This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Synonyms: nicotinamide riboside salvage pathway, nicotinamide adenine dinucleotide salvage
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → NAD Metabolism → NAD Biosynthesis|
Nicotinamide adenine dinucleotide (NAD) and its phosphorylated derivative, nicotinamide adenine dinucleotide phosphate (NADP) are two of the most important coenzymes in redox reactions in the cell. Generally, NAD is involved in catabolic reactions, while NADP is involved in anabolic reactions. Because of the positive charge on the nitrogen atom in the nicotinamide ring, the oxidized forms of these compounds are often depicted as NAD+ and NADP+, respectively.
Most oxidation reactions in cells are accomplished by the removal of hydrogen atoms. In reactions where NAD or NADP participate, two hydrogen atoms are typically removed from the substrate. During the reduction of NAD+ (or NADP+) the molecule acquires two electrons and one proton, while the second proton is released into the medium. Thus a typical reaction involving NAD is in the form:
NAD+ + 2H -> NADH + H+
Additional roles for NAD in the cell have been suggested, including involvement in transcriptional regulation, longevity, and age-associated diseases. In yeast, it has been shown that NAD affects longevity and transcriptional silencing through the regulation of the Sir2p family of NAD-dependent deacetylases [Lin03, Lin04].
NAD is synthesised via two major pathways in both prokaryotic and eukaryotic systems; the de novo pathway, and the salvage pathway. In the prokaryotic de novo pathway, the nicotinate moiety of NAD is synthesized from aspartate (see NAD biosynthesis I (from aspartate), while in eukaryotes the de novo pathway starts with tryptophan (NAD biosynthesis II (from tryptophan)).
About This Pathway
In addition to de novo synthesis of NAD (NAD biosynthesis II (from tryptophan)) and regeneration from nicotinamide degradation products and extracellular nicotinate (NAD salvage pathway I), yeast posseses an additional route for synthesizing NAD, called the nicotinamide riboside salvage pathway [Bieganowski04]. In this pathway 1-(β-D ribofuranosyl)nicotinamide is converted to β-nicotinamide D-ribonucleotide and subsequently to NAD+, in reactions catalyzed by the enzymes nicotinamide riboside kinase and nicotinamide mononucleotide adenylyltransferase [Bieganowski04].
Bacteria that lack the enzymes for de novo NAD biosynthesis are able to convert extracellular NAD to less polar degradation products, which are then imported into the cell and processed back to NAD via 1-(β-D ribofuranosyl)nicotinamide (see NAD salvage pathway II) [Bieganowski04]. However, the genes that those bacteria utilize to convert the extracellular NAD into 1-(β-D ribofuranosyl)nicotinamide have not been identified in fungi or animals, which may have only the later part of the pathway, as described here [Bieganowski04].
Superpathways: NAD salvage pathway II
Variants: NAD biosynthesis from 2-amino-3-carboxymuconate semialdehyde , NAD biosynthesis I (from aspartate) , NAD biosynthesis II (from tryptophan) , NAD biosynthesis III , NAD salvage pathway I , superpathway of NAD biosynthesis in eukaryotes
Unification Links: EcoCyc:PWY3O-4106
Bieganowski04: Bieganowski P, Brenner C (2004). "Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans." Cell 117(4);495-502. PMID: 15137942
Anderson02: Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Cohen H, Lin SS, Manchester JK, Gordon JI, Sinclair DA (2002). "Manipulation of a nuclear NAD+ salvage pathway delays aging without altering steady-state NAD+ levels." J Biol Chem 277(21);18881-90. PMID: 11884393
Balducci92: Balducci E, Emanuelli M, Magni G, Raffaelli N, Ruggieri S, Vita A, Natalini P (1992). "Nuclear matrix-associated NMN adenylyltransferase activity in human placenta." Biochem Biophys Res Commun 189(3);1275-9. PMID: 1282798
