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MetaCyc Pathway: NAD biosynthesis I (from aspartate)
Inferred from experimentTraceable author statement to experimental support

Enzyme View:

Pathway diagram: NAD biosynthesis I (from aspartate)

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 adenine dinucleotide biosynthesis

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

Some taxa known to possess this pathway include : Arabidopsis thaliana col, Bacillus cereus, Bacillus subtilis, Cupriavidus metallidurans CH34, Escherichia coli K-12 substr. MG1655, Gossypium hirsutum, Mycobacterium tuberculosis, Nicotiana rustica, Nicotiana tabacum, Pseudomonas aeruginosa, Pseudomonas putida, Ralstonia solanacearum, Ricinus communis

Expected Taxonomic Range: Bacteria , Eukaryota

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 [Lin03, Lin04].

NAD is synthesized via two major pathway families in both prokaryotic and eukaryotic systems; the de novo pathway, and the salvage pathway.

About This Pathway

As a general rule, most prokaryotes utilize the aspartate de novo pathway, in which the nicotinate moiety of NAD is synthesized from aspartate [Begley01], while in eukaryotes, the de novo pathway starts with tryptophan [Panozzo02] ( NAD biosynthesis II (from tryptophan)).

The first attempt to elucidate a procaryotic pathway to NAD was reported by Ortega and Brown in 1960 [Ortega60]. They implicated (incorrectly) glycerol and a dicarboxylic acid as precursors in the synthesis of the pyridine ring of NAD in Escherichia coli. Subsequent work by Chandler et al. [Chandler70] established that L-aspartate is the dicarboxylic acid precursor. Suzuki et al., in 1973, established that the three carbon precursor is dihydroxyacetone phosphate (DHAP) and not glycerol [Suzuki73]. In addition, Andreoli et al demonstrated that quinolinate was a key intermediate in this pathway [Andreoli63]. Eventually it became clear that quinolinate is indeed a precursor, not only in this pathway, but in all known NAD biosynthetic pathways.

In plants:

In plants current evidence strongly supports the NAD biosynthetic route from L-aspartate. However, the finding of gene homologs encoding enzymes of the early steps in the kynurenine pathway ( NAD biosynthesis II (from tryptophan) in the genome sequence of rice ( Oryza sativa) does not rule out this pathway in monocotyledones and remains to be further investigated [Katoh06] [Katoh04].

The genome of the dicotyledonous plant Arabidopsis thaliana contains homologs to all genes that encode enzymatic steps in the corresponding bacterial pathway (this pathway). Many of those homologous sequences are found in cDNA databases [Yamada03] which indicates their transcription and functional role as protein encoding genes.

The first reaction is the conversion of L-aspartate to iminoaspartate catalyzed by the L-aspartate oxidase (AO). This enzyme has been partially purified from cotton [Hosokawa83]. The cDNA has also been isolated from Arabidopsis thaliana and its molecular function confirmed through functional complementation of L-aspartate oxidase deficient Escherichia coli mutants (nadB-) [Katoh06]. It should be pointed out that the catalyzed reaction differs from the enzyme of the same name, assigned to EC, which deaminates L-aspartate forming oxaloacetate and NH3.

Comparable to the L-aspartate oxidase of Arabidopsis thaliana the quinolinate synthase (QS) of this plant has been identified using a genomic approach. It could be demonstrated that the recombinant protein complemented quinolinate synthase deficient Escherichia coli mutants (nadA-) as well as the embryo-lethal phenotype of the homozygous allele in Arabidopsis [Katoh06].

The third reaction in the early steps of NAD biosynthesis from L-aspartate is catalyzed by quinolinate phosphoribosyltransferase (QPRtase) which has been isolated and characterized from different plants [Mann74] [Sinclair00] [Katoh06]. The enzyme catalyzes the formation of nicotinate mononucleotide (NaMN) the first intermediate that is also a component of the NAD recycling cycle [Zheng04] [Noctor06].

The activity of the last two enzymes of the pathway, nicotinic-acid mononucleotide adenylyltransferase (NaMN-AT) and NAD synthase (NAD-S) has been determined in tobacco [Wagner86a] [Wagner86]. For Arabidopsis thaliana those enzymes have been shown to exist as homologs in the genome, each of them encoded by a single gene [Hunt04] [Katoh06] [Katoh04] but their biochemical function remains to be confirmed.

