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Sirtuin 3 (SIRT3) protein regulates long-chain acyl-CoA dehydrogenase by deacetylating conserved lysines near the active site.

Publication ,  Journal Article
Bharathi, SS; Zhang, Y; Mohsen, A-W; Uppala, R; Balasubramani, M; Schreiber, E; Uechi, G; Beck, ME; Rardin, MJ; Vockley, J; Verdin, E ...
Published in: J Biol Chem
November 22, 2013

Long-chain acyl-CoA dehydrogenase (LCAD) is a key mitochondrial fatty acid oxidation enzyme. We previously demonstrated increased LCAD lysine acetylation in SIRT3 knockout mice concomitant with reduced LCAD activity and reduced fatty acid oxidation. To study the effects of acetylation on LCAD and determine sirtuin 3 (SIRT3) target sites, we chemically acetylated recombinant LCAD. Acetylation impeded substrate binding and reduced catalytic efficiency. Deacetylation with recombinant SIRT3 partially restored activity. Residues Lys-318 and Lys-322 were identified as SIRT3-targeted lysines. Arginine substitutions at Lys-318 and Lys-322 prevented the acetylation-induced activity loss. Lys-318 and Lys-322 flank residues Arg-317 and Phe-320, which are conserved among all acyl-CoA dehydrogenases and coordinate the enzyme-bound FAD cofactor in the active site. We propose that acetylation at Lys-318/Lys-322 causes a conformational change which reduces hydride transfer from substrate to FAD. Medium-chain acyl-CoA dehydrogenase and acyl-CoA dehydrogenase 9, two related enzymes with lysines at positions equivalent to Lys-318/Lys-322, were also efficiently deacetylated by SIRT3 following chemical acetylation. These results suggest that acetylation/deacetylation at Lys-318/Lys-322 is a mode of regulating fatty acid oxidation. The same mechanism may regulate other acyl-CoA dehydrogenases.

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Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

November 22, 2013

Volume

288

Issue

47

Start / End Page

33837 / 33847

Location

United States

Related Subject Headings

  • Sirtuin 3
  • Recombinant Proteins
  • Oxidation-Reduction
  • Mitochondria, Liver
  • Mice, Knockout
  • Mice
  • Humans
  • Flavin-Adenine Dinucleotide
  • Fatty Acids
  • Catalytic Domain
 

Citation

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Bharathi, S. S., Zhang, Y., Mohsen, A.-W., Uppala, R., Balasubramani, M., Schreiber, E., … Goetzman, E. S. (2013). Sirtuin 3 (SIRT3) protein regulates long-chain acyl-CoA dehydrogenase by deacetylating conserved lysines near the active site. J Biol Chem, 288(47), 33837–33847. https://doi.org/10.1074/jbc.M113.510354
Bharathi, Sivakama S., Yuxun Zhang, Al-Walid Mohsen, Radha Uppala, Manimalha Balasubramani, Emanuel Schreiber, Guy Uechi, et al. “Sirtuin 3 (SIRT3) protein regulates long-chain acyl-CoA dehydrogenase by deacetylating conserved lysines near the active site.J Biol Chem 288, no. 47 (November 22, 2013): 33837–47. https://doi.org/10.1074/jbc.M113.510354.
Bharathi SS, Zhang Y, Mohsen A-W, Uppala R, Balasubramani M, Schreiber E, et al. Sirtuin 3 (SIRT3) protein regulates long-chain acyl-CoA dehydrogenase by deacetylating conserved lysines near the active site. J Biol Chem. 2013 Nov 22;288(47):33837–47.
Bharathi, Sivakama S., et al. “Sirtuin 3 (SIRT3) protein regulates long-chain acyl-CoA dehydrogenase by deacetylating conserved lysines near the active site.J Biol Chem, vol. 288, no. 47, Nov. 2013, pp. 33837–47. Pubmed, doi:10.1074/jbc.M113.510354.
Bharathi SS, Zhang Y, Mohsen A-W, Uppala R, Balasubramani M, Schreiber E, Uechi G, Beck ME, Rardin MJ, Vockley J, Verdin E, Gibson BW, Hirschey MD, Goetzman ES. Sirtuin 3 (SIRT3) protein regulates long-chain acyl-CoA dehydrogenase by deacetylating conserved lysines near the active site. J Biol Chem. 2013 Nov 22;288(47):33837–33847.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

November 22, 2013

Volume

288

Issue

47

Start / End Page

33837 / 33847

Location

United States

Related Subject Headings

  • Sirtuin 3
  • Recombinant Proteins
  • Oxidation-Reduction
  • Mitochondria, Liver
  • Mice, Knockout
  • Mice
  • Humans
  • Flavin-Adenine Dinucleotide
  • Fatty Acids
  • Catalytic Domain