NAD+激酶
立体化学
三元络合物
酶
化学
水解酶
水解
生物化学
生物物理学
生物
作者
Janneke D Icso,Leonard Barasa,Paul R. Thompson
出处
期刊:Biochemistry
[American Chemical Society]
日期:2023-06-12
卷期号:62 (13): 2065-2078
被引量:2
标识
DOI:10.1021/acs.biochem.3c00081
摘要
Sterile alpha and toll/interleukin receptor (TIR) motif containing protein 1 (SARM1) is an NAD+ hydrolase and cyclase involved in axonal degeneration. In addition to NAD+ hydrolysis and cyclization, SARM1 catalyzes a base exchange reaction between nicotinic acid (NA) and NADP+ to generate NAADP, which is a potent calcium signaling molecule. Herein, we describe efforts to characterize the hydrolysis, cyclization, and base exchange activities of TIR-1, the Caenorhabditis elegans ortholog of SARM1; TIR-1 also catalyzes NAD(P)+ hydrolysis and/or cyclization and regulates axonal degeneration in worms. We show that the catalytic domain of TIR-1 undergoes a liquid-to-solid phase transition that regulates not only the hydrolysis and cyclization reactions but also the base exchange reaction. We define the substrate specificities of the reactions, demonstrate that cyclization and base exchange reactions occur within the same pH range, and establish that TIR-1 uses a ternary complex mechanism. Overall, our findings will aid drug discovery efforts and provide insight into the mechanism of recently described inhibitors.
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