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Review
. 2024 Feb 6;25(4):1956.
doi: 10.3390/ijms25041956.

Sirtuins as Players in the Signal Transduction of Citrus Flavonoids

Giovanni Enrico Lombardo  1 , Caterina Russo  1 , Alessandro Maugeri  2 , Michele Navarra  1
Affiliations
Review

Sirtuins as Players in the Signal Transduction of Citrus Flavonoids

Giovanni Enrico Lombardo et al. Int J Mol Sci. .

Abstract

Sirtuins (SIRTs) belong to the family of nicotine adenine dinucleotide (NAD+)-dependent class III histone deacetylases, which come into play in the regulation of epigenetic processes through the deacetylation of histones and other substrates. The human genome encodes for seven homologs (SIRT1-7), which are localized into the nucleus, cytoplasm, and mitochondria, with different enzymatic activities and regulatory mechanisms. Indeed, SIRTs are involved in different physio-pathological processes responsible for the onset of several human illnesses, such as cardiovascular and neurodegenerative diseases, obesity and diabetes, age-related disorders, and cancer. Nowadays, it is well-known that Citrus fruits, typical of the Mediterranean diet, are an important source of bioactive compounds, such as polyphenols. Among these, flavonoids are recognized as potential agents endowed with a wide range of beneficial properties, including antioxidant, anti-inflammatory, hypolipidemic, and antitumoral ones. On these bases, we offer a comprehensive overview on biological effects exerted by Citrus flavonoids via targeting SIRTs, which acted as modulator of several signaling pathways. According to the reported studies, Citrus flavonoids appear to be promising SIRT modulators in many different pathologies, a role which might be potentially evaluated in future therapies, along with encouraging the study of those SIRT members which still lack proper evidence on their support.

Keywords: Citrus fruits; SIRT1; SIRT2; SIRT3; SIRT4; SIRT5; SIRT6; SIRT7; flavonoids; polyphenols.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The chemical reaction catalyzed by SIRTs consists of forming an imidate intermediate, which can either combine with nicotinamide, regenerating NAD+, or proceed forward until deacetylation of acetyl-lysine residues.
Figure 2
Figure 2
Biological effects mediated by the deacetylase activity of SIRTs.
Figure 3
Figure 3
Molecular structures of the main flavonoids and polyphenolic precursors present in Citrus fruits and investigated for their role in the various SIRTs.
Figure 4
Figure 4
Crystal structure of the SIRT1 catalytic domain (in green) bound to NAD (in orange) and zinc (in violet; PDB: 4I5I).
Figure 5
Figure 5
Human SIRT2 (in magenta) in complex with zinc (in violet) and NAD (in orange; PDB: 4RMG).
Figure 6
Figure 6
Crystal structure of SIRT3 (in cyan) in complex with zinc (in violet) and NAD (in orange; PDB: 4BV3).
Figure 7
Figure 7
Crystal structure of SIRT4 (in purple) from Xenopus tropicalis in complex with ADP-ribose (in yellow) superimposed to NAD (in orange) and zinc (in violet; PDB: 5OJN).
Figure 8
Figure 8
Crystal structure of SIRT5 (in yellow) in complex with zinc (in violet) and NAD (in orange; PDB: 3RIY).
Figure 9
Figure 9
Crystal structure of SIRT6 (in gray) in complex with ADP-ribose (in yellow) superimposed to NAD (in orange) and zinc (in violet; PDB: 6QCD).
Figure 10
Figure 10
Crystal structure of N-terminal domain of human SIRT7 (PDB: 5IQZ).
Figure 11
Figure 11
Pathways influenced by Citrus flavonoids via the modulation of SIRTs. Green arrows indicate activation, while red ones indicate inhibition.
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