Wu, Tong; Zhu, Jian; Strickland, Amy; Ko, Kwang Woo; Sasaki, Yo; Dingwall, Caitlin B.; Yamada, Yurie; Figley, Matthew D.; Mao, Xianrong; Neiner, Alicia; Bloom, A. Joseph; DiAntonio, Aaron; Milbrandt, Jeffrey published the artcile< Neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss>, Application In Synthesis of 350-03-8, the main research area is neurotoxin allosteric activation mechanism SARM neuronal loss; NAMPT; NMNAT; Vacor; base exchange reaction; mass spectrometry; metabolism; myelin; neurolytic block; sciatic nerve; tibial nerve.
SARM1 is an inducible TIR-domain NAD+ hydrolase that mediates pathol. axon degeneration. SARM1 is activated by an increased ratio of NMN to NAD+, which competes for binding to an allosteric activating site. When NMN binds, the TIR domain is released from autoinhibition, activating its NAD+ hydrolase activity. The discovery of this allosteric activating site led us to hypothesize that other NAD+-related metabolites might activate SARM1. Here, we show the nicotinamide analog 3-acetylpyridine (3-AP), first identified as a neurotoxin in the 1940s, is converted to 3-APMN, which activates SARM1 and induces SARM1-dependent NAD+ depletion, axon degeneration, and neuronal death. In mice, systemic treatment with 3-AP causes rapid SARM1-dependent death, while local application to the peripheral nerve induces SARM1-dependent axon degeneration. We identify 2-aminopyridine as another SARM1-dependent neurotoxin. These findings identify SARM1 as a candidate mediator of environmental neurotoxicity and suggest that SARM1 agonists could be developed into selective agents for neurolytic therapy.
Cell Reports published new progress about Allosterism. 350-03-8 belongs to class pyridine-derivatives, and the molecular formula is C7H7NO, Application In Synthesis of 350-03-8.