NAD+ biosynthetic pathways (WP3645)

NAD+ biosynthetic pathways. NAD+ levels are maintained by three independent pathways. First, the Preiss-Handler pathway uses dietary nicotinic acid and the enzyme nicotinic acid phosphoribosyltransferase (NAPRT) to generate NAMN, which is then transformed into NAAD by NAMN transferase (NMNAT). Three forms of this enzyme (NMNAT1, -2, and -3) have distinct subcellular localizations. The process is completed by the transformation of NAAD into NAD+ by NAD+ synthase (NADS). Second, the de novo synthesis pathway of NAD from tryptophan occurs through the kinurenine pathway (5). The first step in this pathway is the rate-limiting conversion of tryptophan to N-formylkinurenine (N-formylkin) by either IDO or TDO. Formylkinurenine is transformed into L-kinurenine (L-kin), 3-hydroxykinurenine, and 3-hydroxyanthranilic acid (3-HAA) and finally to ACMS. This compound can spontaneously condense and rearrange into quinolinic acid, which is transformed into NAMN, at which point it converges with the Preiss-Handler pathway. ACMS can also be decarboxylated into AMS by ACMS decarboxylase (ACMSD), leading to its oxidation into acetyl-CoA via the TCA cycle. Third, the NAD+ salvage pathway recycles the nicotinamide generated as a by-product of the enzymatic activities of NAD+-consuming enzymes: sirtuins, PARPs, and the cADPR synthases (CD38 and CD157). Initially, NAMPT recycles nicotinamide into NMN, which is then converted into NAD+ via the different NMNATs. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP3645 CPTAC Assay Portal]
last edited

Authors

Khanspers, AlexanderPico, Jmelius, MaintBot, and Eweitz

Cited In

Organism

Homo sapiens

Communities

Annotations

Pathway Ontology: classic metabolic pathway nicotinamide adenine dinucleotide biosynthetic pathway

Participants

Label Type Compact Identifier
SIRT1 GeneProduct ensembl:ENSG00000096717
ACMS Metabolite hmdb:HMDB0001330
Nicotinamide Metabolite hmdb:HMDB0001406
Nicotinic acid Metabolite hmdb:HMDB0001488
Tryptophan Metabolite hmdb:HMDB0000929
L-Kynurenine Metabolite hmdb:HMDB0000684
N-Formylkin Metabolite hmdb:HMDB0001200
NADSYN1 GeneProduct ensembl:ENSG00000172890
QPRT GeneProduct ensembl:ENSG00000103485
Nicotinic acid adenine dinucleotide Metabolite hmdb:HMDB0001179
TCA cycle Pathway None
TDO2 GeneProduct ncbigene:6999
IDO1 GeneProduct ensembl:ENSG00000131203
3-HAA Metabolite hmdb:HMDB0001476
Nicotinic acid mononucleotide Metabolite hmdb:HMDB0001132
CD38 GeneProduct ensembl:ENSG00000004468
NADH Metabolite hmdb:HMDB0001487
BST1 GeneProduct ensembl:ENSG00000109743
NMNAT1 GeneProduct ensembl:ENSG00000173614
Nicotinamide mononucleotide Metabolite chemspider:13553
ACMSD GeneProduct ensembl:ENSG00000153086
Nicotinamide riboside Metabolite hmdb:HMDB0000855
AMS Metabolite hmdb:HMDB0001330
Quinolinic acid Metabolite hmdb:HMDB0000232
NAMPT GeneProduct ensembl:ENSG00000105835
NAPRT1 GeneProduct ensembl:ENSG00000147813
PARP1 GeneProduct ensembl:ENSG00000143799
SIRT2 GeneProduct ensembl:ENSG00000068903
NAD Metabolite hmdb:HMDB0000902
NMNAT1 GeneProduct ensembl:ENSG00000173614
PARP4 GeneProduct ensembl:ENSG00000102699
PARP2 GeneProduct ensembl:ENSG00000129484
TNKS GeneProduct ensembl:ENSG00000173273
TNKS2 GeneProduct ensembl:ENSG00000107854
SIRT3 GeneProduct ensembl:ENSG00000142082
SIRT4 GeneProduct ensembl:ENSG00000089163
SIRT5 GeneProduct ensembl:ENSG00000124523
SIRT6 GeneProduct ensembl:ENSG00000077463
SIRT7 GeneProduct ensembl:ENSG00000187531
SIRT7 GeneProduct ensembl:ENSG00000187531

References

  1. Bogan KL, Brenner C. Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu Rev Nutr. 2008;28:115–30. PubMed Europe PMC Scholia
  2. Verdin E. NAD⁺ in aging, metabolism, and neurodegeneration. Science. 2015 Dec 4;350(6265):1208–13. PubMed Europe PMC Scholia