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. 16 R.W.Bürli et al.2.4 The Sirtuins (Class III HDACs)2.4.1 Structure, Mechanism, and Function of SirtuinsThe class III histone deacetylases are referred to as the sirtuins.Seven mammaliansirtuins (Sirt1-7) are known to date and are classified by similarity to the Sir2 familyfrom yeast.Most of them catalyze the deacetylation of Ne-acetylated lysine sidechains of histones as well as other protein substrates.Sirt1 alone is reported tohave in excess of 30 substrates, which include p53, FOXO1, FOXO4, COUP-TF,NCOR, NF-kB-p65, and MEF2, respectively [84].Sirt2 has been shown to be atubulin deacetylase and an important regulator of cell division and myelinogenesis[85 87].Sirt4 catalyzes ADP-ribosylation and Sirt6 accelerates both reaction types[88].While sirtuins are expressed ubiquitously across tissue types [89], theirintracellular localization varies: Sirt1, 6, and 7 are predominantly found in thenucleus, whereas Sirt1 and 2 are cytoplasmic, and isoforms 3, 4, and 5 are localizedin mitochondria [90].Various studies indicate that modulation of sirtuin activity (activation orinhibition) may lead to beneficial therapeutic effects, depending on the disease.There is ample evidence that overexpression of Sir2 (equivalent to the mamma-lian homolog Sirt1) leads to prolonged lifespan in various species, including yeast[91], fruit flies [92], and nematodes [93].Furthermore, increased longevity due toa calorie restricted diet has been connected to upregulated sirtuin activity [92 94].Enhancement of longevity and other health-promoting effects of sirtuins hasfrequently been attributed to regulation of metabolism.Since neuronal degenera-tion is a major pathophysiological aspect of aging, understanding the mechanismsof sirtuin-mediated neuroprotection promises novel strategies in clinical interven-tion of neurodegenerative diseases [95].Inhibition of sirtuin function may also bebeneficial in cancer therapy; for instance, prevention of Sirt1-mediated deacetyla-tion of p53 might facilitate apoptosis in response to DNA damage and oxidativestress [96].Compared to the zinc-dependent HDACs, the sirtuins act by a very differentmechanism and require NAD+ as a cofactor.Unsurprisingly, they show no sequencesimilarity with the other HDACs and are structurally very distinct [97].The size ofmost sirtuins (Sirt2 to Sirt7) varies from 310 to 400 amino acid residues, while Sirt1is larger (747 residues).Multiple crystal structures of eukaryotic and prokaryoticsirtuin proteins have been reported, which either are apo-forms or include ligandssuch as NADþ derivatives, Ne-acetylated lysine substrates, and/or other smallmolecules [98 110].These data have shed much light on the mode of action ofthis enzyme class.As illustrated in Fig.9, sirtuins convert one equivalent of NAD+ to nicotin-amide and 20-O-acetyl-ADP-ribose (20-OAADPr) to deacetylate an Ne-acetyllysine group [111].This mechanism requires a conformational change of NAD+resulting in weakening of the C10-N bond, which is induced upon binding of thesubstrate to the enzyme [109, 112].A nucleophilic substitution at the anomeric The Role of Histone Deacetylases in Neurodegenerative Diseases 17ONH2OONH2 NNH2nicotinamideADP NADPN+ADPO+O OOO O N+NPPHHO OHHO OHO OH NP HHNAD+ HO-alkylimidateNAD+ Nµ-acetyl LysNNHinvariant HisADPADPADP ADPOO OH ADPO OOHOO OOOHOHO OHO OHO OO+ H HO OHONPO NPH+ H2'-OAADPR H2NP H2+Nbicyclic intermediatefree LysNprotein substratePHFig.9 Description of the catalytic cycle of sirtuins: Ne-acetylated lysine substrate and NADþ areconverted to free lysine, nicotinamide, and 20-OAADPRcenter of the ribosyl unit leads to release of nicotinamide and formation of anO-alkylimidate intermediate.Importantly, the enzyme protects this activatedintermediate from hydrolysis [113], which otherwise would revert the processback to Ne-acetyl lysine.Instead, the invariant histidine functions as a generalbase assisting in a neighboring group participation of HO-C30 and HO-C20, whichprovides a bicyclic intermediate [114].Hydrolysis of this intermediate, again sup-ported by the invariant histidine, liberates the deacetylated substrate and 20-O-acetylated ADP-ribose (20-OAADPR).All sirtuins share a catalytic NAD+ binding domain, which is fairly well con-served across the family [115] and a substrate-binding pocket [ Pobierz caÅ‚ość w formacie PDF ]
