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Cell. 2014 Dec 18;159(7):1615-25. doi: 10.1016/j.cell.2014.11.046.

Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity.

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  • 1Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA; Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, 3086, Australia.
  • 2Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA.
  • 3Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA. Electronic address: icristea@princeton.edu.

Abstract

Sirtuins (SIRTs) are critical enzymes that govern genome regulation, metabolism, and aging. Despite conserved deacetylase domains, mitochondrial SIRT4 and SIRT5 have little to no deacetylase activity, and a robust catalytic activity for SIRT4 has been elusive. Here, we establish SIRT4 as a cellular lipoamidase that regulates the pyruvate dehydrogenase complex (PDH). Importantly, SIRT4 catalytic efficiency for lipoyl- and biotinyl-lysine modifications is superior to its deacetylation activity. PDH, which converts pyruvate to acetyl-CoA, has been known to be primarily regulated by phosphorylation of its E1 component. We determine that SIRT4 enzymatically hydrolyzes the lipoamide cofactors from the E2 component dihydrolipoyllysine acetyltransferase (DLAT), diminishing PDH activity. We demonstrate SIRT4-mediated regulation of DLAT lipoyl levels and PDH activity in cells and in vivo, in mouse liver. Furthermore, metabolic flux switching via glutamine stimulation induces SIRT4 lipoamidase activity to inhibit PDH, highlighting SIRT4 as a guardian of cellular metabolism.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
25525879
[PubMed - indexed for MEDLINE]
PMCID:
PMC4344121
Free PMC Article
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