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MetaCyc Pathway: NAD biosynthesis III
Traceable author statement to experimental support

Enzyme View:

Pathway diagram: NAD biosynthesis III

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 : Aggregatibacter actinomycetemcomitans, Chromobacterium violaceum, Deinococcus radiodurans, Mycoplasma genitalium, Mycoplasma pneumoniae M129, Pasteurella multocida, Shewanella putrefaciens, Synechococcus elongatus, Synechocystis sp. PCC 6803, [Haemophilus] ducreyi

Expected Taxonomic Range: Bacteria

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

Members of the family Pasteurellaceae do not poccess either the NAD de novo biosynthesis pathway or the NAD salvage pathway, and rely on the presence of NAD or related compounds in the growth medium. They have been classified into two distinct classes based on their specific requirement: members of the so called "V-factor-dependent" class, which includes the pathogen Haemophilus influenzae, require supplements in which the pyridine nucleotide source must possess an intact pyridine-ribose bond and the pyridine-carbonyl group must be amidated. Thus, they require either NAD, nicotineamide mononucleotide (NMN) or nicotinamide riboside (NR). On the other hand, members of the "V-factor-independent" class possess the enzyme nicotinamide phosphoribosyl transferase, which converts nicotinamide (NAm) to NMN, and are able to to synthesize NAD from NAm as well [OReilly86].

In 1973 Kasarov and Moat reported the presence of nicotinamide phosphoribosyltransferase in Haemophilus haemoglobinophilus [Kasarov73]. Almost three decades later, Martin et al were able to clone the gene encoding the enzyme from pNAD1, a plasmid of [Haemophilus] ducreyi which confers V-factor independence on that strain [Munson04, Martin01]. The presence of this gene, named nadV, was shown to confer V-factor independence on other strains, including Haemophilus influenzae and Actinobacillus pleuropneumoniae [Martin01].

While a similar gene has not been found in Escherichia coli [Kurnasov02], genes with significant sequence homology were found in many other organisms, including the human pre-B-cell colony enhancing factor PBEF and the bacterial species Mycoplasma genitalium, Mycoplasma pneumoniae, Shewanella putrefaciens, Synechocystis sp., Deinococcus radiodurans, Pasteurella multocida, and Actinobacillus actinomycetemcomitans [Martin01]. The human pre-B-cell colony enhancing factor has been purifed and shown to be a nicotinamide phosphoribosyltransferase [Rongvaux02, Revollo04].

Unlike the reaction catalyzed by NadV, the second reaction in this pathway is not unique. It is part of an NAD salvage pathway found in many organsms including Escherichia coli (see NAD salvage pathway II). In these organisms the reaction is catalyzed by the fusion protein nicotinamide mononucleotide adenylyltransferase / ribosylnicotineamide kinase encoded by the nadR gene.

In some cases, such as the case of [Haemophilus] ducreyi, both NadV and NadR exist simultaneously, and combined they catalyze this pathway [Kurnasov02].

Yet in other organisms the second reaction is catalyzed by a different protein, encoded by the nadM gene which (in these organisms) is usually found in the same operon as the nadV gene. nadM encodes a bifunctional enzyme similar to both archaeal nicotinamide mononucleotide adenylyltransferase and archaeal 'Nudix' (nucleoside diphosphate linked moiety X) hydrolases (enzymes that catalyze the hydrolysis of a phosphate from ADP sugars, such as ADP-D-ribose). It has been suggested that in these organisms this pathway is responsible for the recycling of endogenous nicotinamide, which may be generated by the hydrolysis of NAD to nicotinamide and ADP-ribose by a documented but not characterized enzyme [Silman95, Gerdes06]. Such a pathway would provide an explanation for the Nudix hydrolase portion of the fusion protein.