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. 16 R.W.Bürli et al.2.4 The Sirtuins (Class III HDACs)2.4.1 Structure, Mechanism, and Function of SirtuinsThe class III histone deacetylases are referred to as the sirtuins.Seven mammaliansirtuins (Sirt1-7) are known to date and are classified by similarity to the Sir2 familyfrom yeast.Most of them catalyze the deacetylation of Ne-acetylated lysine sidechains of histones as well as other protein substrates.Sirt1 alone is reported tohave in excess of 30 substrates, which include p53, FOXO1, FOXO4, COUP-TF,NCOR, NF-kB-p65, and MEF2, respectively [84].Sirt2 has been shown to be atubulin deacetylase and an important regulator of cell division and myelinogenesis[85 87].Sirt4 catalyzes ADP-ribosylation and Sirt6 accelerates both reaction types[88].While sirtuins are expressed ubiquitously across tissue types [89], theirintracellular localization varies: Sirt1, 6, and 7 are predominantly found in thenucleus, whereas Sirt1 and 2 are cytoplasmic, and isoforms 3, 4, and 5 are localizedin mitochondria [90].Various studies indicate that modulation of sirtuin activity (activation orinhibition) may lead to beneficial therapeutic effects, depending on the disease.There is ample evidence that overexpression of Sir2 (equivalent to the mamma-lian homolog Sirt1) leads to prolonged lifespan in various species, including yeast[91], fruit flies [92], and nematodes [93].Furthermore, increased longevity due toa calorie restricted diet has been connected to upregulated sirtuin activity [92 94].Enhancement of longevity and other health-promoting effects of sirtuins hasfrequently been attributed to regulation of metabolism.Since neuronal degenera-tion is a major pathophysiological aspect of aging, understanding the mechanismsof sirtuin-mediated neuroprotection promises novel strategies in clinical interven-tion of neurodegenerative diseases [95].Inhibition of sirtuin function may also bebeneficial in cancer therapy; for instance, prevention of Sirt1-mediated deacetyla-tion of p53 might facilitate apoptosis in response to DNA damage and oxidativestress [96].Compared to the zinc-dependent HDACs, the sirtuins act by a very differentmechanism and require NAD+ as a cofactor.Unsurprisingly, they show no sequencesimilarity with the other HDACs and are structurally very distinct [97].The size ofmost sirtuins (Sirt2 to Sirt7) varies from 310 to 400 amino acid residues, while Sirt1is larger (747 residues).Multiple crystal structures of eukaryotic and prokaryoticsirtuin proteins have been reported, which either are apo-forms or include ligandssuch as NADþ derivatives, Ne-acetylated lysine substrates, and/or other smallmolecules [98 110].These data have shed much light on the mode of action ofthis enzyme class.As illustrated in Fig.9, sirtuins convert one equivalent of NAD+ to nicotin-amide and 20-O-acetyl-ADP-ribose (20-OAADPr) to deacetylate an Ne-acetyllysine group [111].This mechanism requires a conformational change of NAD+resulting in weakening of the C10-N bond, which is induced upon binding of thesubstrate to the enzyme [109, 112].A nucleophilic substitution at the anomeric The Role of Histone Deacetylases in Neurodegenerative Diseases 17ONH2OONH2 NNH2nicotinamideADP NADPN+ADPO+O OOO O N+NPPHHO OHHO OHO OH NP HHNAD+ HO-alkylimidateNAD+ Nµ-acetyl LysNNHinvariant HisADPADPADP ADPOO OH ADPO OOHOO OOOHOHO OHO OHO OO+ H HO OHONPO NPH+ H2'-OAADPR H2NP H2+Nbicyclic intermediatefree LysNprotein substratePHFig.9 Description of the catalytic cycle of sirtuins: Ne-acetylated lysine substrate and NADþ areconverted to free lysine, nicotinamide, and 20-OAADPRcenter of the ribosyl unit leads to release of nicotinamide and formation of anO-alkylimidate intermediate.Importantly, the enzyme protects this activatedintermediate from hydrolysis [113], which otherwise would revert the processback to Ne-acetyl lysine.Instead, the invariant histidine functions as a generalbase assisting in a neighboring group participation of HO-C30 and HO-C20, whichprovides a bicyclic intermediate [114].Hydrolysis of this intermediate, again sup-ported by the invariant histidine, liberates the deacetylated substrate and 20-O-acetylated ADP-ribose (20-OAADPR).All sirtuins share a catalytic NAD+ binding domain, which is fairly well con-served across the family [115] and a substrate-binding pocket [ Pobierz caÅ‚ość w formacie PDF ]