If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Locations of Mapped Genes:
Synonyms: pyridine nucleotide cycling, PNC pathway, nicotinamide adenine dinucleotide salvage
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → NAD Metabolism → NAD Biosynthesis|
Even though NAD molecules are not consumed during oxidation reactions, they have a relatively short half-life. For example, in E. 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 [Park88]. 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 E. coli [Hillyard81], while PNC VI is the major cycle of Salmonella typhimurium [Foster80].
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
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
Andreoli72: Andreoli AJ, Okita TW, Bloom R, Grover TA (1972). "The pyridine nucleotide cycle: presence of a nicotinamide mononucleotide-specific glycohydrolase in Escherichia coli." Biochem Biophys Res Commun 1972;49(1);264-9. PMID: 4342726
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
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
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
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
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
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
Jauch05: Jauch R, Humm A, Huber R, Wahl MC (2005). "Structures of Escherichia coli NAD synthetase with substrates and products reveal mechanistic rearrangements." J Biol Chem 280(15);15131-40. PMID: 15699042
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