NAD Biosynthesis

Kurnasov, Oleg V.; Goral, Vasiliy N.; Colabroy, Keri L.; Gerdes, Svetlana; Anantha, Shubha; Osterman, Andrei L.; Begley, Tadhg P.

doi:10.1016/j.chembiol.2003.11.011

Cited by 190 publications

(83 citation statements)

References 39 publications

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“…The first reaction step can be catalyzed by two different enzymes with different substrate specificity, whereas the last reaction step occurs spontaneously without the aid of an enzyme. The kynurenine pathway is characteristic for animals and fungi (Gaertner and Subbayya Shetty 1977; Rongvaux et al 2003) and a few groups of Bacteria (Kurnasov et al 2003; Lima et al 2009). In mammals, about 90% of tryptophan is degraded through the kynurenine pathway, and some pathway intermediates represent neuroactive compounds (Rongvaux et al 2003; Schwarcz et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Gene Transfers Shaped the Evolution of De Novo NAD + Biosynthesis in Eukaryotes

Ternes

Schönknecht

2014

Genome Biology and Evolution

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NAD+ is an essential molecule for life, present in each living cell. It can function as an electron carrier or cofactor in redox biochemistry and energetics, and serves as substrate to generate the secondary messenger cyclic ADP ribose and nicotinic acid adenine dinucleotide phosphate. Although de novo NAD+ biosynthesis is essential, different metabolic pathways exist in different eukaryotic clades. The kynurenine pathway starting with tryptophan was most likely present in the last common ancestor of all eukaryotes, and is active in fungi and animals. The aspartate pathway, detected in most photosynthetic eukaryotes, was probably acquired from the cyanobacterial endosymbiont that gave rise to chloroplasts. An evolutionary analysis of enzymes catalyzing de novo NAD+ biosynthesis resulted in evolutionary trees incongruent with established organismal phylogeny, indicating numerous gene transfers. Endosymbiotic gene transfers probably introduced the aspartate pathway into eukaryotes and may have distributed it among different photosynthetic clades. In addition, several horizontal gene transfers substituted eukaryotic genes with bacterial orthologs. Although horizontal gene transfer is accepted as a key mechanism in prokaryotic evolution, it is supposed to be rare in eukaryotic evolution. The essential metabolic pathway of de novo NAD+ biosynthesis in eukaryotes was shaped by numerous gene transfers.

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Section: Introductionmentioning

confidence: 99%

Gene Transfers Shaped the Evolution of De Novo NAD + Biosynthesis in Eukaryotes

Ternes

Schönknecht

2014

Genome Biology and Evolution

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“…Two pathways have been identified, one involving the direct formation of quinolinic acid from aspartate and dihydroxyacetone phosphate, 1 the other requiring a five-step degradation of tryptophan. 2 The final step in this degradation is catalyzed by the non-heme Fe(II)-dependent enzyme 3-hydroxyanthranilate-3,4-dioxygenase (HAD). This enzyme catalyzes the oxidative ring opening of 3-hydroxyanthranilate (1) to 2-amino-3-carboxymuconic semialdehyde (ACMS, 2) which then cyclizes to quinolinate (3).…”

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confidence: 99%

The Pyridine Ring of NAD Is Formed by a Nonenzymatic Pericyclic Reaction

Colabroy

Begley

2004

J. Am. Chem. Soc.

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The biosynthesis of quinolinate 3, the precursor to the pyridine ring of NAD, is still poorly understood. Two pathways have been identified, one involving the direct formation of quinolinic acid from aspartate and dihydroxyacetone phosphate, the other requiring a five-step degradation of tryptophan. The final step in this degradation is catalyzed by the non-heme Fe(II)-dependent enzyme 3-hydroxyanthranilate-3,4-dioxygenase (HAD). This enzyme catalyzes the oxidative ring opening of 3-hydroxyanthranilate (1) to 2-amino-3-carboxymuconic semialdehyde (ACMS, 2) which then cyclizes to quinolinate (3). In this communication, we demonstrate the following: (1) cyclization of ACMS to 3 is not HAD catalyzed, (2) the most stable form of ACMS in solution is an all trans isomer which undergoes facile cis to trans isomerization about the C2-C3 and C4-C5 double bonds via transient formation of its enol tautomer (6), (3) a model study on the ring opening of N,N-dimethylcarbamoylpyridinium with hydroxide and methoxide suggests that the cyclization of ACMS occurs by an electrocyclization reaction of its enol tautomer 6. Thus, the biosynthesis of quinolinic acid, by the tryptophan pathway, is likely to be a member of a growing family of natural products whose biosynthesis involves a pericyclic reaction.

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“…For pathogens, this recycling pathway offers the possibility of obtaining this cofactor directly from their host. Recently it was also discovered that some prokaryotes synthesized NAD de novo from tryptophan (14), a pathway that had previously been considered unique to eukaryotes. The Preiss-Handler pathway (15) is a recycling pathway that occurs in many microorganisms and consists of nicotinate phosphoribosyltransferase (EC 2.4.2.11 or PncB) as well as the two enzymes of the universal pathway, nicotinic acid mononucleotide adenylyltransferase (EC 2.7.7.18 or NaMNAT, encoded by nadD) and NAD synthetase (EC 6.3.5.1, encoded by nadE) (Fig.…”

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Biosynthesis and Recycling of Nicotinamide Cofactors in Mycobacterium tuberculosis

Boshoff

Tahlan

et al. 2008

Journal of Biological Chemistry

146

168

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Despite the presence of genes that apparently encode NAD salvage-specific enzymes in its genome, it has been previously thought that Mycobacterium tuberculosis can only synthesize NAD de novo. Transcriptional analysis of the de novo synthesis and putative salvage pathway genes revealed an up-regulation of the salvage pathway genes in vivo and in vitro under conditions of hypoxia. [14 C]Nicotinamide incorporation assays in M. tuberculosis isolated directly from the lungs of infected mice or from infected macrophages revealed that incorporation of exogenous nicotinamide was very efficient in in vivo-adapted cells, in contrast to cells grown aerobically in vitro. Two putative nicotinic acid phosphoribosyltransferases, PncB1 (Rv1330c) and PncB2 (Rv0573c), were examined by a combination of in vitro enzymatic activity assays and allelic exchange studies. These studies revealed that both play a role in cofactor salvage. Mutants in the de novo pathway died upon removal of exogenous nicotinamide during active replication in vitro. Cell death is induced by both cofactor starvation and disruption of cellular redox homeostasis as electron transport is impaired by limiting NAD. Inhibitors of NAD synthetase, an essential enzyme common to both recycling and de novo synthesis pathways, displayed the same bactericidal effect as sudden NAD starvation of the de novo pathway mutant in both actively growing and nonreplicating M. tuberculosis. These studies demonstrate the plasticity of the organism in maintaining NAD levels and establish that the two enzymes of the universal pathway are attractive chemotherapeutic targets for active as well as latent tuberculosis.

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NAD Biosynthesis

Cited by 190 publications

References 39 publications

Gene Transfers Shaped the Evolution of De Novo NAD + Biosynthesis in Eukaryotes

Gene Transfers Shaped the Evolution of De Novo NAD + Biosynthesis in Eukaryotes

The Pyridine Ring of NAD Is Formed by a Nonenzymatic Pericyclic Reaction

Biosynthesis and Recycling of Nicotinamide Cofactors in Mycobacterium tuberculosis

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