79. Jiang H, Khan S, Wang Y, Charron G, He B, Sebastian C, Du J, Kim R, Ge E,
Mostoslavsky R, Hang HC, Hao Q, Lin H (2013) SIRT6 regulates TNF-alpha secretion
through hydrolysis of long-chain fatty acyl lysine. Nature 496(7443):110–113. https://doi.
org/10.1038/nature12038
80. Avalos JL, Boeke JD, Wolberger C (2004) Structural basis for the mechanism and regulation
of Sir2 enzymes. Mol Cell 13(5):639–648
81. Avalos JL, Bever KM, Wolberger C (2005) Mechanism of sirtuin inhibition by nicotinamide:
altering the NAD(+) cosubstrate specificity of a Sir2 enzyme. Mol Cell 17(6):855–868. https://
doi.org/10.1016/j.molcel.2005.02.022
82. Cosgrove MS, Bever K, Avalos JL, Muhammad S, Zhang X, Wolberger C (2006) The
structural basis of sirtuin substrate affinity. Biochemistry 45(24):7511–7521. https://doi.org/
10.1021/bi0526332
83. Hoff KG, Avalos JL, Sens K, Wolberger C (2006) Insights into the sirtuin mechanism from
ternary complexes containing NAD+ and acetylated peptide. Structure 14(8):1231–1240.
https://doi.org/10.1016/j.str.2006.06.006
84. Hawse WF, Hoff KG, Fatkins DG, Daines A, Zubkova OV, Schramm VL, Zheng W,
Wolberger C (2008) Structural insights into intermediate steps in the Sir2 deacetylation
reaction. Structure 16(9):1368–1377. https://doi.org/10.1016/j.str.2008.05.015
85. Min J, Landry J, Sternglanz R, Xu RM (2001) Crystal structure of a SIR2 homolog-NAD
complex. Cell 105(2):269–279
86. Zhao K, Harshaw R, Chai X, Marmorstein R (2004) Structural basis for nicotinamide cleavage
and ADP-ribose transfer by NAD(+)-dependent Sir2 histone/protein deacetylases. Proc Natl
Acad Sci U S A 101(23):8563–8568. https://doi.org/10.1073/pnas.0401057101
87. Zhao K, Chai X, Marmorstein R (2003) Structure of a Sir2 substrate, Alba, reveals a
mechanism for deacetylation-induced enhancement of DNA binding. J Biol Chem 278
(28):26071–26077. https://doi.org/10.1074/jbc.M303666200
88. Pannek M, Simic Z, Fuszard M, Meleshin M, Rotili D, Mai A, Schutkowski M, Steegborn C
(2017) Crystal structures of the mitochondrial deacylase Sirtuin 4 reveal isoform-specific acyl
recognition and regulation features. Nat Commun 8(1):1513. https://doi.org/10.1038/s41467017-01701-2
89. Schiedel M, Robaa D, Rumpf T, Sippl W, Jung M (2018) The current state of NAD(+)dependent histone deacetylases (sirtuins) as novel therapeutic targets. Med Res Rev 38
(1):147–200. https://doi.org/10.1002/med.21436
90. Rumpf T, Schiedel M, Karaman B, Roessler C, North BJ, Lehotzky A, Olah J, Ladwein KI,
Schmidtkunz K, Gajer M, Pannek M, Steegborn C, Sinclair DA, Gerhardt S, Ovadi J,
Schutkowski M, Sippl W, Einsle O, Jung M (2015) Selective Sirt2 inhibition by ligandinduced rearrangement of the active site. Nat Commun 6. https://doi.org/10.1038/
ncomms7263
91. Neugebauer RC, Sippl W, Jung M (2008) Inhibitors of NAD+ dependent histone deacetylases
(sirtuins). Curr Pharm Des 14(6):562–573
92. Trapp J, Jochum A, Meier R, Saunders L, Marshall B, Kunick C, Verdin E, Goekjian P,
Sippl W, Jung M (2006) Adenosine mimetics as inhibitors of NAD(+)-dependent histone
deacetylases, from kinase to sirtuin inhibition. J Med Chem 49(25):7307–7316. https://doi.
org/10.1021/jm060118b
93. Karaman B, Jung M, Sippl W (2016) Chapter 11 – structure-based design and computational
studies of sirtuin inhibitors. Epi-informatics. Academic Press, Boston, pp 297–325. https://doi.
org/10.1016/B978-0-12-802808-7.00011-3
94. Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, Volk CB,
Maxwell MM, Rochet JC, McLean PJ, Young AB, Abagyan R, Feany MB, Hyman BT,
Kazantsev AG (2007) Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models
of Parkinson’s disease. Science 317(5837):516–519. https://doi.org/10.1126/science.1143780
Structure-Based Design of Epigenetic Inhibitors
481
Mostoslavsky R, Hang HC, Hao Q, Lin H (2013) SIRT6 regulates TNF-alpha secretion
through hydrolysis of long-chain fatty acyl lysine. Nature 496(7443):110–113. https://doi.
