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Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5.

Title data

Schlicker, Christine ; Gertz, Melanie ; Papatheodorou, Panagiotis ; Kachholz, Barbara ; Becker, Christian F. W. ; Steegborn, Clemens:
Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5.
In: Journal of Molecular Biology. Vol. 382 (10 October 2008) Issue 3 . - pp. 790-801.
ISSN 0022-2836
DOI: https://doi.org/10.1016/j.jmb.2008.07.048

Abstract in another language

The enzymes of the Sirtuin family of nicotinamide-adenine-dinucleotide-dependent protein deacetylases are emerging key players in nuclear and cytosolic signaling, but also in mitochondrial regulation and aging. Mammalian mitochondria contain three Sirtuins, Sirt3, Sirt4, and Sirt5. Only one substrate is known for Sirt3 as well as for Sirt4, and up to now, no target for Sirt5 has been reported. Here, we describe the identification of novel substrates for the human mitochondrial Sirtuin isoforms Sirt3 and Sirt5. We show that Sirt3 can deacetylate and thereby activate a central metabolic regulator in the mitochondrial matrix, glutamate dehydrogenase. Furthermore, Sirt3 deacetylates and activates isocitrate dehydrogenase 2, an enzyme that promotes regeneration of antioxidants and catalyzes a key regulation point of the citric acid cycle. Sirt3 thus can regulate flux and anapleurosis of this central metabolic cycle. We further find that the N- and C-terminal regions of Sirt3 regulate its activity against glutamate dehydrogenase and a peptide substrate, indicating roles for these regions in substrate recognition and Sirtuin regulation. Sirt5, in contrast to Sirt3, deacetylates none of the mitochondrial matrix proteins tested. Instead, it can deacetylate cytochrome c, a protein of the mitochondrial intermembrane space with a central function in oxidative metabolism, as well as apoptosis initiation. Using a mitochondrial import assay, we find that Sirt5 can indeed be translocated into the mitochondrial intermembrane space, but also into the matrix, indicating that localization might contribute to Sirt5 regulation and substrate selection.

Further data

Item Type: Article in a journal
Refereed: Yes
Additional notes: PubMed-ID: 18680753
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry > Chair Biochemistry - Univ.-Prof. Dr. Clemens Steegborn
Faculties
Faculties > Faculty of Biology, Chemistry and Earth Sciences
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry
Result of work at the UBT: No
DDC Subjects: 500 Science > 540 Chemistry
Date Deposited: 16 Apr 2015 11:33
Last Modified: 16 Apr 2015 11:33
URI: https://eref.uni-bayreuth.de/id/eprint/10304