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:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → NAD Metabolism → NAD Biosynthesis|
Some taxa known to possess this pathway include
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 [Lin03b, Lin04a].
NAD is synthesised via two major pathways 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 (see NAD biosynthesis I (from aspartate)). In eukaryotes, the de novo pathway starts with tryptophan (this pathway).
The role of tryptophan as a precursor in eukaryotic NAD biosynthesis was first suggested by nutritional studies in which humans stricken with pellagra, a nicotinamide (niacine) deficiency disease, recovered after the addition of tryptophan or niacin to their diets [Krehl45]. Other studies established tryptophan as a precursor of NAD in many animal and plant systems [Foster80]. This pathway is closely related to the catabolic pathway of tryptophan ( L-tryptophan degradation I (via anthranilate)), suggesting an evolutionary link between the two.
Though rare, the synthesis of NAD from tryptophan in prokaryotes has been observed in several organisms. Wilson and Henderson reported that Xanthomonas arboricola pv. pruni requires niacin for growth and can use tryptophan or 3-hydroxyanthranilic acid as a substitute [Wilson63]. Some members of the Actinomycete group were also reported to utilize tryptophan for NAD biosynthesis [Lingens64].
Recent studies based on comparative genome analysis have identified the five genes involved in the "eukaryotic" pathway in several bacterial strains, confirming that some bacteria may indeed utilize this pathway rather than the aspartate pathway [Kurnasov03].
In yeast, the de novo pathway consists of six enzymatic steps (catalyzed by the products of the BNA genes) and one non-enzymatic reaction. After the last enzymatic reaction (catalyzed by Bna6p), the de novo pathway converges with the salvage pathway [Panozzo02].
In plants current evidence strongly supports the NAD biosynthetic route from L-aspartate ( NAD biosynthesis I (from aspartate)). However, the finding of gene homologs encoding enzymes of the early steps in the kynurenine pathway (this pathway) in the genome sequence of rice ( Oryza sativa) does not rule out this pathway in monocotyledones and remains to be further investigated [Katoh06] [Katoh04].
Superpathways: superpathway of NAD biosynthesis in eukaryotes
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
Kurnasov03: Kurnasov O, Goral V, Colabroy K, Gerdes S, Anantha S, Osterman A, Begley TP (2003). "NAD biosynthesis: identification of the tryptophan to quinolinate pathway in bacteria." Chem Biol 10(12);1195-204. PMID: 14700627
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
AlberatiGiani96: Alberati-Giani D, Buchli R, Malherbe P, Broger C, Lang G, Kohler C, Lahm HW, Cesura AM (1996). "Isolation and expression of a cDNA clone encoding human kynureninase." Eur J Biochem 239(2);460-8. PMID: 8706755
AlberatiGiani97: Alberati-Giani D, Cesura AM, Broger C, Warren WD, Rover S, Malherbe P (1997). "Cloning and functional expression of human kynurenine 3-monooxygenase." FEBS Lett 410(2-3);407-12. PMID: 9237672
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
Austin09: Austin CJ, Astelbauer F, Kosim-Satyaputra P, Ball HJ, Willows RD, Jamie JF, Hunt NH (2009). "Mouse and human indoleamine 2,3-dioxygenase display some distinct biochemical and structural properties." Amino Acids 36(1);99-106. PMID: 18274832
Balducci92: Balducci E, Emanuelli M, Magni G, Raffaelli N, Ruggieri S, Vita A, Natalini P (1992). "Nuclear matrix-associated NMN adenylyltransferase activity in human placenta." Biochem Biophys Res Commun 189(3);1275-9. PMID: 1282798
Basran08: Basran J, Rafice SA, Chauhan N, Efimov I, Cheesman MR, Ghamsari L, Raven EL (2008). "A kinetic, spectroscopic, and redox study of human tryptophan 2,3-dioxygenase." Biochemistry 47(16);4752-60. PMID: 18370401
Berger05: Berger F, Lau C, Dahlmann M, Ziegler M (2005). "Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms." J Biol Chem 280(43);36334-41. PMID: 16118205
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
Breton00: Breton J, Avanzi N, Magagnin S, Covini N, Magistrelli G, Cozzi L, Isacchi A (2000). "Functional characterization and mechanism of action of recombinant human kynurenine 3-hydroxylase." Eur J Biochem 267(4);1092-9. PMID: 10672018
Calderone02: Calderone V, Trabucco M, Menin V, Negro A, Zanotti G (2002). "Cloning of human 3-hydroxyanthranilic acid dioxygenase in Escherichia coli: characterisation of the purified enzyme and its in vitro inhibition by Zn2+." Biochim Biophys Acta 1596(2);283-92. PMID: 12007609
Comings95: Comings DE, Muhleman D, Dietz G, Sherman M, Forest GL (1995). "Sequence of human tryptophan 2,3-dioxygenase (TDO2): presence of a glucocorticoid response-like element composed of a GTT repeat and an intronic CCCCT repeat." Genomics 29(2);390-6. PMID: 8666386
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
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