Updated BioCyc iOS App now
available in iTunes store
Updated BioCyc iOS App now
available in iTunes store
Updated BioCyc iOS App now
available in iTunes store
Updated BioCyc iOS App now
available in iTunes store
Updated BioCyc iOS App now
available in iTunes store

MetaCyc Pathway: NAD salvage pathway I
Traceable author statement to experimental support

Enzyme View:

Pathway diagram: NAD salvage pathway I

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: pyridine nucleotide cycling, PNC pathway, nicotinamide adenine dinucleotide salvage

Superclasses: BiosynthesisCofactors, Prosthetic Groups, Electron Carriers BiosynthesisNAD MetabolismNAD Biosynthesis

Some taxa known to possess this pathway include : Escherichia coli K-12 substr. MG1655, Saccharomyces cerevisiae, Salmonella enterica enterica serovar Typhimurium

Expected Taxonomic Range: Bacteria , Fungi

General Background

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 [Lin03a, 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

Even though NAD molecules are not consumed during oxidation reactions, they have a relatively short half-life. For example, in Escherichia coli the NAD+ half-life is 90 minutes. Once enzymatically degraded, the pyrimidine moiety of the molecule can be recouped via the NAD salvage cycles. This pathway is used for two purposes: it recycles the internally degraded NAD products nicotinamide D-ribonucleotide (also known as nicotinamide mononucleotide, or NMN) and nicotinamide, and it is used for the assimilation of exogenous NAD+.

Since the NAD+ molecule is highly polar, it has to be hydrolyzed before it can be transported across the cytoplasmic membrane for final uptake. It does seem to be able to penetrate the external membrane, though, as the enzymes that break it down are found in the periplasm [Park88b]. NAD+ is first hydrolyzed by NAD pyrophosphatase into NMN , which can be hydrolyzed further to nicotinamide by NMN nucleosidase. Both enzymes are periplasmic. Both NMN and nicotinamide can be transported across the inner membrane into the cytoplasm. Once there, nicotinamide is converted via nicotinate to nicotinate nucleotide, at which point the pathway merges with the de novo biosynthesis pathway, and continues to NAD via deamido-NAD.

There are several flavors of the salvage pathway found in different organisms, and even within the same organism. The one described above contains 6 reaction steps, and is often referred to as the PNC VI pathway, for Pyridine Nucleotide Cycling. However, there are also a four-step cycle and a five-step cycle, termed PNC IV and V, respectively [Foster79, Foster80]. In the PNC IV cycle, the enzyme NMN amidohydrolase (also called NMN deamidase) converts NMN (which can be transported across the inner membrane in Enterobacteria) directly to nicotinate nucleotide, bypassing the enzymes nicotinamidase (PncA) and nicotine phosphoribosyl transferase (PncB), which are members of the PNC VI cycle. PNC IV is the major intracellular recycling pathway in Escherichia coli [Hillyard81], while PNC VI is the major cycle of Salmonella enterica enterica serovar Typhimurium [Foster80] and yeast [Panozzo02, Anderson02].

Superpathways: superpathway of NAD biosynthesis in eukaryotes

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 II, NAD salvage pathway III

Unification Links: EcoCyc:PYRIDNUCSAL-PWY

Created 27-Apr-2005 by Hong E, Saccharomyces Genome Database
Revised 09-May-2005 by Caspi R, SRI International


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

Foster79: Foster JW, Kinney DM, Moat AG (1979). "Pyridine nucleotide cycle of Salmonella typhimurium: isolation and characterization of pncA, pncB, and pncC mutants and utilization of exogenous nicotinamide adenine dinucleotide." J Bacteriol 137(3);1165-75. PMID: 220211

Foster80: Foster JW, Baskowsky-Foster AM (1980). "Pyridine nucleotide cycle of Salmonella typhimurium: in vivo recycling of nicotinamide adenine dinucleotide." J Bacteriol 142(3);1032-5. PMID: 6445894

Hillyard81: Hillyard D, Rechsteiner M, Manlapaz-Ramos P, Imperial JS, Cruz LJ, Olivera BM (1981). "The pyridine nucleotide cycle. Studies in Escherichia coli and the human cell line D98/AH2." J Biol Chem 1981;256(16);8491-7. PMID: 7021549

Lin03a: Lin SJ, Guarente L (2003). "Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease." Curr Opin Cell Biol 15(2);241-6. PMID: 12648681

Lin04: Lin SJ, Ford E, Haigis M, Liszt G, Guarente L (2004). "Calorie restriction extends yeast life span by lowering the level of NADH." Genes Dev 18(1);12-6. PMID: 14724176

Panozzo02: Panozzo C, Nawara M, Suski C, Kucharczyka R, Skoneczny M, Becam AM, Rytka J, Herbert CJ (2002). "Aerobic and anaerobic NAD+ metabolism in Saccharomyces cerevisiae." FEBS Lett 517(1-3);97-102. PMID: 12062417

