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Development of Peptide-Based Sirtuin Defatty-Acylase Inhibitors Identified by the Fluorescence Probe, SFP3, That Can Efficiently Measure Defatty-Acylase Activity of Sirtuin.

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Sirtuins (SIRTs) are a family of nicotinamide adenine dinucleotide-dependent histone deacetylases that serve as epigenetic regulators of many physiological processes. Recent studies have shown that in addition to their well-known… Click to show full abstract

Sirtuins (SIRTs) are a family of nicotinamide adenine dinucleotide-dependent histone deacetylases that serve as epigenetic regulators of many physiological processes. Recent studies have shown that in addition to their well-known deacetylase activity, sirtuins also exhibit deacylase activity, such as demyristoylase activity. Here, we show that our previously reported sirtuin fluorescence probe, SFP3, can measure the defatty-acylase activity of SIRT1-3, enabling selective assay of the deacylase activity. We further utilized this finding to develop the first inhibitors of SIRT2 defatty-acylase activity. Notably, most previously reported sirtuin inhibitors, including compound TM, AGK2, and SirReal2, showed almost no SIRT2 defatty-acylase-inhibitory activity, but are essentially specific deacetylase inhibitors. These results suggest that the active sites catalyzing the deacetylase and defatty-acylase activities of sirtuins may be independent.

Keywords: fluorescence probe; probe sfp3; defatty acylase; acylase activity; activity

Journal Title: Journal of medicinal chemistry
Year Published: 2019

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