Nicotinamide-nucleotide adenylyltransferase
| Nicotinamide-nucleotide adenylyltransferase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 Nicotinamide-nucleotide adenylyltransferase (nuclear) hexamer, Human | |||||||||
| Identifiers | |||||||||
| EC no. | 2.7.7.1 | ||||||||
| CAS no. | 9032-70-6 | ||||||||
| Databases | |||||||||
| BRENDA | enzyme data | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | enzyme entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| Rhea | reactions | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
| |||||||||
Nicotinamide-nucleotide adenylyltransferase (NMNAT) (EC 2.7.7.1) is an enzyme that catalyzes the reversible chemical reaction that produces nicotinamide adenine dinucleotide from adenosine triphosphate and nicotinamide mononucleotide.
Function
Nicotinamide adenine dinucleotide, is a coenzyme found in all cells.[1] It is produced by nicotinamide-nucleotide adenylyltransferase, which combines adenosine triphosphate and nicotinamide mononucleotide, with inorganic pyrophosphate (PPi) produced as a byproduct:
The enzyme has been characterised from mammalian liver, Escherichia coli and yeast.[2][3][4]
Humans have three protein isoforms: NMNAT1 (widespread), NMNAT2 (predominantly in brain), and NMNAT3 (highest in liver, heart, skeletal muscle, and erythrocytes).[5] Mutations in the NMNAT1 gene lead to the LCA9 form of Leber congenital amaurosis.[5] Mutations in NMNAT2 or NMNAT3 genes are not known to cause any human disease.[5] NMNAT2 is critical for neurons: loss of NMNAT2 is associated with neurodegeneration.[5] All NMNAT isoforms reportedly decline with age.[6]
Isoform cellular localization
The three protein isoforms have the following cellular localizations[7]
- NMNAT1 : Nucleus
- NMNAT2 : Cytoplasm
- NMNAT3 : Mitochondrion or cytoplasm
All three NMNATs compete for the nicotinamide mononucleotide produced by nicotinamide phosphoribosyltransferase.[8]
Nomenclature
This enzyme is a transferases, specifically one 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.[9]
Structural studies
As of late 2007, 11 structures have been solved for this class of enzymes, with PDB accession codes PDB: 1EJ2, PDB: 1GZU, PDB: 1HYB, PDB: 1KKU, PDB: 1KQN, PDB: 1KQO, PDB: 1KR2, PDB: 1M8F, PDB: 1M8G, PDB: 1M8J, and PDB: 1M8K.
Clinical significance
Chronic inflammation due to obesity and other causes reduced NMNAT and NAD+ levels in many tissues.[10]
References
- ↑ Nelson, David L.; Cox, Michael M. (2005). Principles of Biochemistry (4th ed.). New York: W. H. Freeman. ISBN 0-7167-4339-6.
- ↑ 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 (2): 318–23. doi:10.1042/bj0800318. PMC 1244001. PMID 13684981.
- ↑ Dahmen W, Webb B, Preiss J (1967). "The deamido-diphosphopyridine nucleotide and diphosphopyridine nucleotide pyrophosphorylases of Escherichia coli and yeast". Arch. Biochem. Biophys. 120 (2): 440–50. doi:10.1016/0003-9861(67)90262-7. PMID 4291828.
- ↑ Kornberg A; Pricer WE (1951). "Enzymatic cleavage of diphosphopyridine nucleotide with radioactive pyrophosphate". J. Biol. Chem. 191 (2): 535–541. doi:10.1016/S0021-9258(18)55958-5. PMID 14861199.
- 1 2 3 4 Brazill JM, Li C, Zhu Y, Zhai RG (2017). "NMNAT: It's an NAD + Synthase... It's a Chaperone... It's a Neuroprotector". Current Opinion in Genetics & Development. 44: 156–162. doi:10.1016/j.gde.2017.03.014. PMC 5515290. PMID 28445802.
- ↑ McReynolds MR, Chellappa L, Baur JA (2020). "Age-related NAD + Decline". Experimental Gerontology. 134 110888. doi:10.1016/j.exger.2020.110888. PMC 7442590. PMID 32097708. S2CID 211237873.
- ↑ Rajman L, Chwalek K, Sinclair DA (2018). "Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence". Cell Metabolism. 27 (3): 529–547. doi:10.1016/j.cmet.2018.02.011. PMC 6342515. PMID 29514064.
- ↑ Hurtado-Bagès S, Knobloch G, Ladurner AG, Buschbeck M (2020). "The taming of PARP1 and its impact on NAD + metabolisme". Molecular Metabolism. 38 100950. doi:10.1016/j.molmet.2020.01.014. PMC 7300387. PMID 32199820.
- ↑ Enzyme 2.7.7.1 at KEGG Pathway Database.
- ↑ Yaku K, Okabe K, Nakagawa T (2018). "NAD metabolism: Implications in aging and longevity". Ageing Research Reviews. 47: 1–17. doi:10.1016/j.arr.2018.05.006. PMID 29883761. S2CID 47002665.