Abstract
Sirtuins are enzymes that catalyze NAD+ dependent protein deacetylation. The natural polyphenolic compound resveratrol received renewed interest when recent findings implicated resveratrol as a potent SIRT1 activator capable of mimicking the effects of calorie restriction. However, resveratrol directly interacts with fluorophore-containing peptide substrates. It was demonstrated that the SIRT1 activation of resveratrol is affected by the amino acid composition of the substrate. Resveratrol did increase the enzyme activity in cases in which hydrophobic amino acids are at the +1 position to the acetylated lysine in the substrate. Alkylresorcinols (ARs) are compounds that belong to the family of phenolic lipids, and they are found in numerous biological species. Here we show that the natural activators ARs increased the Vmax of recombinant SIRT1 for NAD+ and peptide substrate, and that ARs decreased acetylated histone in human monocyte cells by stimulating SIRT1-dependent deacetylation of substrates. ARs also extended the lifespan of Drosophila melanogaster, which was shown to be dependent on functional Sir2. Our results demonstrated that ARs are natural catalytic activators for sirtuin.
Highlights
Sir2-like proteins are a family of NAD+-dependent protein deacetylases conserved from Escherichia coli to humans[1]
Because long-alkyl ARs are indissoluble in water, we could not determine the concentration-dependency of the SIRT1 activation by the long-alkyl ARs
We investigated whether olivetol can activate SIRT1
Summary
Sir2-like proteins (sirtuins) are a family of NAD+-dependent protein deacetylases conserved from Escherichia coli to humans[1]. Sirtuin has physiologic functions that are exerted regardless of the differences between males and females, but resveratrol was shown to extend the lifespan of male but not female Drosophila melanogaster[11]. We screened a number of phytochemical libraries for a SIRT1 activator using the CycLex kit, and we identified resorcinolic lipids as possible candidate substance. ARs are found in grain husk such as that of wheat or rye at concentrations between 300 and 1500 μg/g19. ARs have been observed to have bioactivities in many in vitro models, and grain husk ingestion may be important in food and human nutrition[19]. ARs are absorbed from the human intestine, and their plasma concentrations are maintained as short-to-medium-term biomarkers of the intake of whole-grain wheat and rye, because the estimated half-life of plasma ARs is
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