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Metabolites 2014, 4(3), 640-654; doi:10.3390/metabo4030640
Brief Report

The Succinated Proteome of FH-Mutant Tumours

1,†
, 2,†
, 1
, 1
, 2
, 3
, 4
 and 1,*
Received: 16 May 2014; in revised form: 21 July 2014 / Accepted: 24 July 2014 / Published: 7 August 2014
(This article belongs to the Special Issue Cancer Metabolomics)
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Abstract: Inherited mutations in the Krebs cycle enzyme fumarate hydratase (FH) predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC). Loss of FH activity in HLRCC tumours causes accumulation of the Krebs cycle intermediate fumarate to high levels, which may act as an oncometabolite through various, but not necessarily mutually exclusive, mechanisms. One such mechanism, succination, is an irreversible non-enzymatic modification of cysteine residues by fumarate, to form S-(2-succino)cysteine (2SC). Previous studies have demonstrated that succination of proteins including glyceraldehyde 3-phosphate dehydrogenase (GAPDH), kelch-like ECH-associated protein 1 (KEAP1) and mitochondrial aconitase (ACO2) can have profound effects on cellular metabolism. Furthermore, immunostaining for 2SC is a sensitive and specific biomarker for HLRCC tumours. Here, we performed a proteomic screen on an FH-mutant tumour and two HLRCC-derived cancer cell lines and identified 60 proteins where one or more cysteine residues were succinated; 10 of which were succinated at cysteine residues either predicted, or experimentally proven, to be functionally significant. Bioinformatic enrichment analyses identified most succinated targets to be involved in redox signaling. To our knowledge, this is the first proteomic-based succination screen performed in human tumours and cancer-derived cells and has identified novel 2SC targets that may be relevant to the pathogenesis of HLRCC.
Keywords: fumarate hydratase; succination; cysteine; renal cancer; hereditary leiomyomatosis and renal cell cancer (HLRCC); oncometabolite; biomarker; reactive oxygen species (ROS) fumarate hydratase; succination; cysteine; renal cancer; hereditary leiomyomatosis and renal cell cancer (HLRCC); oncometabolite; biomarker; reactive oxygen species (ROS)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Yang, M.; Ternette, N.; Su, H.; Dabiri, R.; Kessler, B.M.; Adam, J.; Teh, B.T.; Pollard, P.J. The Succinated Proteome of FH-Mutant Tumours. Metabolites 2014, 4, 640-654.

AMA Style

Yang M, Ternette N, Su H, Dabiri R, Kessler BM, Adam J, Teh BT, Pollard PJ. The Succinated Proteome of FH-Mutant Tumours. Metabolites. 2014; 4(3):640-654.

Chicago/Turabian Style

Yang, Ming; Ternette, Nicola; Su, Huizhong; Dabiri, Raliat; Kessler, Benedikt M.; Adam, Julie; Teh, Bin T.; Pollard, Patrick J. 2014. "The Succinated Proteome of FH-Mutant Tumours." Metabolites 4, no. 3: 640-654.


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