NAD salvage pathway II (WP2487)

Escherichia coli

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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].

Authors

Cizar and Alex Pico

Activity

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Organisms

Escherichia coli

Communities

Annotations

Pathway Ontology

pyridine nucleotide biosynthetic pathway purine salvage pathway nicotinamide adenine dinucleotide biosynthetic pathway

Participants

Label Type Compact URI Comment
Phosphate Metabolite hmdb:HMDB0001429
Water Metabolite hmdb:HMDB0002111
Adenosinetriphosphate Metabolite hmdb:HMDB0000538
NADP Metabolite hmdb:HMDB0000217
Nicotinamide ribotide Metabolite hmdb:HMDB0000229
NAD Metabolite hmdb:HMDB0000902
Water Metabolite hmdb:HMDB0002111
Hydrogen Ion Metabolite hmdb:HMDB0059597
Hydrogen Ion Metabolite hmdb:HMDB0059597
Adenosinemonophosphate Metabolite hmdb:HMDB0000045
Water Metabolite hmdb:HMDB0002111
Phosphate Metabolite hmdb:HMDB0001429
Nicotinamideriboside Metabolite hmdb:HMDB0000855
Nicotinamide ribotide Metabolite hmdb:HMDB0000229
Hydrogen Ion Metabolite hmdb:HMDB0059597
ADP Metabolite hmdb:HMDB0001341
NAD Metabolite hmdb:HMDB0000902
Hydrogen Ion Metabolite hmdb:HMDB0059597
Adenosinetriphosphate Metabolite hmdb:HMDB0000538
Pyrophosphate Metabolite hmdb:HMDB0000250
nadR GeneProduct ensembl:EBESCG00000001171
nudC GeneProduct ensembl:EBESCG00000003522
nadR GeneProduct ensembl:EBESCG00000001171

References

  1. The family Pasteurellaceae: modern approaches to taxonomy. MacInnes JI, Borr JD. Can J Vet Res. 1990 Apr;54 Suppl:S6-11. PubMed Europe PMC Scholia
  2. Recognition of a gene involved in the regulation of nicotinamide adenine dinucleotide biosynthesis. Tritz GJ, Chandler JL. J Bacteriol. 1973 Apr;114(1):128–36. PubMed Europe PMC Scholia
  3. Pyridine nucleotide metabolism in Escherichia coli. I. Exponential growth. Lundquist R, Olivera BM. J Biol Chem. 1971 Feb 25;246(4):1107–16. PubMed Europe PMC Scholia
  4. Nucleoside salvage pathway for NAD biosynthesis in Salmonella typhimurium. Liu G, Foster J, Manlapaz-Ramos P, Olivera BM. J Bacteriol. 1982 Dec;152(3):1111–6. PubMed Europe PMC Scholia
  5. The Escherichia coli NadR regulator is endowed with nicotinamide mononucleotide adenylyltransferase activity. Raffaelli N, Lorenzi T, Mariani PL, Emanuelli M, Amici A, Ruggieri S, et al. J Bacteriol. 1999 Sep;181(17):5509–11. PubMed Europe PMC Scholia
  6. NadN and e (P4) are essential for utilization of NAD and nicotinamide mononucleotide but not nicotinamide riboside in Haemophilus influenzae. Kemmer G, Reilly TJ, Schmidt-Brauns J, Zlotnik GW, Green BA, Fiske MJ, et al. J Bacteriol. 2001 Jul;183(13):3974–81. PubMed Europe PMC Scholia
  7. Ribosylnicotinamide kinase domain of NadR protein: identification and implications in NAD biosynthesis. Kurnasov OV, Polanuyer BM, Ananta S, Sloutsky R, Tam A, Gerdes SY, et al. J Bacteriol. 2002 Dec;184(24):6906–17. PubMed Europe PMC Scholia
  8. Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease. Lin SJ, Guarente L. Curr Opin Cell Biol. 2003 Apr;15(2):241–6. PubMed Europe PMC Scholia
  9. Calorie restriction extends yeast life span by lowering the level of NADH. Lin SJ, Ford E, Haigis M, Liszt G, Guarente L. Genes Dev. 2004 Jan 1;18(1):12–6. PubMed Europe PMC Scholia
  10. The phosphorolysis of nicotinamide riboside. ROWEN JW, KORNBERG A. J Biol Chem. 1951 Dec;193(2):497–507. PubMed Europe PMC Scholia
  11. Evolution of the NadR regulon in Enterobacteriaceae. Gerasimova AV, Gelfand MS. J Bioinform Comput Biol. 2005 Aug;3(4):1007–19. PubMed Europe PMC Scholia
  12. NADP(H) phosphatase activities of archaeal inositol monophosphatase and eubacterial 3’-phosphoadenosine 5’-phosphate phosphatase. Fukuda C, Kawai S, Murata K. Appl Environ Microbiol. 2007 Sep;73(17):5447–52. PubMed Europe PMC Scholia
  13. The genetic basis of parallel and divergent phenotypic responses in evolving populations of Escherichia coli. Ostrowski EA, Woods RJ, Lenski RE. Proc Biol Sci. 2008 Feb 7;275(1632):277–84. PubMed Europe PMC Scholia
  14. Trigger enzymes: bifunctional proteins active in metabolism and in controlling gene expression. Commichau FM, Stülke J. Mol Microbiol. 2008 Feb;67(4):692–702. PubMed Europe PMC Scholia
  15. Structure and function of NAD kinase and NADP phosphatase: key enzymes that regulate the intracellular balance of NAD(H) and NADP(H). Kawai S, Murata K. Biosci Biotechnol Biochem. 2008 Apr;72(4):919–30. PubMed Europe PMC Scholia