of the SIRT1 catalyzed deacetylation reaction at about 11 μM concentration via a K m
(value of substrate concentration at half maximal velocity)-lowering mechanism
[138]. Furthermore, resveratrol was also reported to stimulate the deacetylation
activity of SIRT5 (by twofold); this was observed with the substrate consisting of
fluorescent moieties. Interestingly resveratrol inhibited the deacetylation reaction of
SIRT3 and desuccinylase reaction of SIRT5 [176]. Several other synthetic activators
called sirtuin-activating compounds (STACs) related to resveratrol have been developed [166, 169, 171, 177].
Cao et al. [174] showed that the N-terminal domain is required for the stimulation
of SIRT1’s deacetylase activity by resveratrol (Fig. 14); in particular, Glu230 in this
domain was demonstrated to be critical for stimulation. In addition, Dai et al. [175]
demonstrated that residues 183–229 in the N-terminal domain were involved in
STAC binding. The crystal structure of SIRT1 with three resveratrol molecules
(Res1-Res3) and a 7-amino-4-methylcoumarin (AMC)-containing peptide revealed
that the binding of two of these resveratrols to the SIRT1 N-terminal domain was
probably due to a tighter binding between SIRT1 and the peptide substrate. The
OH
HO
OH
HO
OH
O
O
OH
OH
OH
Resveratrol (56)
Quercetin (57)
O
O
OCH 3
O
OCH 3
OH
HO
O
Terpenylated coumarin (58)
N
N
N
H
N
N
S
O
N
HN
SRT1720 (59)
N
O
O
O
O
Dihydropyridines (62)
N
N
N
NH 2
S
O
O
F
Pyrroloquinoxalines (64)
N
N
H
N
F 3 C
Azabenzimidazole
STAC-5 (61)
N
N
O
HN
O
OCH 3
Oxazolopyridines (63)
HN
O
N
N
S
HN
O
N
N
HN
NH
Thiazolopyridine
STAC-2 (60)
O NH
N
S
N
NH
H 3 CO
Fig. 13 Molecular structures of some sirtuin activators
Sirtuin Inhibitors and Activators
77