SARM1 is a multi-functional NAD(P)ase with prominent base exchange activity, all regulated bymultiple physiologically relevant NAD metabolites.
SARM1 is a multi-functional NAD(P)ase with prominent base exchange activity, all regulated bymultiple physiologically relevant NAD metabolites.
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DOI：
10.1016/j.isci.2022.103812
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发表时间：
2022-02-18
期刊：
影响因子：
5.8
通讯作者：
Orsomando G
中科院分区：
文献类型：
--
作者：
Angeletti C;Amici A;Gilley J;Loreto A;Trapanotto AG;Antoniou C;Merlini E;Coleman MP;Orsomando G
SARM 1是一种NAD（P）糖水解酶和TLR适配器，在程序性轴突死亡（沃勒变性）中具有重要的促变性作用。与其他NAD（P）酶一样，它催化需要充分研究的多种反应。在这里，我们比较了重组人SARM 1，人CD38，和加州曲霉ADP核糖基环化酶的这些多个活动。SARM 1在中性pH下具有最高的转糖苷（碱交换）活性，并且对于某些碱，这主导NAD（P）水解和环化。所有SARM 1活性，包括在中性pH值下的碱交换，在两种代谢物的生理水平下通过增加的NMN：NAD比率来激活。SARM 1碱基交换也发生在DRG神经元中，因此很可能是钙动员剂NaADP的生理来源。最后，我们确定调控游离吡啶，NADP，烟酸核苷（NaR）对SARM 1，所有的治疗利益。了解哪些特定的SARM 1功能负责轴突变性对于其在疾病中的靶向至关重要。碱基交换是SARM 1活性的主要部分，有时完全占主导地位生理相关的NMN：NAD比例可以调节SARM 1的所有多种活性生理NADP可以比NAD更有效地抑制SARM 1，并且通过不同的位点，NaR和VR都选择性地抑制SARM 1，因此可能是效应物或药物先导生物科学;分子生理学;神经科学
SARM1 is an NAD(P) glycohydrolase and TLR adapter with an essential, prodegenerative role in programmed axon death (Wallerian degeneration). Like other NAD(P)ases, it catalyzes multiple reactions that need to be fully investigated. Here, we compare these multiple activities for recombinant human SARM1, human CD38, and Aplysia californica ADP ribosyl cyclase. SARM1 has the highest transglycosidation (base exchange) activity at neutral pH and with some bases this dominates NAD(P) hydrolysis and cyclization. All SARM1 activities, including base exchange at neutral pH, are activated by an increased NMN:NAD ratio, at physiological levels of both metabolites. SARM1 base exchange occurs also in DRG neurons and is thus a very likely physiological source of calcium-mobilizing agent NaADP. Finally, we identify regulation by free pyridines, NADP, and nicotinic acid riboside (NaR) on SARM1, all of therapeutic interest. Understanding which specific SARM1 function(s) is responsible for axon degeneration is essential for its targeting in disease. Base exchange is a prominent, and sometimes completely dominant, SARM1 activity Physiologically relevant NMN:NAD ratios may regulate all of SARM1's multiple activities Physiological NADP may inhibit SARM1 more potently than NAD and via a distinct site NaR and VR both selectively inhibit SARM1 and are thus possible effectors or drug leads Biological sciences; Molecular physiology; Neuroscience
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DOI：
10.1038/s41583-020-0269-3
发表时间：
2020-04
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Coleman MP;Höke A
通讯作者：
Höke A
影响因子：
12.4
作者：
通讯作者：
--
影响因子：
8.6
作者：
Buonvicino, Daniela;Mazzola, Francesca;Chiarugi, Alberto
通讯作者：
Chiarugi, Alberto
影响因子：
4.8
作者：
Bogan, Katrina L.;Evans, Charles;Brenner, Charles
通讯作者：
Brenner, Charles
影响因子：
5.3
作者：
Gould, Stacey Anne;White, Matthew;Adalbert, Robert
通讯作者：
Adalbert, Robert