Berger05: Berger F, Lau C, Dahlmann M, Ziegler M (2005). "Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms." J Biol Chem 280(43);36334-41. PMID: 16118205
Emanuelli01: Emanuelli M, Carnevali F, Saccucci F, Pierella F, Amici A, Raffaelli N, Magni G (2001). "Molecular cloning, chromosomal localization, tissue mRNA levels, bacterial expression, and enzymatic properties of human NMN adenylyltransferase." J Biol Chem 276(1);406-12. PMID: 11027696
Emanuelli99: Emanuelli M, Carnevali F, Lorenzi M, Raffaelli N, Amici A, Ruggieri S, Magni G (1999). "Identification and characterization of YLR328W, the Saccharomyces cerevisiae structural gene encoding NMN adenylyltransferase. Expression and characterization of the recombinant enzyme." FEBS Lett 455(1-2);13-7. PMID: 10428462
Garavaglia02: Garavaglia S, D'Angelo I, Emanuelli M, Carnevali F, Pierella F, Magni G, Rizzi M (2002). "Structure of human NMN adenylyltransferase. A key nuclear enzyme for NAD homeostasis." J Biol Chem 277(10);8524-30. PMID: 11751893
Kurnasov02: Kurnasov OV, Polanuyer BM, Ananta S, Sloutsky R, Tam A, Gerdes SY, Osterman AL (2002). "Ribosylnicotinamide kinase domain of NadR protein: identification and implications in NAD biosynthesis." J Bacteriol 184(24);6906-17. PMID: 12446641
Natalini86: Natalini P, Ruggieri S, Raffaelli N, Magni G (1986). "Nicotinamide mononucleotide adenylyltransferase. Molecular and enzymatic properties of the homogeneous enzyme from baker's yeast." Biochemistry 25(12);3725-9. PMID: 3013296
Raffaelli02: Raffaelli N, Sorci L, Amici A, Emanuelli M, Mazzola F, Magni G (2002). "Identification of a novel human nicotinamide mononucleotide adenylyltransferase." Biochem Biophys Res Commun 297(4);835-40. PMID: 12359228
Raffaelli97: Raffaelli N, Pisani FM, Lorenzi T, Emanuelli M, Amici A, Ruggieri S, Magni G (1997). "Characterization of nicotinamide mononucleotide adenylyltransferase from thermophilic archaea." J Bacteriol 179(24);7718-23. PMID: 9401030
Raffaelli99: Raffaelli N, Lorenzi T, Mariani PL, Emanuelli M, Amici A, Ruggieri S, Magni G (1999). "The Escherichia coli NadR regulator is endowed with nicotinamide mononucleotide adenylyltransferase activity." J Bacteriol 1999;181(17);5509-11. PMID: 10464228
Raffaelli99a: Raffaelli N, Lorenzi T, Amici A, Emanuelli M, Ruggieri S, Magni G (1999). "Synechocystis sp. slr0787 protein is a novel bifunctional enzyme endowed with both nicotinamide mononucleotide adenylyltransferase and 'Nudix' hydrolase activities." FEBS Lett 444(2-3);222-6. PMID: 10050763
Schweiger01: Schweiger M, Hennig K, Lerner F, Niere M, Hirsch-Kauffmann M, Specht T, Weise C, Oei SL, Ziegler M (2001). "Characterization of recombinant human nicotinamide mononucleotide adenylyl transferase (NMNAT), a nuclear enzyme essential for NAD synthesis." FEBS Lett 492(1-2);95-100. PMID: 11248244
Sorci07: Sorci L, Cimadamore F, Scotti S, Petrelli R, Cappellacci L, Franchetti P, Orsomando G, Magni G (2007). "Initial-rate kinetics of human NMN-adenylyltransferases: substrate and metal ion specificity, inhibition by products and multisubstrate analogues, and isozyme contributions to NAD+ biosynthesis." Biochemistry 46(16);4912-22. PMID: 17402747
Werner02: Werner E, Ziegler M, Lerner F, Schweiger M, Heinemann U (2002). "Crystal structure of human nicotinamide mononucleotide adenylyltransferase in complex with NMN." FEBS Lett 516(1-3);239-44. PMID: 11959140
Zhang03: Zhang X, Kurnasov OV, Karthikeyan S, Grishin NV, Osterman AL, Zhang H (2003). "Structural characterization of a human cytosolic NMN/NaMN adenylyltransferase and implication in human NAD biosynthesis." J Biol Chem 278(15);13503-11. PMID: 12574164
Zhou02: Zhou T, Kurnasov O, Tomchick DR, Binns DD, Grishin NV, Marquez VE, Osterman AL, Zhang H (2002). "Structure of human nicotinamide/nicotinic acid mononucleotide adenylyltransferase. Basis for the dual substrate specificity and activation of the oncolytic agent tiazofurin." J Biol Chem 277(15);13148-54. PMID: 11788603
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