Differential regulation of SIRT5 activity by reduced nicotinic acid riboside (NARH)

SIRT5, one of the human sirtuins, catalyzes the removal of acyl substitutions from lysine residues in a NAD⁺-dependent manner. In addition to the deacetylase activity, SIRT5 also demonstrates strong desuccinylase, demalonylase, and deglutarylase activity. Through deacylating a broad spectrum of cellular proteins and enzymes, SIRT5 is heavily involved in the regulation of energy metabolism, reactive oxygen species (ROS) reduction, and ammonia detoxification. Accumulating evidence also suggests SIRT5 as a potential therapeutic target for the treatment of neurodegenerative diseases, metabolic disorders, and cancer. In the current study, we report the identification and characterization of a SIRT5 modulator, reduced nicotinic acid riboside (NARH). It shows differential regulation of the distinct activities of SIRT5: it activates desuccinylation, but mildly suppresses deacetylation. NARH binds to SIRT5 in the absence of NAD⁺ and demonstrates cellular target engagement and activity. The potential NARH binding site is further investigated using a suite of biochemical and computational approaches. The current study provides greatly needed mechanistic understanding of SIRT5 regulation, as well as a novel chemical scaffold for further activator development.