Overview:

SIRT4 is a member of the sirtuin family of proteins which are homologs to the yeast Sir2 protein. Sirtuin family contain a sirtuin core domain and are grouped into four classes with SIRT4 being a member of class IV. SIRT4 lacks deacetylase activity but has ADP-ribosyltransferase activity (1). Immunoprecipitation analysis shows that SIRT4 interacts with the mitochondrial enzyme glutamate dehydrogenase (GDH), and functional analysis show that SIRT4 ADP-ribosylates and inhibits GDH (2). Downregulation of SIRT4 by RNA interference activates GDH, thereby upregulating insulin secretion in response to glucose and amino acids.

References:

1. Frye, R. A. Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem. Biophys. Res. Commun. 260: 273-279, 1999.

2. Haigis, M. C. et al: SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 126: 941-954, 2006.