Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection.

ABSTRACT: SARM1 is an inducible NAD⁺ hydrolase that is the central executioner of pathological axon loss. Recently, we elucidated the molecular mechanism of SARM1 activation, demonstrating that SARM1 is a metabolic sensor regulated by the levels of NAD⁺ and its precursor, nicotinamide mononucleotide (NMN), via their competitive binding to an allosteric site within the SARM1 N-terminal ARM domain. In healthy neurons with abundant NAD⁺, binding of NAD⁺ blocks access of NMN to this allosteric site. However, with injury or disease the levels of the NAD⁺ biosynthetic enzyme NMNAT2 drop, increasing the NMN/ NAD⁺ ratio and thereby promoting NMN binding to the SARM1 allosteric site, which in turn induces a conformational change activating the

SUBMITTER: Sasaki Y 

PROVIDER: S-EPMC8571713 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature