Many natural compounds possess an ability to inhibit the sirtuins. One of the
compounds which was able to inhibit sirtuins was extracted from the bark of
Garcinia cochinchinensis containing guttiferone G and hyperforin. In particular, a
structurally similar but synthetic compound, aristoforin (compound 55 in Fig. 11),
displayed IC 50 values of 7 μM and 21 μM for SIRT1 and SIRT2, respectively, and it
displayed an antiproliferative effect on HUVEC cells [163]. The tanikolide dimer
from the Madagascar marine cyanobacterium Lyngbya majuscula was identified as a
potent SIRT2 inhibitor (IC 50 ¼ 176 nM or 2.4 μM depending on assay). Synthetic
stereoisomers had equal potency for SIRT1 (IC 50 ¼ 29–36 μM) and SIRT2
(IC 50 ¼ 2.4–3.3 μM) [164].
3 Sirtuin Activators
The identification of sirtuin activators has proved to be challenging, and thus far,
fewer activators have been reported than inhibitors. Several SIRT1 activators have
been published over the years since SIRT1 activation would be desirable in many
age-related and metabolic conditions [42, 138, 165–171]. In recent years, there has
been an intense debate about the identified SIRT1 activators; it has been claimed that
sirtuins are only activated when hydrophobic fluorescent moieties have been
attached to the peptide substrates, but not when unmodified peptides or the native
protein substrates were used [172, 173].
Subsequently, these compounds were demonstrated to activate SIRT1 catalyzed
deacetylation through an allosteric mechanism. This means that the binding of a
small molecule to an allosteric site can induce a conformational change subsequently
modifying the affinity of the enzyme for its native substrate [166, 171]. The crystal
structures with activators [174, 175] revealed that most of the SIRT1 activators were
binding to a SIRT1-specific N-terminal domain, which was postulated to induce a
closure of the substrate-containing active site. The rational design of sirtuin activators, however, has been lacking and only few activators for other than SIRT1 have
been published so far. This might partly be due to the absence of a deep understanding of the kinetics of sirtuin-catalyzed deacylation and especially an elucidation of
the activation property has proven to be far more elusive. Nonetheless, recently,
some SIRT6 activators have been identified.
3.1 Natural Compounds Activating Sirtuins
Certain plant polyphenols, members of a large and diverse group of plant secondary
metabolites, were the first compounds discovered to be able to increase sirtuin
activity [138]. The most potent of these compounds was resveratrol (compound
56 in Fig. 13), which was observed to stimulate the catalytic activity of yeast and
human sirtuins. Dose-response experiments showed that resveratrol doubled the rate
76
M. Rahnasto-Rilla et al.
compounds which was able to inhibit sirtuins was extracted from the bark of
Garcinia cochinchinensis containing guttiferone G and hyperforin. In particular, a
structurally similar but synthetic compound, aristoforin (compound 55 in Fig. 11),
displayed IC 50 values of 7 μM and 21 μM for SIRT1 and SIRT2, respectively, and it
displayed an antiproliferative effect on HUVEC cells [163]. The tanikolide dimer
from the Madagascar marine cyanobacterium Lyngbya majuscula was identified as a
potent SIRT2 inhibitor (IC 50 ¼ 176 nM or 2.4 μM depending on assay). Synthetic
stereoisomers had equal potency for SIRT1 (IC 50 ¼ 29–36 μM) and SIRT2
(IC 50 ¼ 2.4–3.3 μM) [164].
3 Sirtuin Activators
The identification of sirtuin activators has proved to be challenging, and thus far,
fewer activators have been reported than inhibitors. Several SIRT1 activators have
been published over the years since SIRT1 activation would be desirable in many
age-related and metabolic conditions [42, 138, 165–171]. In recent years, there has
been an intense debate about the identified SIRT1 activators; it has been claimed that
sirtuins are only activated when hydrophobic fluorescent moieties have been
attached to the peptide substrates, but not when unmodified peptides or the native
protein substrates were used [172, 173].
Subsequently, these compounds were demonstrated to activate SIRT1 catalyzed
deacetylation through an allosteric mechanism. This means that the binding of a
small molecule to an allosteric site can induce a conformational change subsequently
modifying the affinity of the enzyme for its native substrate [166, 171]. The crystal
structures with activators [174, 175] revealed that most of the SIRT1 activators were
binding to a SIRT1-specific N-terminal domain, which was postulated to induce a
closure of the substrate-containing active site. The rational design of sirtuin activators, however, has been lacking and only few activators for other than SIRT1 have
been published so far. This might partly be due to the absence of a deep understanding of the kinetics of sirtuin-catalyzed deacylation and especially an elucidation of
the activation property has proven to be far more elusive. Nonetheless, recently,
some SIRT6 activators have been identified.
3.1 Natural Compounds Activating Sirtuins
Certain plant polyphenols, members of a large and diverse group of plant secondary
metabolites, were the first compounds discovered to be able to increase sirtuin
activity [138]. The most potent of these compounds was resveratrol (compound
56 in Fig. 13), which was observed to stimulate the catalytic activity of yeast and
human sirtuins. Dose-response experiments showed that resveratrol doubled the rate
76
M. Rahnasto-Rilla et al.