NAD salvage pathway II (Escherichia coli)

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1-15NADPphosphatasePhosphateNADPAdenosinetriphosphatenadR5′-nucleotidaseWaterNicotinamide ribotidenudCNADWaterHydrogen IonHydrogen IonAdenosinemonophosphateWaterPhosphateNicotinamideribosideNicotinamide ribotideHydrogen IonADPNADHydrogen IonAdenosinetriphosphatePyrophosphatenadR


This pathway is an NAD salvage pathway which proceeds via the intermediate nicotinamide riboside (N-ribosylnicotinamide, or NR). While the presence of this pathway has been suggested for several organisms including Escherichia coli [Kurnasov02], it is of particular importance to Haemophilus influenzae and other V-factor-dependent members of the Pasteurella family. These organisms lack the enzymes necessary for the de novo synthesis of NAD, as well as most of the enzymes for the more common NAD salvage pathway, and therefore require exogenous NAD supply in the form of one of the V-factor compounds, which include NADP, NAD, NMN, and NR. However, only the non-phosphorylated V factor, NR, can be transported across the inner membrane into the cytoplasm, where it can be converted to NAD and NADP [Kurnasov02]. Thus this pathway is critical for these organisms [MacInnes90].

Since NAD+, which is obtained from extracellular sources, is highly polar, it has to be hydrolyzed before it can be transported across the cytoplasmic membrane for final uptake. A key enzyme in this pathway is a periplasmic protein that hydrolyzes NAD+ to nicotinamide mononucleotide (NMN), and hydrolyzes NMN to nicotinamide riboside (NR) [Kemmer01]. The nicotinamide riboside thus formed is transported across the inner membrane into the cytoplasm, where it is it is converted back to NMN, and eventually, to NAD+.

The identity of the NR transporter has not been confirmed experimentally, but it is suggested that it is encoded by the pnuC gene, although earlier work with the PnuC protein of Salmonella enterica serovar Typhimurium suggested that it encodes the transport of NMN [Liu82, Kemmer01].

NADP+ is recycled in the same manner, following dephosphorylation to NAD+. In H. influenzae, this dephosphorylation is performed by the outer membrane glycoprotein e (P4), encoded by the hel gene.

While the pathway is predicted to be present in Enterobacteriaceae, it probably serves a minor role compared to de novo biosynthesis and the main NAD salvage cycle (NAD salvage pathway I). Some of the enzymatic activities associated with this pathway have been described in Enterobacteriaceae as early as 1951 [Rowen51], but it was only recently that the genes responsible for them were identified. Surprisingly, several activities were found to be functions of the multifunctional protein NadR, which was initially believed to have a role in regulation only [Raffaelli99, Kurnasov02].



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  1. Ostrowski EA, Woods RJ, Lenski RE; ''The genetic basis of parallel and divergent phenotypic responses in evolving populations of Escherichia coli.''; Proc Biol Sci, 2008 PubMed Europe PMC Scholia
  2. Kemmer G, Reilly TJ, Schmidt-Brauns J, Zlotnik GW, Green BA, Fiske MJ, Herbert M, Kraiss A, Schlör S, Smith A, Reidl J; ''NadN and e (P4) are essential for utilization of NAD and nicotinamide mononucleotide but not nicotinamide riboside in Haemophilus influenzae.''; J Bacteriol, 2001 PubMed Europe PMC Scholia
  3. Liu G, Foster J, Manlapaz-Ramos P, Olivera BM; ''Nucleoside salvage pathway for NAD biosynthesis in Salmonella typhimurium.''; J Bacteriol, 1982 PubMed Europe PMC Scholia
  4. MacInnes JI, Borr JD; ''The family Pasteurellaceae: modern approaches to taxonomy.''; Can J Vet Res, 1990 PubMed Europe PMC Scholia
  5. Lin SJ, Ford E, Haigis M, Liszt G, Guarente L; ''Calorie restriction extends yeast life span by lowering the level of NADH.''; Genes Dev, 2004 PubMed Europe PMC Scholia
  6. Kawai S, Murata K; ''Structure and function of NAD kinase and NADP phosphatase: key enzymes that regulate the intracellular balance of NAD(H) and NADP(H).''; Biosci Biotechnol Biochem, 2008 PubMed Europe PMC Scholia
  7. Lundquist R, Olivera BM; ''Pyridine nucleotide metabolism in Escherichia coli. I. Exponential growth.''; J Biol Chem, 1971 PubMed Europe PMC Scholia
  8. Raffaelli N, Lorenzi T, Mariani PL, Emanuelli M, Amici A, Ruggieri S, Magni G; ''The Escherichia coli NadR regulator is endowed with nicotinamide mononucleotide adenylyltransferase activity.''; J Bacteriol, 1999 PubMed Europe PMC Scholia
  9. Lin SJ, Guarente L; ''Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease.''; Curr Opin Cell Biol, 2003 PubMed Europe PMC Scholia
  10. Commichau FM, Stülke J; ''Trigger enzymes: bifunctional proteins active in metabolism and in controlling gene expression.''; Mol Microbiol, 2008 PubMed Europe PMC Scholia
  11. Tritz GJ, Chandler JL; ''Recognition of a gene involved in the regulation of nicotinamide adenine dinucleotide biosynthesis.''; J Bacteriol, 1973 PubMed Europe PMC Scholia
  12. Fukuda C, Kawai S, Murata K; ''NADP(H) phosphatase activities of archaeal inositol monophosphatase and eubacterial 3'-phosphoadenosine 5'-phosphate phosphatase.''; Appl Environ Microbiol, 2007 PubMed Europe PMC Scholia
  13. Gerasimova AV, Gelfand MS; ''Evolution of the NadR regulon in Enterobacteriaceae.''; J Bioinform Comput Biol, 2005 PubMed Europe PMC Scholia
  14. ROWEN JW, KORNBERG A; ''The phosphorolysis of nicotinamide riboside.''; J Biol Chem, 1951 PubMed Europe PMC Scholia
  15. Kurnasov OV, Polanuyer BM, Ananta S, Sloutsky R, Tam A, Gerdes SY, Osterman AL; ''Ribosylnicotinamide kinase domain of NadR protein: identification and implications in NAD biosynthesis.''; J Bacteriol, 2002 PubMed Europe PMC Scholia


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106100view12:00, 16 August 2019MaintBotHMDB identifier normalization
71964view23:56, 23 October 2013MaintBotremoved data source from nodes without identifier
62864view10:28, 3 May 2013CizarModified description
62650view07:41, 1 May 2013CizarSpecify description
62649view07:41, 1 May 2013CizarSpecify description
62648view07:40, 1 May 2013CizarSpecify description
62647view07:40, 1 May 2013CizarSpecify description
62267view22:22, 26 April 2013AlexanderPicoOntology Term : 'pyridine nucleotide biosynthetic pathway' added !
62266view22:21, 26 April 2013AlexanderPicoOntology Term : 'purine salvage pathway' added !
62249view21:49, 26 April 2013AlexanderPicoOntology Term : 'NAD biosynthetic pathway' added !
62246view21:45, 26 April 2013AlexanderPicoModified categories
62005view09:43, 23 April 2013CizarRecorrected a gene
62004view09:37, 23 April 2013Cizaradded and corrected some annotations
61953view07:39, 22 April 2013CizarGrouped metabolites and aligned them
61801view10:22, 19 April 2013CizarModified description
61800view10:04, 19 April 2013Cizaradded references
61796view09:51, 19 April 2013CizarNew pathway

External references


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NameTypeDatabase referenceComment
ADPMetaboliteHMDB0001341 (HMDB)
Adenosine monophosphateMetaboliteHMDB0000045 (HMDB)
Adenosine triphosphateMetaboliteHMDB0000538 (HMDB)
Hydrogen IonMetaboliteHMDB0059597 (HMDB)
NADMetaboliteHMDB0000902 (HMDB)
NADP phosphataseGeneProduct
NADPMetaboliteHMDB0000217 (HMDB)
Nicotinamide ribosideMetaboliteHMDB0000855 (HMDB)
Nicotinamide ribotideMetaboliteHMDB0000229 (HMDB)
PhosphateMetaboliteHMDB0001429 (HMDB)
PyrophosphateMetaboliteHMDB0000250 (HMDB)
WaterMetaboliteHMDB0002111 (HMDB)
nadRGeneProductEBESCG00000001171 (Ensembl)
nudCGeneProductEBESCG00000003522 (Ensembl)

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