The Silent Information Regulator family of genes is a highly conserved group of genes that encode nicotinamide adenine dinucleotide-dependent protein deacetylases, initially classified as Class III histone deacetylases. The first discovered and best characterized of these genes is Saccharomyces cerevisiae Sir2, which is involved in silencing of mating type loci, telomere maintenance, DNA damage response, and cell aging. SirT4, a mammalian homolog of Sir2, is localized to the mitochondria and has been implicated in the regulation of cell metabolism, oxidative stress, genomic stability, and aging. In addition to deacetylase activity, multiple additional enzymatic activities have been attributed to SirT4, including protein deacylation, ADP-ribosylation, and NAD-dependent protein lipoamidase activity. SirT4 regulates the metabolism of glutamine, lipids, and glucose through direct deacetylation of malonyl CoA decarboxylase, ADP-ribosylation of glutamine dehydrogenase, and hydrolysis of the lipoamide cofactors from the E2 component dihydrolipoyllysine acetyltransferase of the pyruvate dehydrogenase complex. SirT4 is a tumor suppressor protein, and expression is reduced or lost in a large number of cancers, resulting in the acceleration of tumor morbidity and metastasis.
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