Superpathways: aspartate superpathway

Variants: NAD biosynthesis from 2-amino-3-carboxymuconate semialdehyde, NAD biosynthesis II (from tryptophan), NAD biosynthesis III, NAD salvage pathway I, NAD salvage pathway II, NAD salvage pathway III, superpathway of NAD biosynthesis in eukaryotes


Created 31-Jan-1995 by Riley M, Marine Biological Laboratory
Revised 09-May-2005 by Caspi R, SRI International
Reviewed 14-Oct-2006 by Foerster H, TAIR


Andreoli63: Andreoli AJ, Ikeda M, Nishizuka Y, Hayaishi O (1963). "Quinolinic acid: a precursor to nicotinamide adenine dinucleotide in Escherichia coli." Biochem Biophys Res Commun 12;92-7. PMID: 14013029

Begley01: Begley TP, Kinsland C, Mehl RA, Osterman A, Dorrestein P (2001). "The biosynthesis of nicotinamide adenine dinucleotides in bacteria." Vitam Horm 61;103-19. PMID: 11153263

Chandler70: Chandler JL, Gholson RK, Scott TA (1970). "Studies on the de novo biosynthesis of NAD in Escherichia coli. I. Labelling patterns from precursors." Biochim Biophys Acta 222(2);523-6. PMID: 4321550

Hosokawa83: Hosokawa Y, Mitchell E, Gholson RK (1983). "Higher plants contain L-asparate oxidase, the first enzyme of the Escherichia coli quinolinate synthetase system." Biochem Biophys Res Commun 111(1);188-93. PMID: 6338879

Hunt04: Hunt L, Lerner F, Ziegler M (2004). "NAD - new roles in signalling and gene regulation in plants." New Phytologist 163, 31-44.

Katoh04: Katoh A, Hashimoto T (2004). "Molecular biology of pyridine nucleotide and nicotine biosynthesis." Front Biosci 9;1577-86. PMID: 14977569

Katoh06: Katoh A, Uenohara K, Akita M, Hashimoto T (2006). "Early steps in the biosynthesis of NAD in Arabidopsis start with aspartate and occur in the plastid." Plant Physiol 141(3);851-7. PMID: 16698895

Lin03: 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

Mann74: Mann DF, Byerrum RU (1974). "Quinolinic acid phosphoribosyltransferase from castor bean endosperm. I. Purification and characterization." J Biol Chem 249(21);6817-23. PMID: 4422841

Noctor06: Noctor G, Queval G, Gakiere B (2006). "NAD(P) synthesis and pyridine nucleotide cycling in plants and their potential importance in stress conditions." J Exp Bot 57(8);1603-20. PMID: 16714307

Ortega60: Ortega MV, Brown GM (1960). "Precursors of nicotinic acid in Escherichia coli." J Biol Chem 235;2939-45. PMID: 13731310

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

Sinclair00: Sinclair SJ, Murphy KJ, Birch CD, Hamill JD (2000). "Molecular characterization of quinolinate phosphoribosyltransferase (QPRtase) in Nicotiana." Plant Mol Biol 44(5);603-17. PMID: 11198422

Suzuki73: Suzuki N, Carlson J, Griffith G, Gholson RK (1973). "Studies on the de novo biosynthesis of NAD in Escherichia coli. V. Properties of the quinolinic acid synthetase system." Biochim Biophys Acta 304(2);309-15. PMID: 4351074

Wagner86: Wagner R, Feth F, Wagner KG (1986). "Regulation in tobacco callus of enzyme activities of the nicotine pathway II. The pyridine-nucleotide cycle." Planta,168, 408-413.

Wagner86a: Wagner R, Feth F, Wagner KG (1986). "The regulation of enzyme activities of the nicotine pathway in tobacco." Physiol. Plantarum, 68, 667-672.