org/10.1038/nature12038
80. Avalos JL, Boeke JD, Wolberger C (2004) Structural basis for the mechanism and regulation
of Sir2 enzymes. Mol Cell 13(5):639–648
81. Avalos JL, Bever KM, Wolberger C (2005) Mechanism of sirtuin inhibition by nicotinamide:
altering the NAD(+) cosubstrate specificity of a Sir2 enzyme. Mol Cell 17(6):855–868. https://
doi.org/10.1016/j.molcel.2005.02.022
82. Cosgrove MS, Bever K, Avalos JL, Muhammad S, Zhang X, Wolberger C (2006) The
structural basis of sirtuin substrate affinity. Biochemistry 45(24):7511–7521. https://doi.org/
10.1021/bi0526332
83. Hoff KG, Avalos JL, Sens K, Wolberger C (2006) Insights into the sirtuin mechanism from
ternary complexes containing NAD+ and acetylated peptide. Structure 14(8):1231–1240.
https://doi.org/10.1016/j.str.2006.06.006
84. Hawse WF, Hoff KG, Fatkins DG, Daines A, Zubkova OV, Schramm VL, Zheng W,
Wolberger C (2008) Structural insights into intermediate steps in the Sir2 deacetylation
reaction. Structure 16(9):1368–1377. https://doi.org/10.1016/j.str.2008.05.015
85. Min J, Landry J, Sternglanz R, Xu RM (2001) Crystal structure of a SIR2 homolog-NAD
complex. Cell 105(2):269–279
86. Zhao K, Harshaw R, Chai X, Marmorstein R (2004) Structural basis for nicotinamide cleavage
and ADP-ribose transfer by NAD(+)-dependent Sir2 histone/protein deacetylases. Proc Natl
Acad Sci U S A 101(23):8563–8568. https://doi.org/10.1073/pnas.0401057101
87. Zhao K, Chai X, Marmorstein R (2003) Structure of a Sir2 substrate, Alba, reveals a
mechanism for deacetylation-induced enhancement of DNA binding. J Biol Chem 278
(28):26071–26077. https://doi.org/10.1074/jbc.M303666200
88. Pannek M, Simic Z, Fuszard M, Meleshin M, Rotili D, Mai A, Schutkowski M, Steegborn C
(2017) Crystal structures of the mitochondrial deacylase Sirtuin 4 reveal isoform-specific acyl
recognition and regulation features. Nat Commun 8(1):1513. https://doi.org/10.1038/s41467017-01701-2
89. Schiedel M, Robaa D, Rumpf T, Sippl W, Jung M (2018) The current state of NAD(+)dependent histone deacetylases (sirtuins) as novel therapeutic targets. Med Res Rev 38
(1):147–200. https://doi.org/10.1002/med.21436
90. Rumpf T, Schiedel M, Karaman B, Roessler C, North BJ, Lehotzky A, Olah J, Ladwein KI,
Schmidtkunz K, Gajer M, Pannek M, Steegborn C, Sinclair DA, Gerhardt S, Ovadi J,
Schutkowski M, Sippl W, Einsle O, Jung M (2015) Selective Sirt2 inhibition by ligandinduced rearrangement of the active site. Nat Commun 6. https://doi.org/10.1038/
ncomms7263
91. Neugebauer RC, Sippl W, Jung M (2008) Inhibitors of NAD+ dependent histone deacetylases
(sirtuins). Curr Pharm Des 14(6):562–573
92. Trapp J, Jochum A, Meier R, Saunders L, Marshall B, Kunick C, Verdin E, Goekjian P,
Sippl W, Jung M (2006) Adenosine mimetics as inhibitors of NAD(+)-dependent histone
deacetylases, from kinase to sirtuin inhibition. J Med Chem 49(25):7307–7316. https://doi.
org/10.1021/jm060118b
93. Karaman B, Jung M, Sippl W (2016) Chapter 11 – structure-based design and computational
studies of sirtuin inhibitors. Epi-informatics. Academic Press, Boston, pp 297–325. https://doi.
org/10.1016/B978-0-12-802808-7.00011-3
94. Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, Volk CB,
Maxwell MM, Rochet JC, McLean PJ, Young AB, Abagyan R, Feany MB, Hyman BT,
Kazantsev AG (2007) Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models
of Parkinson’s disease. Science 317(5837):516–519. https://doi.org/10.1126/science.1143780
Structure-Based Design of Epigenetic Inhibitors
481