Nicotinamide mononucleotide adenylyltransferase (NMNAT) is the central enzyme of the NAD biosynthetic pathway. Three human NMNAT isoforms have recently been identified, but isoform-specific functions are presently unknown, although a tissue-specific role has been suggested. Analyses of the subcellular localization confirmed NMNAT1 to be a nuclear protein, whereas NMNAT2 and -3 were localized to the Golgi complex and the mitochondria, respectively. This differential subcellular localization points to an organelle-specific, nonredundant function of each of the three proteins. Comparison of the kinetic properties showed that particularly NMNAT3 exhibits a high tolerance toward substrate modifications. Moreover, as opposed to preferred NAD+ synthesis by NMNAT1, the other two isoforms could also form NADH directly from the reduced nicotinamide mononucleotide, supporting a hitherto unknown pathway of NAD generation. A variety of physiological intermediates was tested and exerted only minor influence on the catalytic activities of the NMNATs. However, gallotannin was found to be a potent inhibitor, thereby compromising its use as a specific inhibitor of poly-ADP-ribose glycohydrolase. The presence of substrate-specific and independent nuclear, mitochondrial, and Golgi-specific NAD biosynthetic pathways is opposed to the assumption of a general cellular NAD pool. Their existence appears to be consistent with important compartment-specific functions rather than to reflect simple functional redundance.

中文翻译：

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三种人烟酰胺单核苷酸腺苷酸转移酶同工型的亚细胞区划和不同的催化性能。

烟酰胺单核苷酸腺苷酸转移酶（NMNAT）是NAD生物合成途径的核心酶。最近已经鉴定出三种人类NMNAT同工型，但是尽管已经提出了组织特有的作用，但是目前尚不知道同工型特异的功能。亚细胞定位的分析证实NMNAT1是一种核蛋白，而NMNAT2和-3分别定位于高尔基体和线粒体。这种不同的亚细胞定位指向了三种蛋白质中每一种的细胞器特异性，非冗余功能。动力学性质的比较表明，特别是NMNAT3对底物修饰表现出高耐受性。而且，与NMNAT1首选的NAD +合成相反，其他两个同工型也可以直接从还原的烟酰胺单核苷酸形成NADH，支持迄今为止未知的NAD生成途径。测试了多种生理中间体，它们对NMNAT的催化活性影响很小。然而，发现没食子单宁是有效的抑制剂，从而损害了其作为聚-ADP-核糖糖水解酶的特异性抑制剂的用途。底物特异性和独立的核，线粒体和高尔基体特异性NAD生物合成途径的存在与一般细胞NAD池的假设相反。它们的存在似乎与重要的特定于隔离专区的功能保持一致，而不是反映简单的功能冗余。测试了多种生理中间体，它们对NMNAT的催化活性影响很小。然而，发现没食子单宁是有效的抑制剂，从而损害了其作为聚-ADP-核糖糖水解酶的特异性抑制剂的用途。底物特异性和独立的核，线粒体和高尔基体特异性NAD生物合成途径的存在与一般细胞NAD池的假设相反。它们的存在似乎与重要的特定于隔离专区的功能保持一致，而不是反映简单的功能冗余。测试了多种生理中间体，它们对NMNAT的催化活性影响很小。然而，发现没食子单宁是有效的抑制剂，从而损害了其作为聚-ADP-核糖糖水解酶的特异性抑制剂的用途。底物特异性和独立的核，线粒体和高尔基体特异性NAD生物合成途径的存在与一般细胞NAD池的假设相反。它们的存在似乎与重要的特定于隔离专区的功能保持一致，而不是反映简单的功能冗余。底物特异性和独立的核，线粒体和高尔基体特异性NAD生物合成途径的存在与一般细胞NAD池的假设相反。它们的存在似乎与重要的特定于隔离专区的功能保持一致，而不是反映简单的功能冗余。底物特异性和独立的核，线粒体和高尔基体特异性NAD生物合成途径的存在与一般细胞NAD池的假设相反。它们的存在似乎与重要的特定于隔离专区的功能保持一致，而不是反映简单的功能冗余。