Yamada03: Yamada K, Lim J, Dale JM, Chen H, Shinn P, Palm CJ, Southwick AM, Wu HC, Kim C, Nguyen M, Pham P, Cheuk R, Karlin-Newmann G, Liu SX, Lam B, Sakano H, Wu T, Yu G, Miranda M, Quach HL, Tripp M, Chang CH, Lee JM, Toriumi M, Chan MM, Tang CC, Onodera CS, Deng JM, Akiyama K, Ansari Y, Arakawa T, Banh J, Banno F, Bowser L, Brooks S, Carninci P, Chao Q, Choy N, Enju A, Goldsmith AD, Gurjal M, Hansen NF, Hayashizaki Y, Johnson-Hopson C, Hsuan VW, Iida K, Karnes M, Khan S, Koesema E, Ishida J, Jiang PX, Jones T, Kawai J, Kamiya A, Meyers C, Nakajima M, Narusaka M, Seki M, Sakurai T, Satou M, Tamse R, Vaysberg M, Wallender EK, Wong C, Yamamura Y, Yuan S, Shinozaki K, Davis RW, Theologis A, Ecker JR (2003). "Empirical analysis of transcriptional activity in the Arabidopsis genome." Science 302(5646);842-6. PMID: 14593172

Zheng04: Zheng XQ, Nagai C, Ashihara H (2004). "Pyridine nucleotide cycle and trigonelline (N-methylnicotinic acid) synthesis in developing leaves and fruits of Coffea arabica." Physiologia Plantarum, 122, 404-411.

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

Bhatia96: Bhatia R, Calvo KC (1996). "The sequencing expression, purification, and steady-state kinetic analysis of quinolinate phosphoribosyl transferase from Escherichia coli." Arch Biochem Biophys 325(2);270-8. PMID: 8561507

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

Bossi02: Bossi RT, Negri A, Tedeschi G, Mattevi A (2002). "Structure of FAD-bound L-aspartate oxidase: insight into substrate specificity and catalysis." Biochemistry 41(9);3018-24. PMID: 11863440

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

Brown90: Brown OR, Seither RL (1990). "Paraquat toxicity and pyridine nucleotide coenzyme synthesis: a data correction." Free Radic Biol Med 8(2);113-6. PMID: 2139629

Ceciliani00: Ceciliani F, Caramori T, Ronchi S, Tedeschi G, Mortarino M, Galizzi A (2000). "Cloning, overexpression, and purification of Escherichia coli quinolinate synthetase." Protein Expr Purif 2000;18(1);64-70. PMID: 10648170

Chandler72: Chandler JL, Gholson RK (1972). "De novo biosynthesis of nicotinamide adenine dinucleotide in Escherichia coli: excretion of quinolinic acid by mutants lacking quinolinate phosphoribosyl transferase." J Bacteriol 111(1);98-102. PMID: 4360223

Cicchillo05: Cicchillo RM, Tu L, Stromberg JA, Hoffart LM, Krebs C, Booker SJ (2005). "Escherichia coli quinolinate synthetase does indeed harbor a [4Fe-4S] cluster." J Am Chem Soc 127(20);7310-1. PMID: 15898769

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

DraczynskaLusia92: Draczynska-Lusiak B, Brown OR (1992). "Protein A of quinolinate synthetase is the site of oxygen poisoning of pyridine nucleotide coenzyme synthesis in Escherichia coli." Free Radic Biol Med 13(6);689-93. PMID: 1459486

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

Flachmann88: Flachmann R, Kunz N, Seifert J, Gutlich M, Wientjes FJ, Laufer A, Gassen HG (1988). "Molecular biology of pyridine nucleotide biosynthesis in Escherichia coli. Cloning and characterization of quinolinate synthesis genes nadA and nadB." Eur J Biochem 1988;175(2);221-8. PMID: 2841129

Gardner90: Gardner PR, Fridovich I (1990). "Quinolinate phosphoribosyl transferase is not the oxygen-sensitive site of nicotinamide adenine dinucleotide biosynthesis." Free Radic Biol Med 8(2);117-9. PMID: 2139630

Gardner91: Gardner PR, Fridovich I (1991). "Quinolinate synthetase: the oxygen-sensitive site of de novo NAD(P)+ biosynthesis." Arch Biochem Biophys 284(1);106-11. PMID: 1846509

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

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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