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

Revised 02-Jun-2006 by Caspi R, SRI International


Gerdes06: Gerdes SY, Kurnasov OV, Shatalin K, Polanuyer B, Sloutsky R, Vonstein V, Overbeek R, Osterman AL (2006). "Comparative genomics of NAD biosynthesis in cyanobacteria." J Bacteriol 188(8);3012-23. PMID: 16585762

Kasarov73: Kasarov, L.B.B, Moat, A.G. (1973). "Biosynthesis of NAD in Haemophilus haemoglobinophilus." Biochim Biophys Acta 320(2);372-8. PMID: 4356297

Kurnasov02: Kurnasov OV, Polanuyer BM, Ananta S, Sloutsky R, Tam A, Gerdes SY, Osterman AL (2002). "Ribosylnicotinamide kinase domain of NadR protein: identification and implications in NAD biosynthesis." J Bacteriol 184(24);6906-17. PMID: 12446641

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

Martin01: Martin PR, Shea RJ, Mulks MH (2001). "Identification of a plasmid-encoded gene from Haemophilus ducreyi which confers NAD independence." J Bacteriol 183(4);1168-74. PMID: 11157928

Munson04: Munson RS, Zhong H, Mungur R, Ray WC, Shea RJ, Mahairas GG, Mulks MH (2004). "Haemophilus ducreyi strain ATCC 27722 contains a genetic element with homology to the vibrio RS1 element that can replicate as a plasmid and confer NAD independence on haemophilus influenzae." Infect Immun 72(2);1143-6. PMID: 14742562

OReilly86: O'Reilly T, Niven DF (1986). "Pyridine nucleotide metabolism by extracts derived from Haemophilus parasuis and H. pleuropneumoniae." Can J Microbiol 32(9);733-7. PMID: 2946387

Revollo04: Revollo JR, Grimm AA, Imai S (2004). "The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells." J Biol Chem 279(49);50754-63. PMID: 15381699

Rongvaux02: Rongvaux A, Shea RJ, Mulks MH, Gigot D, Urbain J, Leo O, Andris F (2002). "Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesis." Eur J Immunol 32(11);3225-34. PMID: 12555668

Silman95: Silman NJ, Carr NG, Mann NH (1995). "ADP-ribosylation of glutamine synthetase in the cyanobacterium Synechocystis sp. strain PCC 6803." J Bacteriol 177(12);3527-33. PMID: 7768863

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

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

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

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Natalini86: Natalini P, Ruggieri S, Raffaelli N, Magni G (1986). "Nicotinamide mononucleotide adenylyltransferase. Molecular and enzymatic properties of the homogeneous enzyme from baker's yeast." Biochemistry 25(12);3725-9. PMID: 3013296

Preiss57: Preiss, J., Handler, P. (1957). "Enzymatic synthesis of nicotinamide mononucleotide." J Biol Chem 225(2);759-70. PMID: 13416279

Raffaelli02: Raffaelli N, Sorci L, Amici A, Emanuelli M, Mazzola F, Magni G (2002). "Identification of a novel human nicotinamide mononucleotide adenylyltransferase." Biochem Biophys Res Commun 297(4);835-40. PMID: 12359228

Raffaelli97: Raffaelli N, Pisani FM, Lorenzi T, Emanuelli M, Amici A, Ruggieri S, Magni G (1997). "Characterization of nicotinamide mononucleotide adenylyltransferase from thermophilic archaea." J Bacteriol 179(24);7718-23. PMID: 9401030

Raffaelli99: Raffaelli N, Lorenzi T, Amici A, Emanuelli M, Ruggieri S, Magni G (1999). "Synechocystis sp. slr0787 protein is a novel bifunctional enzyme endowed with both nicotinamide mononucleotide adenylyltransferase and 'Nudix' hydrolase activities." FEBS Lett 444(2-3);222-6. PMID: 10050763

Raffaelli99a: Raffaelli N, Lorenzi T, Mariani PL, Emanuelli M, Amici A, Ruggieri S, Magni G (1999). "The Escherichia coli NadR regulator is endowed with nicotinamide mononucleotide adenylyltransferase activity." J Bacteriol 1999;181(17);5509-11. PMID: 10464228

Sorci07: Sorci L, Cimadamore F, Scotti S, Petrelli R, Cappellacci L, Franchetti P, Orsomando G, Magni G (2007). "Initial-rate kinetics of human NMN-adenylyltransferases: substrate and metal ion specificity, inhibition by products and multisubstrate analogues, and isozyme contributions to NAD+ biosynthesis." Biochemistry 46(16);4912-22. PMID: 17402747

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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
Page generated by Pathway Tools version 19.5 (software by SRI International) on Mon May 2, 2016, biocyc14.