NAD
+-dependent histone deacetylases (sirtuins) play important roles in epigenetic regulation but also through nonhistone substrates for ot
her key cellular events and have been linked to t
he pathogenesis of cancer, neurodegeneration, and metabolic diseases. T
he subtype Sirt5 has been shown recently to act as a desuccinylating and demalonylating enzyme. We have establis
hed an assay for bioc
hemical testing of Sirt5 using a small labeled succinylated lysine derivative. We present a comparative study on t
he profiling of several establis
hed sirtuin inhibitors on Sirt1鈥? 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 t
he low micromolar range, which are selective over Sirt3 that can be found in t
he same cell compartment as Sirt5.
Keywords:
sirtuin; Sirt5; desuccinylation; sirtinol; AMC assay