Research Article: SIRT1 and SIRT3 Deacetylate Homologous Substrates: AceCS1,2 and HMGCS1,2

Date Published: June 19, 2011

Publisher: Impact Journals LLC

Author(s): Matthew D. Hirschey, Tadahiro Shimazu, John A. Capra, Katherine S. Pollard, Eric Verdin.

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Abstract

SIRT1 and SIRT3 are NAD+-dependent protein deacetylases that are evolutionarily conserved across mammals. These proteins are located in the cytoplasm/nucleus and mitochondria, respectively. Previous reports demonstrated that human SIRT1 deacetylates Acetyl-CoA Synthase 1 (AceCS1) in the cytoplasm, whereas SIRT3 deacetylates the homologous Acetyl-CoA Synthase 2 (AceCS2) in the mitochondria. We recently showed that 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2) is deacetylated by SIRT3 in mitochondria, and we demonstrate here that SIRT1 deacetylates the homologous 3-hydroxy-3-methylglutaryl CoA synthase 1 (HMGCS1) in the cytoplasm. This novel pattern of substrate homology between cytoplasmic SIRT1 and mitochondrial SIRT3 suggests that considering evolutionary relationships between the sirtuins and their substrates may help to identify and understand the functions and interactions of this gene family. In this perspective, we take a first step by characterizing the evolutionary history of the sirtuins and these substrate families.

Partial Text

Sirtuins are a family of NAD+-dependent protein deacetylases/ADP ribosyltransferases that target a wide range of cellular proteins involved in aging [1-3], DNA repair [4], and metabolic regulation [5]. The sirtuins are present across the tree of life. The number of sirtuins in different species’ genomes ranges from one in E. coli (CobB) to seven in mammals (SIRT1-7). A yeast sirtuin family protein Sir2p functions as an histone deacetylase, and regulates replicative senescence and life span [3]. Among the seven mammalian sirtuins, SIRT1, the closest homologue of yeast Sir2p, is found in the cytoplasm and nucleus and plays diverse physiological roles in cellular signaling, transcriptional regulation (reviewed in [6]). Its orthologs, Sir2.1 and dSIR2, play similar roles in worms [2] and flies [1], respectively. Clustering of the sirtuins based on sequence similarity produces four general classes of sirtuins (Figure 1) [7]. Of all sirtuins, Class I sirtuins (SIRT1, SIRT2, SIRT3 in mammals) exhibit the most robust deacetylase activity on a variety of natural and synthetic acetylated substrates. Class II sirtuins (SIRT4) have no detectable deacetylase activity and instead show weak ADP-ribosyltransferase activity [8, 9]; class III sirtuins (SIRT5) have only weak deacetylase activity on the histone substrate [10, 11]; class IV sirtuins have ADP ribosyltransferase and deacetylase activity (SIRT6) or unknown activity (SIRT7) [12, 13]. An additional class of sirtuins referred to as Class U is intermediate between Class I and IV and has only been observed in bacteria. Of the human mitochondrial sirtuins, SIRT3 has the most similar sequence to SIRT1, so we investigated the possibility that SIRT3 regulates similar functions in the mitochondria as SIRT1 regulates in the cytoplasm.

 

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