Tryptophan catabolism leading to NAD+ production (WP4210)
Homo sapiens
Scheme of mammalian tryptophan catabolism. Briefly, in mammalian cells, tryptophan is used mostly for protein synthesis. In a second quantitatively important pathway (driven by IDO in most cell types and by TDO more specifically in liver cells), it is the starting point of the kynurenine pathway. The kynurenine pathway gives birth to several metabolites, providing the appropriate enzymes that metabolize the various kynurenine intermediates are expressed. The main route of the kynurenine pathway leads to the formation of N -formyl kynurenine, L -kynurenine, 3-hydroxykynurenine, 3-hydroxyanthra- nilic acid, quinolinic acid, nicotinic acid, and in fine nicotinamine adenine dinucleotides. Additional lateral branches of the kynurenine pathway lead to the formation of other terminal kynurenines, such as KA, xanthurenic acid, and anthranilic acid. Kynurenines indicated in boldface type ( i.e. L -kynurenine and KA) correspond to the most abundant kynurenines found in caput epididymal tissue. Outside the kynurenine pathway, tryptophan is also the precursor of serotonin and melatonin. A very small proportion of tryptophan is also transformed into indol derivatives, such as indoxyl acetic acid. Conversion of Trp to N -formyl kynurenine is achieved via IDO and/or TDO. The kynurenine pathway can lead to the intracellular NAD+ production and consumption. De novo synthesis begins with the conversion of tryptophan to quinolate, which is converted to NaMN. NaMN is then adenylylated to form nicotinic acid adenine dinucleotide (NaAD+), which is converted to NAD+. NAD+-consuming enzymes break the bond between the Nam and ADP-ribosyl moieties. Nam, which is also provided in the diet, is salvaged to NMN, which is adenylylated to form NAD+. Na, which is provided in the diet and, potentially, by bacterial degradative pathways in vertebrates, is salvaged to form NaMN. NR, which occurs extracellularly in blood and milk and can be provided in the diet, is salvaged to NMN. Na and Nam are also converted to nicotinuric acid and N-methylnicotinamide elimination products.
Authors
Denise Slenter and Egon WillighagenActivity
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Cited In
- Bioinformatics analysis of potential therapeutic targets for COVID-19 infection in patients with carotid atherosclerosis (2022).
- Identification of the shared gene signatures and pathways between sarcopenia and type 2 diabetes mellitus (2022).
- Discovering life's directed metabolic (sub)paths to interpret human biochemical markers using the DSMN tool.
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Organisms
Homo sapiensCommunities
Annotations
Pathway Ontology
nicotinamide adenine dinucleotide biosynthetic pathway nicotinamide adenine dinucleotide metabolic pathway kynurenine metabolic pathway de novo nicotinamide adenine dinucleotide biosynthetic pathway nicotinamide adenine nucleotide utilization pathway nicotinamide adenine dinucleotide biosynthesis, the salvage pathway tryptophan degradation pathwayLabel | Type | Compact URI | Comment |
---|---|---|---|
Nicotinic acid mononucleotide | Metabolite | chebi:37008 | |
NMN | Metabolite | wikidata:Q27094156 | Nicotinamide Mononucleotide |
NAD+ | Metabolite | wikidata:Q28775 | |
Nicotinic acid adenine dinucleotide (NaAD+) | Metabolite | wikidata:Q905651 | Assuming that NAADP+ is referred to (since the phosphate group is needed for stabilisation). |
Nicotinuric acid | Metabolite | wikidata:Q27107528 | |
5-HT | Metabolite | wikidata:Q167934 | pre-cursor for serotonin/melatonin |
N-methylnicotinamide | Metabolite | wikidata:Q27088080 | |
Tryptophan (Trp) | Metabolite | wikidata:Q181003 | |
L-alanine | Metabolite | wikidata:Q218642 | |
2-Amino-3-carboxymuconatesemialdehyde | Metabolite | pubchem.compound:5280673 | |
ADP-ribosyl | Metabolite | wikidata:Q27074316 | aka ADP ribose |
NR | Metabolite | wikidata:Q3334152 | N-ribosylnicotinamide = NRoccurs extracellularly in blood and milk and can be provided in the diet |
N-formyl kynurenine | Metabolite | wikidata:Q27104120 | |
L-kynurenine | Metabolite | wikidata:Q415768 | most abundant kynurenines found in caput epididymal tissue |
3-OH kynurenine (HK) | Metabolite | wikidata:Q2815992 | |
3-OH anthranilic acid (HAA) | Metabolite | wikidata:Q2823213 | |
Quinolinic acid (QA) | Metabolite | wikidata:Q411945 | |
Nicotinic acid (NA) | Metabolite | wikidata:Q11324215 | Provided by diet and, potentially, by bacterial degradative pathways in vertebrates |
Nicotinamide | Metabolite | wikidata:Q192423 | |
Kynurenic acid (KA) | Metabolite | wikidata:Q642217 | most abundant kynurenines found in caput epididymal tissue |
Xanthurenic acid (XA) | Metabolite | wikidata:Q5961262 | |
Anthranilic acid (AA) | Metabolite | wikidata:Q385140 | |
Indoxyl acetic acid (IAA) | Metabolite | wikidata:Q411208 | indol derivative |
Nam | Metabolite | wikidata:Q192423 | |
3-hydroxyanthranilate dioxygenase | Protein | uniprot:P46952 | |
Nrk1 | Protein | uniprot:Q9NWW6 | nicotinamide riboside kinases |
IDO | Protein | uniprot:P14902 | in most cell types |
Naprt | Protein | uniprot:Q6XQN6 | Na phosphoribosyltransferase |
3-HAO | Protein | uniprot:P46952 | 3-hydroxyamino oxidase ( 3HAO ) |
PBEF | Protein | uniprot:P43490 | Nam phosphoribosyltransferase |
Nmnat1 | Protein | uniprot:Q9HAN9 | |
Nadsyn1 | Protein | uniprot:Q6IA69 | aka glutamine-dependent NAD+ synthetase |
TDO | Protein | uniprot:P48775 | in liver cells |
AFMID | Protein | uniprot:Q63HM1 | formaminase (arylformamidase; AFMID ) |
KAT | Protein | uniprot:Q8N5Z0 | kynurenine aminotransferase ( KAT ; also known as AADAT) |
K3H | Protein | uniprot:O15229 | kynurenine 3-hydroxylase ( K3H ; also known as KMO) |
KYNU | Protein | uniprot:Q16719 | kynureninase |
QPRT | Protein | uniprot:Q15274 | phosphoribosyltransferase |
Nmnat2 | Protein | uniprot:Q9BZQ4 | |
Nmnat3 | Protein | uniprot:Q96T66 | |
Nrk2 | Protein | uniprot:Q9NPI5 | nicotinamide riboside kinases |
References
- Kynurenine metabolism in hyperthyroidism. A biochemical basis for the low NAD(P) level in hyperthyroid rat liver. Okamoto H, Okada F, Hayaishi O. J Biol Chem. 1971 Dec 25;246(24):7759–63. PubMed Europe PMC Scholia
- NAD+ metabolism in health and disease. Belenky P, Bogan KL, Brenner C. Trends Biochem Sci. 2007 Jan;32(1):12–9. PubMed Europe PMC Scholia
- Deficient tryptophan catabolism along the kynurenine pathway reveals that the epididymis is in a unique tolerogenic state. Jrad-Lamine A, Henry-Berger J, Gourbeyre P, Damon-Soubeyrand C, Lenoir A, Combaret L, et al. J Biol Chem. 2011 Mar 11;286(10):8030–42. PubMed Europe PMC Scholia