Park88b: Park UE, Roth JR, Olivera BM (1988). "Salmonella typhimurium mutants lacking NAD pyrophosphatase." J Bacteriol 170(8);3725-30. PMID: 2841298

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Allibert87: Allibert P, Willison JC, Vignais PM (1987). "Complementation of nitrogen-regulatory (ntr-like) mutations in Rhodobacter capsulatus by an Escherichia coli gene: cloning and sequencing of the gene and characterization of the gene product." J Bacteriol 169(1);260-71. PMID: 3025172

Andreoli69: Andreoli AJ, Grover T, Gholson RK, Matney TS (1969). "Evidence for a functional pyridine nucleotide cycle in Escherichia coli." Biochim Biophys Acta 192(3);539-41. PMID: 4312778

Baecker78: Baecker PA, Yung SG, Rodriguez M, Austin E, Andreoli AJ (1978). "Periplasmic localization of nicotinate phosphoribosyltransferase in Escherichia coli." J Bacteriol 1978;133(3);1108-12. PMID: 346557

Bork94: Bork P, Koonin EV (1994). "A P-loop-like motif in a widespread ATP pyrophosphatase domain: implications for the evolution of sequence motifs and enzyme activity." Proteins 20(4);347-55. PMID: 7731953

BRENDA14: BRENDA team (2014). Imported from BRENDA version existing on Aug 2014.

Dahmen67: Dahmen W, Webb B, Preiss J (1967). "The deamido-diphosphopyridine nucleotide and diphosphopyridine nucleotide pyrophosphorylases of Escherichia coli and yeast." Arch Biochem Biophys 1967;120(2);440-50. PMID: 4291828

De09: De Lay N, Gottesman S (2009). "The Crp-activated small noncoding regulatory RNA CyaR (RyeE) links nutritional status to group behavior." J Bacteriol 191(2);461-76. PMID: 18978044

DiazMejia09: Diaz-Mejia JJ, Babu M, Emili A (2009). "Computational and experimental approaches to chart the Escherichia coli cell-envelope-associated proteome and interactome." FEMS Microbiol Rev 33(1);66-97. PMID: 19054114

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

Galeazzi11: Galeazzi L, Bocci P, Amici A, Brunetti L, Ruggieri S, Romine M, Reed S, Osterman AL, Rodionov DA, Sorci L, Raffaelli N (2011). "Identification of nicotinamide mononucleotide deamidase of the bacterial pyridine nucleotide cycle reveals a novel broadly conserved amidohydrolase family." J Biol Chem 286(46);40365-75. PMID: 21953451

Gaudet10: Gaudet P, Livstone M, Thomas P (2010). "Annotation inferences using phylogenetic trees." PMID: 19578431

Gerdes02: Gerdes SY, Scholle MD, D'Souza M, Bernal A, Baev MV, Farrell M, Kurnasov OV, Daugherty MD, Mseeh F, Polanuyer BM, Campbell JW, Anantha S, Shatalin KY, Chowdhury SA, Fonstein MY, Osterman AL (2002). "From genetic footprinting to antimicrobial drug targets: examples in cofactor biosynthetic pathways." J Bacteriol 184(16);4555-72. PMID: 12142426

GOA01: GOA, MGI (2001). "Gene Ontology annotation based on Enzyme Commission mapping." Genomics 74;121-128.

GOA01a: GOA, DDB, FB, MGI, ZFIN (2001). "Gene Ontology annotation through association of InterPro records with GO terms."

GOA06: GOA, SIB (2006). "Electronic Gene Ontology annotations created by transferring manual GO annotations between orthologous microbial proteins."

Hara03a: Hara N, Yamada K, Terashima M, Osago H, Shimoyama M, Tsuchiya M (2003). "Molecular identification of human glutamine- and ammonia-dependent NAD synthetases. Carbon-nitrogen hydrolase domain confers glutamine dependency." J Biol Chem 278(13);10914-21. PMID: 12547821

Imsande61: Imsande J (1961). "Pathway of diphosphopyridine nucleotide biosynthesis in Escherichia coli." J Biol Chem 1961;236(5):1494-1497. PMID: 13717628

Imsande62: Imsande J, Pardee AB (1962). "Regulation of pyridine nucleotide biosynthesis in Escherichia coli." J Biol Chem 237(4):1305-8.

Isaksson78: Isaksson LA, Takata R (1978). "The temperature sensitive mutant 72c. I. Pleiotropic growth behaviour and changed response to some antibiotics and mutations in the transcription or translation apparatus." Mol Gen Genet 161(1);9-14. PMID: 353503

Showing only 20 references. To show more, press the button "Show all references".

Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by Pathway Tools version 19.5 (software by SRI International) on Mon May 2, 2016, biocyc14.