SIRT5-Mediated Lysine Desuccinylation Impacts Diverse Metabolic Pathways
By Jeongsoon Park, Yue Chen, D. Tishkoff, Chao Peng, M. Tan, Lu Dai, Zhongyu Xie, Yi Zhang, Bernadette M. M. Zwaans, M. Skinner and 2 more. Molecules and Cells, 2013
909 citations recorded by the source corpus.
SUMMARY Protein function is regulated by diverse posttranslational modifications. The mitochondrial sirtuin SIRT5 removes malonyl and succinyl moieties from target lysines. The spectrum of protein substrates subject to these modifications is unknown. We report systematic profiling of the mammalian succinylome, identifying 2,565 succinylation sites on 779 proteins. Most of these do not overlap with acetylation sites, suggesting differential regulation of succinylation and acetylation. Our analysis reveals potential impacts of lysine succinylation on enzymes involved in mitochondrial metabolism; e.g., amino acid degradation, the tricarboxylic acid cycle (TCA) cycle, and fatty acid metabolism. Lysine succinylation is also present on cytosolic and nuclear proteins; indeed, we show that a substantial fraction of SIRT5 is extra-mitochondrial. SIRT5 represses biochemical activity of, and cellular respiration through, two protein complexes identified in our analysis, pyruvate dehydrogenase complex and succinate dehydrogenase. Our data reveal widespread roles for lysine succinylation in regulating metabolism and potentially other cellular functions.
Subfields: Epidemiology, Geriatrics and Gerontology, Physiology
View Paper: https://www.semanticscholar.org/paper/47c40fa699d766e0ebccc68356e6ef46b90364b9
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Citations in the corpus
- NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential (2020, background): “For instance, SIRT5 increases the activity of GAPDH by demalonylation, thereby controlling the energetic flux through glycolysis.(227,234,235) Collectively, sirtuins orchestrate an integrated modulation of metabolic pathways via NAD-dependent post-translational regulation in response to diverse nutr”
- Mitochondrial dysfunction in cell senescence and aging (2022, background): “In addition, SIRT4 and SIRT5 also regulate mitochondrial signaling and are involved in rewiring various metabolic pathways (92, 93).”
- Lysine Glutarylation Is a Protein Post-Translational Modification Regulated by SIRT5 (2014, methodology): “Together, association of three key cellular metabolites in these pathways strongly suggests that succinylation and malonylation PTMs have roles in metabolism (Park et al., 2013).”
- Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “…ATP synthesized de novo (based on serine availability) is critical for the SAM cycle regardless of whether methionine is present, and the role of serine is highlighted in supporting DNA/RNA methylation through the maintenance of nucleotide levels (Maddocks et al., 2016; Parker and Metallo, 2016).”
- pSuc-Lys: Predict lysine succinylation sites in proteins with PseAAC and ensemble random forest approach. (2016, background): “[4] identified 2,565 succinylation sites from 779 proteins and they revealed that lysine succinylation have potential impacts on enzymes involved in mitochondrial metabolism including amino acid degradation, tricarboxylic acid cycle (TCA) and fatty acid metabolism.”
- The Metabolic Signature of Macrophage Responses (2019, background): “High cytosolic succinate levels favor post-translational lysine succinylation on proteins, a process that profoundly modifies protein functions since it alters their charge and structure (104, 105).”
- SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks (2013, neutral): “After completion of our study, data emerged on lysine succinylation in liver tissue and SIRT5 targeted succinylation in MEFs from WT and Sirt5 / animals (Park et al., 2013).”