Inhibitors of the NAD<sup>+</sup>‑Dependent Protein Desuccinylase and Demalonylase Sirt5
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Abstract
NAD<sup>+</sup>-dependent histone deacetylases (sirtuins)
play important roles in epigenetic regulation but also through nonhistone
substrates for other key cellular events and have been linked to the
pathogenesis of cancer, neurodegeneration, and metabolic diseases.
The subtype Sirt5 has been shown recently to act as a desuccinylating
and demalonylating enzyme. We have established an assay for biochemical
testing of Sirt5 using a small labeled succinylated lysine derivative.
We present a comparative study on the profiling of several established
sirtuin inhibitors on Sirt1–3 as well as Sirt5 and also present
initial results on a screening for new compounds that block Sirt5.
Thiobarbiturates were identified as new Sirt5 inhibitors in the low
micromolar range, which are selective over Sirt3 that can be found
in the same cell compartment as Sirt5