Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.2.1.13 (acetyl-CoA synthetase)
 451 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report that human acetyl-CoA synthetase 2 (AceCS2) is a mitochondrial matrix protein. AceCS2 is reversibly acetylated at Lys-642 in the active site of the enzyme. The mitochondrial sirtuin SIRT3 interacts with AceCS2 and deacetylates Lys-642 both in vitro and in vivo. Deacetylation of AceCS2 by SIRT3 activates the acetyl-CoA synthetase activity of AceCS2. This report identifies the first acetylated substrate protein of SIRT3. Our findings show that a mammalian sirtuin directly controls the activity of a metabolic enzyme by means of reversible lysine acetylation. Because the activity of a bacterial ortholog of AceCS2, called ACS, is controlled via deacetylation by a bacterial sirtuin protein, our observation highlights the conservation of a metabolic regulatory pathway from bacteria to humans.
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PMID:Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. 1678 62

SIRT3, one of seven mammalian sirtuins, is a NAD-dependent deacetylase. SIRT3 localizes to mitochondria where it deacetylates and thus activates acetyl-CoA synthetase 2 (AceCS2), indicating a role for SIRT3 in metabolism. Here we provide evidence that SIRT3 also impacts upon apoptosis and cell growth control. Using RNAi under basal (non-stress) conditions we show that SIRT3 is required for apoptosis induced by selective silencing of Bcl-2 in HCT116 human epithelial cancer cells. Identical treatment of ARPE19 epithelial non-cancer cells induces G(1) growth arrest which also proved to be SIRT3-dependent. Previously we have identified SIRT1 and JNK2 as constitutive suppressors of apoptosis in HCT116 cells. We now demonstrate that SIRT3 functions in JNK2-regulated apoptosis but is dispensable for SIRT1-regulated apoptosis. SIRT3 is also dispensable for stress-induced apoptosis. Thus the pro-apoptotic functioning of SIRT3 is selectively coupled with defined pathways regulating cell survival under basal conditions.
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PMID:SIRT3 is pro-apoptotic and participates in distinct basal apoptotic pathways. 1795 39

SIRT3 is a major mitochondrial NAD(+)-dependent protein deacetylase playing important roles in regulating mitochondrial metabolism and energy production and has been linked to the beneficial effects of exercise and caloric restriction. SIRT3 is emerging as a potential therapeutic target to treat metabolic and neurological diseases. We report the first sets of crystal structures of human SIRT3, an apo-structure with no substrate, a structure with a peptide containing acetyl lysine of its natural substrate acetyl-CoA synthetase 2, a reaction intermediate structure trapped by a thioacetyl peptide, and a structure with the dethioacetylated peptide bound. These structures provide insights into the conformational changes induced by the two substrates required for the reaction, the acetylated substrate peptide and NAD(+). In addition, the binding study by isothermal titration calorimetry suggests that the acetylated peptide is the first substrate to bind to SIRT3, before NAD(+). These structures and biophysical studies provide key insight into the structural and functional relationship of the SIRT3 deacetylation activity.
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PMID:Crystal structures of human SIRT3 displaying substrate-induced conformational changes. 1953 40

Sirtuins are NAD(+)-dependent protein deacetylases that regulate gene silencing, energy metabolism and aging from bacteria to mammals. SIRT3, a mammalian mitochondrial sirtuin, deacetylates acetyl-CoA synthetase (AceCS2) in the mitochondria. AceCS2 is conserved from bacteria to humans, catalyzes the conversion of acetate to acetyl-CoA and enables peripheral tissues to utilize acetate during fasting conditions. Here, we review the regulation of acetate metabolism by sirtuins, the remarkable conservation of this metabolic regulatory pathway and its emerging role in the regulation of aging and longevity.
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PMID:Acetate metabolism and aging: An emerging connection. 2047 25

The sirtuins are a family of NAD(+)-dependent protein deacetylases that regulate cell survival, metabolism, and longevity. Three sirtuins, SIRT3-5, localize to mitochondria. Expression of SIRT3 is selectively activated during fasting and calorie restriction. SIRT3 regulates the acetylation level and enzymatic activity of key metabolic enzymes, such as acetyl-CoA synthetase, long-chain acyl-CoA dehydrogenase, and 3-hydroxy-3-methylglutaryl-CoA synthase 2, and enhances fat metabolism during fasting. SIRT5 exhibits demalonylase/desuccinylase activity, and lysine succinylation and malonylation are abundant mitochondrial protein modifications. No convincing enzymatic activity has been reported for SIRT4. Here, we review the emerging role of mitochondrial sirtuins as metabolic sensors that respond to changes in the energy status of the cell and modulate the activities of key metabolic enzymes via protein deacylation.
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PMID:Mitochondrial protein acylation and intermediary metabolism: regulation by sirtuins and implications for metabolic disease. 2308 51