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首页> 外文OA文献 >Pathways and Subcellular Compartmentation of NAD Biosynthesis in Human Cells: FROM ENTRY OF EXTRACELLULAR PRECURSORS TO MITOCHONDRIAL NAD GENERATION*
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Pathways and Subcellular Compartmentation of NAD Biosynthesis in Human Cells: FROM ENTRY OF EXTRACELLULAR PRECURSORS TO MITOCHONDRIAL NAD GENERATION*

机译：人类细胞中NAD生物合成的途径和亚细胞隔室：从进入细胞外前体到线粒体NAD的产生*

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摘要

NAD is a vital redox carrier, and its degradation is a key element of important regulatory pathways. NAD-mediated functions are compartmentalized and have to be fueled by specific biosynthetic routes. However, little is known about the different pathways, their subcellular distribution, and regulation in human cells. In particular, the route(s) to generate mitochondrial NAD, the largest subcellular pool, is still unknown. To visualize organellar NAD changes in cells, we targeted poly(ADP-ribose) polymerase activity into the mitochondrial matrix. This activity synthesized immunodetectable poly(ADP-ribose) depending on mitochondrial NAD availability. Based on this novel detector system, detailed subcellular enzyme localizations, and pharmacological inhibitors, we identified extracellular NAD precursors, their cytosolic conversions, and the pathway of mitochondrial NAD generation. Our results demonstrate that, besides nicotinamide and nicotinic acid, only the corresponding nucleosides readily enter the cells. Nucleotides (e.g. NAD and NMN) undergo extracellular degradation resulting in the formation of permeable precursors. These precursors can all be converted to cytosolic and mitochondrial NAD. For mitochondrial NAD synthesis, precursors are converted to NMN in the cytosol. When taken up into the organelles, NMN (together with ATP) serves as substrate of NMNAT3 to form NAD. NMNAT3 was conclusively localized to the mitochondrial matrix and is the only known enzyme of NAD synthesis residing within these organelles. We thus present a comprehensive dissection of mammalian NAD biosynthesis, the groundwork to understand regulation of NAD-mediated processes, and the organismal homeostasis of this fundamental molecule.
机译：NAD是重要的氧化还原载体，其降解是重要调控途径的关键要素。 NAD介导的功能是分隔的，必须通过特定的生物合成途径提供动力。然而，人们对人类细胞中的不同途径，其亚细胞分布和调节了解甚少。特别地，产生线粒体NAD（最大的亚细胞池）的途径仍然未知。为了可视化细胞中细胞器NAD的变化，我们将聚（ADP-核糖）聚合酶活性靶向到线粒体基质中。该活性根据线粒体NAD的可用性合成了可免疫检测的聚（ADP-核糖）。基于此新型检测器系统，详细的亚细胞酶定位和药理抑制剂，我们确定了细胞外NAD前体，其胞质转化以及线粒体NAD生成的途径。我们的结果表明，除烟酰胺和烟酸外，只有相应的核苷才容易进入细胞。核苷酸（例如NAD和NMN）经历细胞外降解，导致形成可渗透的前体。这些前体都可以转化为胞质和线粒体NAD。对于线粒体NAD合成，前体在细胞质中转化为NMN。当被吸收到细胞器中时，NMN（与ATP一起）充当NMNAT3的底物以形成NAD。 NMNAT3最终局限在线粒体基质中，并且是位于这些细胞器中的唯一已知NAD合成酶。因此，我们介绍了哺乳动物NAD生物合成的综合解剖，了解了NAD介导的过程调控的基础，以及该基本分子的机体内稳态。

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