Disease relevance of NMNAT1

• Previous studies demonstrated that overexpression of nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1) or exogenous application of nicotinamide adenine dinucleotide (NAD) can protect axons of cultured dorsal root ganglion (DRG) neurons from degeneration caused by mechanical or neurotoxic injury [1].
• The RNK and NMNAT enzymatic activities of recombinant NadR proteins from Salmonella enterica serovar Typhimurium and Haemophilus influenzae were quantitatively characterized [2].
• Based on these results and previous data, the full-size multifunctional NadR protein (as in Escherichia coli) is composed of (i) an N-terminal DNA-binding domain involved in the transcriptional regulation of NAD biosynthesis, (ii) a central nicotinamide mononucleotide adenylyltransferase (NMNAT) domain, and (iii) a C-terminal RNK domain [2].
• The slow Wallerian degeneration protein (Wld(S)), a fusion protein containing amino-terminal E4B and full-length nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1), delays axon degeneration caused by physical damages, toxins and genetic mutations which result in patients being diagnosed with neurodegenerative diseases [3].
• This method was successfully applied to the determination of NMNAT activity in human placental and bull testis extracts, as well as in rat pheochromocytoma (PC12) cells [4].

High impact information on NMNAT1

• 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 [5].
• 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 [5].
• Pyridine nucleotide adenylyltransferase (PNAT) is an indispensable central enzyme in the NAD biosynthesis pathways catalyzing the condensation of pyridine mononucleotide (NMN or NaMN) with the AMP moiety of ATP to form NAD (or NaAD) [6].
• The tiazofurin resistance is mainly associated with the low NMNAT activity in the cell [7].
• Nicotinamide/nicotinate mononucleotide (NMN/ NaMN)adenylyltransferase (NMNAT) is an indispensable enzyme in the biosynthesis of NAD(+) and NADP(+) [7].

Biological context of NMNAT1

• Its subcellular localization and tissue distribution are distinct from the previously identified human nuclear PNAT-1 and PNAT-2 [6].
• Human NMNAT displays unique dual substrate specificity toward both NMN and NaMN, thus flexible in participating in both de novo and salvage pathways of NAD synthesis [7].
• Structure of human NMN adenylyltransferase. A key nuclear enzyme for NAD homeostasis [8].
• NMNAT appears to be a substrate of nuclear kinases and contains at least three potential phosphorylation sites [9].
• Using human genomic databases, hNMNAT-2 was localized to chromosome 1q25 within a 171 kb gene, whereas hNMNAT-1 is on chromosome 1p32-35 [10].

Anatomical context of NMNAT1

• Nicotinamide mononucleotide adenylyltransferase activity in human erythrocytes [11].
• This paper presents data about the presence of the NMN adenylyltransferase at the nuclear matrix level of human placenta nuclei [12].
• The overexpression of Wld(S) delayed the neurite degeneration by vincristine, whereas that of Nmnat1 did not delay it much [3].
• Pyridine nucleotide levels and the activities of enzymes involved in NAD synthesis (nicotinic acid phosphoribosyltransferase, nicotinic acid- and nicotinamide mononucleotide-adenylyltransferase) have been assayed in human normal lymphocytes by an HPLC method using radioactive or nonradioactive substrates [13].
• We generated Wld(S) or Nmnat1-overexpressing Neuro2A cell lines, in which neuronal differentiation including neurite elongation can be induced by retinoic acid [3].

Associations of NMNAT1 with chemical compounds

• The enzyme nicotinamide mononucleotide adenylyltransferase is an ubiquitous enzyme catalyzing an essential step in NAD (NADP) biosynthetic pathway [14].
• We have solved the crystal structures of human NMNAT in complex with NAD, deamido-NAD, and a non-hydrolyzable TAD analogue beta-CH(2)-TAD [7].
• The final step in the biosynthesis of nicotinamide-adenine dinucleotide, a major coenzyme in cellular redox reactions and involved in intracellular signaling, is catalyzed by the enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT) [15].
• NAD analogs modified at the ribose adenylyl moiety, named N-2'-MeAD and Na-2'-MeAD, were synthesized as ligands of pyridine nucleotide (NMN/NaMN) adenylyltransferase (NMNAT) [16].
• Modulation of cytotoxicity of benzamide riboside by expression of NMN adenylyltransferase [17].

Other interactions of NMNAT1

• NMNAT strongly inhibited recombinant human poly(ADP-ribose) polymerase 1, however, NMNAT was not modified by poly(ADP-ribose) [9].
• HSP-90 and Nmnat 1, however, were higher in Andean controls in all locations [18].
• Resistance to tiazofurin and related IMPDH inhibitors relate mainly to a decrease in NMN adenylyltransferase activity [19].
• Nuclear matrix-associated NMN adenylyltransferase activity in human placenta [12].

Analytical, diagnostic and therapeutic context of NMNAT1

• Molecular cloning, chromosomal localization, tissue mRNA levels, bacterial expression, and enzymatic properties of human NMN adenylyltransferase [20].
• By using a combination of single isomorphous replacement and density modification techniques, the human NMNAT structure was solved by x-ray crystallography to a 2.5-A resolution, revealing a hexamer that is composed of alpha/beta-topology subunits [8].
• Crystallization and preliminary X-ray analysis of human nicotinamide mononucleotide adenylyltransferase (NMNAT) [21].
• Northern blot analysis revealed highly restricted expression of hNMNAT-2 to brain, heart and muscle tissues, which contrasts with the wide tissue expression of hNMNAT-1; different regions of the brain exhibited differential expression of hNMNAT-2 [10].
• Here we report the first demonstration and characterization of NMN-AT in human red blood cells, by an HPLC method [11].

References