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Mol Cell. 2015 Jul 16;59(2):321-32. doi: 10.1016/j.molcel.2015.05.022. Epub 2015 Jun 11.

SIRT5 Regulates both Cytosolic and Mitochondrial Protein Malonylation with Glycolysis as a Major Target.

Author information

1
Gladstone Institutes and University of California, San Francisco, San Francisco, CA 94158, USA.
2
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
3
Cell Signaling Technology, Inc, 3 Trask Lane, Danvers, MA 01923, USA.
4
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
5
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; KineMed, Inc., Emeryville, CA 94608, USA.
6
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA. Electronic address: bgibson@buckinstitute.org.
7
Gladstone Institutes and University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: everdin@gladstone.ucsf.edu.

Abstract

Protein acylation links energetic substrate flux with cellular adaptive responses. SIRT5 is a NAD(+)-dependent lysine deacylase and removes both succinyl and malonyl groups. Using affinity enrichment and label free quantitative proteomics, we characterized the SIRT5-regulated lysine malonylome in wild-type (WT) and Sirt5(-/-) mice. 1,137 malonyllysine sites were identified across 430 proteins, with 183 sites (from 120 proteins) significantly increased in Sirt5(-/-) animals. Pathway analysis identified glycolysis as the top SIRT5-regulated pathway. Importantly, glycolytic flux was diminished in primary hepatocytes from Sirt5(-/-) compared to WT mice. Substitution of malonylated lysine residue 184 in glyceraldehyde 3-phosphate dehydrogenase with glutamic acid, a malonyllysine mimic, suppressed its enzymatic activity. Comparison with our previous reports on acylation reveals that malonylation targets a different set of proteins than acetylation and succinylation. These data demonstrate that SIRT5 is a global regulator of lysine malonylation and provide a mechanism for regulation of energetic flux through glycolysis.

PMID:
26073543
PMCID:
PMC4571487
DOI:
10.1016/j.molcel.2015.05.022
[Indexed for MEDLINE]
Free PMC Article

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