Nicotinamide-nucleotide adenylyltransferase explained

nicotinamide-nucleotide adenylyltransferase
Ec Number:	2.7.7.1
Cas Number:	9032-70-6
Go Code:	0000309
Width:	270

In enzymology, nicotinamide-nucleotide adenylyltransferase (NMNAT) are enzymes that catalyzes the chemical reaction

ATP + nicotinamide mononucleotide

\rightleftharpoons diphosphate + NAD⁺

Thus, the two substrates of this enzyme are ATP and nicotinamide mononucleotide (NMN), whereas its two products are diphosphate and NAD⁺.

This enzyme participates in nicotinate and nicotinamide metabolism.

Humans have three protein isoforms: NMNAT1 (widespread), NMNAT2 (predominantly in brain), and NMNAT3 (highest in liver, heart, skeletal muscle, and erythrocytes).^[1] Mutations in the NMNAT1 gene lead to the LCA9 form of Leber congenital amaurosis. Mutations in NMNAT2 or NMNAT3 genes are not known to cause any human disease. NMNAT2 is critical for neurons: loss of NMNAT2 is associated with neurodegeneration. All NMNAT isoforms reportedly decline with age.^[2]

Belongs to

This enzyme belongs to the family of transferases, specifically those transferring phosphorus-containing nucleotide groups (nucleotidyltransferases). The systematic name of this enzyme class is ATP:nicotinamide-nucleotide adenylyltransferase. Other names in common use include NAD+ pyrophosphorylase, adenosine triphosphate-nicotinamide mononucleotide transadenylase, ATP:NMN adenylyltransferase, diphosphopyridine nucleotide pyrophosphorylase, nicotinamide adenine dinucleotide pyrophosphorylase, nicotinamide mononucleotide adenylyltransferase, and NMN adenylyltransferase.

Structural studies

As of late 2007, 11 structures have been solved for this class of enzymes, with PDB accession codes,,,,,,,,,, and .

Isoform cellular localization

The three protein isoforms have the following cellular localizations^[3]

• NMNAT1 : Nucleus
• NMNAT2 : Cytoplasm
• NMNAT3 : Mitochondrion or cytoplasm

All three NMNATs compete for the NMN produced by NAMPT.^[4]

Clinical significance

Chronic inflammation due to obesity and other causes reduced NMNAT and NAD+ levels in many tissues.^[5]

References

• ATKINSON MR, JACKSON JF, MORTON RK . 1961 . Nicotinamide mononucleotide adenylyltransferase of pig-liver nuclei. The effects of nicotinamide mononucleotide concentration and pH on dinucleotide synthesis . Biochem. J. . 80 . 318 - 23 . 13684981 . 1244001 . 2 . 10.1042/bj0800318 .
• Dahmen W, Webb B, Preiss J . 1967 . The deamido-diphosphopyridine nucleotide and diphosphopyridine nucleotide pyrophosphorylases of Escherichia coli and yeast . Arch. Biochem. Biophys. . 120 . 440 - 50 . 4291828 . 10.1016/0003-9861(67)90262-7 . 2 .
• Kornberg A . Pricer WE . 1951 . Enzymatic cleavage of diphosphopyridine nucleotide with radioactive pyrophosphate . J. Biol. Chem. . 191 . 535 - 541 . 14861199 . 2. 10.1016/S0021-9258(18)55958-5 . free .

Notes and References

1. Brazill JM, Li C, Zhu Y, Zhai RG . NMNAT: It's an NAD + Synthase… It's a Chaperone… It's a Neuroprotector . . 44 . 156–162 . 2017 . 10.1016/j.gde.2017.03.014 . 5515290 . 28445802.
2. McReynolds MR, Chellappa L, Baur JA . 211237873 . Age-related NAD + Decline . Experimental Gerontology . 134 . 110888 . 2020 . 10.1016/j.exger.2020.110888 . 32097708. 7442590 .
3. Rajman L, Chwalek K, Sinclair DA . Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence . . 27 . 3 . 529–547 . 2018 . 10.1016/j.cmet.2018.02.011 . 6342515 . 29514064.
4. Hurtado-Bagès S, Knobloch G, Ladurner AG, Buschbeck M . The taming of PARP1 and its impact on NAD + metabolisme . . 38 . 100950 . 2020 . 10.1016/j.molmet.2020.01.014 . 7300387 . 32199820.
5. Yaku K, Okabe K, Nakagawa T . NAD metabolism: Implications in aging and longevity . . 47 . 1–17 . 2018 . 10.1016/j.arr.2018.05.006 . 29883761. 47002665 .