a resource for understanding the proteomic adaptation to fumarate accumulation, and a foundation for future efforts to exploit this knowledge for cancer therapy.

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Section: Performingsupporting

confidence: 88%

Heterogeneous adaptation of cysteine reactivity to a covalent oncometabolite

Perez

Bak

Bergholtz

et al. 2020

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…3d-e), consistent with previous observations of FH-regulated changes in redox homeostasis. [9][10]25 Our studies, together with the literature, are consistent with a model in which FH inactivation causes a dependence on enzymes involved in glycolytic metabolism and the production of reducing equivalents in the mitochondria, only the latter of which is reversed by re-introduction of functional FH activity.…”

supporting

confidence: 88%

Heterogeneous adaptation of cysteine reactivity to a covalent oncometabolite

Perez

Bak

Bergholtz

et al. 2020

Preprint

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Metabolism and signaling intersect in the genetic cancer syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a disease in which mutation of the TCA cycle enzyme fumarate hydratase (FH) causes hyperaccumulation of fumarate. This electrophilic oncometabolite can alter gene activity at the level of transcription, via reversible inhibition of epigenetic dioxygenases, as well as posttranslationally, via covalent modification of cysteine residues. To better understand how metabolites function as covalent signals, here we report a chemoproteomic analysis of a kidney-derived HLRCC cell line. Building on previous studies, we applied a general reactivity probe to compile a dataset of cysteine residues sensitive to rescue of cellular FH activity. This revealed a broad upregulation of cysteine reactivity upon FH rescue, caused by an approximately equal proportion of transcriptional and posttranslational regulation in the rescue cell line. Gene ontology analysis highlights new targets and pathways potentially modulated by FH mutation. Comparison of the new dataset to literature studies highlights considerable heterogeneity in the adaptive response of cysteine-containing proteins in different models of HLRCC. Our analysis provides a resource for understanding the proteomic adaptation to fumarate accumulation, and a foundation for future efforts to exploit this knowledge for cancer therapy.

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Radical rearrangement and transfer reactions in proteins

Schöneich

2020

Essays in Biochemistry

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Radical rearrangement and transfer reactions play an important role in the chemical modifications of proteins in vivo and in vitro. These reactions depend on protein sequence, as well as structure and dynamics. Frequently, these reactions have well-defined precedents in the organic chemistry literature, but their occurrence in proteins provides a stage for a number of novel and, perhaps, unexpected reaction products. This essay will provide an overview over a few representative examples of radical rearrangement and transfer reactions.

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Activated Thiol Sepharose‐based proteomic approach to quantify reversible protein oxidation

Cited by 3 publications

References 55 publications

Heterogeneous adaptation of cysteine reactivity to a covalent oncometabolite

Heterogeneous adaptation of cysteine reactivity to a covalent oncometabolite

Heterogeneous adaptation of cysteine reactivity to a covalent oncometabolite

Radical rearrangement and transfer reactions in proteins

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