Department of Biomedicine, University of Bergen, 5009 Bergen, Norway.
Institute of Cytology, Russian Academy of Sciences, 194064 St. Petersburg, Russia.
Biochem Soc Trans. 2019 Feb 28;47(1):119-130. doi: 10.1042/BST20180417. Epub 2019 Jan 9.
Research over the last few decades has extended our understanding of nicotinamide adenine dinucleotide (NAD) from a vital redox carrier to an important signalling molecule that is involved in the regulation of a multitude of fundamental cellular processes. This includes DNA repair, cell cycle regulation, gene expression and calcium signalling, in which NAD is a substrate for several families of regulatory proteins, such as sirtuins and ADP-ribosyltransferases. At the molecular level, NAD-dependent signalling events differ from hydride transfer by cleavage of the dinucleotide into an ADP-ribosyl moiety and nicotinamide. Therefore, non-redox functions of NAD require continuous biosynthesis of the dinucleotide. Maintenance of cellular NAD levels is mainly achieved by nicotinamide salvage, yet a variety of other precursors can be used to sustain cellular NAD levels via different biosynthetic routes. Biosynthesis and consumption of NAD are compartmentalised at the subcellular level, and currently little is known about the generation and role of some of these subcellular NAD pools. Impaired biosynthesis or increased NAD consumption is deleterious and associated with ageing and several pathologies. Insults to neurons lead to depletion of axonal NAD and rapid degeneration, partial rescue can be achieved pharmacologically by administration of specific NAD precursors. Restoring NAD levels by stimulating biosynthesis or through supplementation with precursors also produces beneficial therapeutic effects in several disease models. In this review, we will briefly discuss the most recent achievements and the challenges ahead in this diverse research field.
在过去几十年的研究中，烟酰胺腺嘌呤二核苷酸 (NAD) 的作用已从重要的氧化还原载体扩展到一种重要的信号分子，参与调节多种基本细胞过程。这包括 DNA 修复、细胞周期调控、基因表达和钙信号转导，在这些过程中，NAD 是几种调节蛋白（如沉默调节蛋白和 ADP-核糖基转移酶）的底物。在分子水平上，NAD 依赖性信号事件与通过二核苷酸裂解为 ADP-核糖基部分和烟酰胺的氢化物转移不同。因此，NAD 的非氧化还原功能需要二核苷酸的持续生物合成。细胞 NAD 水平的维持主要通过烟酰胺回收来实现，但许多其他前体可以通过不同的生物合成途径来维持细胞 NAD 水平。NAD 的生物合成和消耗在亚细胞水平上进行分区，目前对于这些亚细胞 NAD 池的一些生成和作用知之甚少。生物合成受损或 NAD 消耗增加是有害的，并与衰老和几种病理学有关。神经元受到损伤会导致轴突 NAD 耗竭和快速退化，通过给予特定的 NAD 前体进行药理学治疗可以部分挽救。通过刺激生物合成或用前体补充来恢复 NAD 水平，在几种疾病模型中也会产生有益的治疗效果。在这篇综述中，我们将简要讨论这一多样化研究领域的最新成果和未来的挑战。
