Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection.
Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection.
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DOI：
10.1016/j.expneurol.2021.113842
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发表时间：
2021-11
影响因子：
5.3
通讯作者：
Milbrandt J
中科院分区：
文献类型：
--
作者：
Sasaki Y;Zhu J;Shi Y;Gu W;Kobe B;Ve T;DiAntonio A;Milbrandt J
Sarm1是一种可诱导的NAD+水解酶，是病理性轴突丢失的中心执行者。最近，我们阐明了Sarm1激活的分子机制，表明Sarm1是一个代谢感受器，受NAD+及其前体烟酰胺单核苷酸(NMN)的水平调节，它们通过竞争结合到Sarm1 N末端臂结构域中的变构位点。在NAD+丰富的健康神经元中，NAD+的结合阻止了NMN对这个变构部位的访问。然而，随着损伤或疾病的发生，NAD+生物合成酶NMNA2的水平下降，增加了NMN/NAD+比率，从而促进了NMN与Sarm1变构位点的结合，这反过来又诱导了激活Sarm1 NAD+水解酶的构象变化。因此，NAD+代谢产物既调节Sarm1的激活，又受Sarm1 NAD+水解酶的调节。NAD+代谢物在Sarm1功能中的双重上游和下游作用阻碍了对操纵NAD+代谢组的轴保护机制的机械性理解。在这里，我们重新评估了两种通过调节NAD+相关代谢物来有效阻止轴突变性的方法，1)NMN生物合成抑制剂FK866与NAD+前体烟酸核苷(NAR)联合使用，以及2)细菌酶NMN脱酰胺酶的神经元表达。我们发现，这些方法不仅导致Sarm1激活剂NMN水平的下降，而且还导致NAD+前体烟酸单核苷酸(NaMN)水平的上升。我们发现NaMN抑制Sarm1的激活，并证明这种NaMN介导的抑制对于这些处理诱导的长期轴突保护是重要的。对NaMN-Arm结构域共晶结构的分析表明，NaMN与NMN竞争结合Sarm1变构位点，并促进Sarm1手臂结构域的开放、自抑制构型。综上所述，这些结果表明，Sarm1变构口袋可以结合一系列不同的代谢物，包括NMN、NAD+和NaMN，以监测细胞NAD+动态平衡和调节Sarm1 NAD+水解酶活性。变构位点的相对混杂可能使开发有效的Sarm1激活的药理抑制剂用于治疗神经退行性疾病。
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 SARM1 NAD+ hydrolase. Hence, NAD+ metabolites both regulate the activation of SARM1 and, in turn, are regulated by the SARM1 NAD+ hydrolase. This dual upstream and downstream role for NAD+ metabolites in SARM1 function has hindered mechanistic understanding of axoprotective mechanisms that manipulate the NAD+ metabolome. Here we reevaluate two methods that potently block axon degeneration via modulation of NAD+ related metabolites, 1) the administration of the NMN biosynthesis inhibitor FK866 in conjunction with the NAD+ precursor nicotinic acid riboside (NaR) and 2) the neuronal expression of the bacterial enzyme NMN deamidase. We find that these approaches not only lead to a decrease in the levels of the SARM1 activator NMN, but also an increase in the levels of the NAD+ precursor nicotinic acid mononucleotide (NaMN). We show that NaMN inhibits SARM1 activation, and demonstrate that this NaMN-mediated inhibition is important for the long-term axon protection induced by these treatments. Analysis of the NaMN-ARM domain co-crystal structure shows that NaMN competes with NMN for binding to the SARM1 allosteric site and promotes the open, autoinhibited configuration of SARM1 ARM domain. Together, these results demonstrate that the SARM1 allosteric pocket can bind a diverse set of metabolites including NMN, NAD+, and NaMN to monitor cellular NAD+ homeostasis and regulate SARM1 NAD+ hydrolase activity. The relative promiscuity of the allosteric site may enable the development of potent pharmacological inhibitors of SARM1 activation for the treatment of neurodegenerative disorders.
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影响因子：
4.2
作者：
Gong B;Pan Y;Vempati P;Zhao W;Knable L;Ho L;Wang J;Sastre M;Ono K;Sauve AA;Pasinetti GM
通讯作者：
Pasinetti GM
影响因子：
12.4
作者：
通讯作者：
--
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
在ALS和其他运动神经疾病患者中，用组成性多动NADase编码变体的SARM1等位基因富集。
影响因子：
7.7
作者：
Gilley J;Jackson O;Pipis M;Estiar MA;Al-Chalabi A;Danzi MC;van Eijk KR;Goutman SA;Harms MB;Houlden H;Iacoangeli A;Kaye J;Lima L;Queen Square Genomics;Ravits J;Rouleau GA;Schüle R;Xu J;Züchner S;Cooper-Knock J;Gan-Or Z;Reilly MM;Coleman MP
通讯作者：
Coleman MP
影响因子：
16.2
作者：
Essuman K;Summers DW;Sasaki Y;Mao X;DiAntonio A;Milbrandt J
通讯作者：
Milbrandt J