Kynurenine Pathway and links to Cellular Senescence (Homo sapiens)

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1, 7, 9112122, 3, 128232221013131383113, 12132211132111386131081113233, 12311Cell differentiationProtectionagainst ROSInflammationCell cycle arrestGlutathioninemetabolismchange in NAD+/NADHFatty AcidOxidationAutophagy99%Cell proliferationApoptosisReduction of ROSArachidonic acidmetabolismOxidative stressReduction of ROSDepletion of cytosolic tryptophanLipid peroxidationSenescenceInflammationCentral Kynurenine Pathway21332other miRNAsNAMNPGE2glutaryl-coACrotonyl-CoABH4NAD de novoSynthesisTDO(S)-3-hydroxy-butanoyl-CoA3-HKAhR SignalingPathwayKynureninaseQuinolinic acidKynurenineAnthranilic acidIFNγACMSDMelatoninTCA CycleJNK SignalingPathwayFOXO1CinnavalininatemiR-493-5pXanthurenic acidacetoacetyl-CoAKLF5Picolinic acidNAD+Coenzyme ASerotonin/MelatoninPathwayKynurenic acidp21KMOQPRTeIF-2alphaAMSAmiR-210-3pIDO1 promoterNAAD3-HAA3-HAOGlycolysisGlutaconyl-CoATryptophanN-FormylkynurenineLiposaccharidesp53IDO1AFMIDNOSAcetyl-CoAACMSA353, 6, 13Kynureninase233KATIDO2IFNβTNFTGFβAhR11TLR 43, 13IL-1R3, 4, 12, 13GCN2


Description

The kynurenine pathway is the major path for Tryptophan (Trp) breakdown (Castro-Portuguez & Sutphin, 2020; Dalton et al.,2020; Kondrikov et al., 2020; Li, Oxenkrug & Yang, 2017; Lindquist et al., 2020; Lugo-Huitron et al., 2013; Oxenkrug, 2011; Platten et al., 2019; Savitz, 2019; Soegdrageret al., 2019; Tan & Guillemin, 2019). The kynurenine (Kyn)/Trp ratio is proposed to be an accurate indicator of biological age as well as an indicator of risk for age-related diseases (Castro-Portuguez & Sutphin, 2020; Li et al., 2017; Lindquist et al., 2020; Oxenkrug, 2011; Platten et al., 2019; Savitz, 2019; Soegdrageret al., 2019).

The first and also rate-limiting enzymes that determine rate of Trp conversion into N-formylkynurenine and further on into Kyn are tryptophan-2,3-dioxygenase (TDO) and indoleamine-2,3-dioxygenase (IDO), out of which the IDO isoform IDO1 is the most important (Castro-Portuguez & Sutphin, 2020; Dalton et al.,2020; Li et al., 2017; Lindquist et al., 2020; Lugo-Huitron et al., 2013; Minhas et al., 2018; Oxenkrug, 2011; Platten et al., 2019; Savitz, 2019; Soegdrageret al., 2019; Tan & Guillemin, 2019). This catalytic enzyme is activated by pro-inflammatory cytokines such as interleukins, interferons gamma and beta or the aryl hydrocarbon receptor (AhR) (Castro-Portuguez & Sutphin, 2020; Dalton et al.,2020; Kondrikov et al., 2020; Li et al., 2017; Lindquist et al., 2020; Lugo-Huitron et al., 2013; Oxenkrug, 2011; Platten et al., 2019; Savitz, 2019; Soegdrageret al., 2019; Tan & Guillemin, 2019).

Next, N-formylkynurenine is converted either into kynurenic acid by a kynurenine aminotransferase (KAT), anthranilic acid by kynureninase or, into Kyn by formidase (AFMID) (Castro-Portuguez & Sutphin, 2020). Kyn can alter the regulation of cell cycle and proliferation and induce oxidative stress through by inducing the transcription of multiple miRNAs (Dalton et al., 2020), activating the p53/p21 pathway (Kondrikov et al., 2020) and binding to AhR, resulting in a positive feedback loop, while further promoting oxidative stress (Castro-Portuguez & Sutphin, Dalton et al., 2020; 2020, Kondrikov et al., 2020).

Kyn is further converted into 3-hydroxykynurenine (3HK) by kynurenine monooxygenase (KMO), then Kynureninase converts 3HK into 3-hydroxyanthranilic acid (3HAA) and then into 2-amino-3-carboxymuconate-6-semialdehyde (ACMSA) (Castro-Portuguez & Sutphin, 2020, Lindquist et al., 2020; Lugo-Huitron et al., 2013; Platten et al., 2019; Savitz, 2019; Tan & Guillemin, 2019). 3-HK can alternatively be converted into xanthurenic acid, a metabolite that modulates the tetrahydrobiopterin (BH4) pathway,(Tan & Guillemin, 2019). 3HAA can be converted either into quinolinic acid and from there enter the de novo NAD synthesis due to the enzymatic action of nicotinate-nucleotide pyrophosphorylase (QPRT), or it can be converted into 2-aminomuconate-6-semialdehyde (AMSA) which can be converted into glutaryl-CoA and enter the TCA cycle and glycolysis (Castro-Portuguez & Sutphin, 2020; Lindquist et al., 2020; Lugo-Huitron et al., 2013; Platten et al., 2019; Savitz, 2019; Tan & Guillemin, 2019).

Comments

 
Most studies were done on C. elegans and mice or in vitro on human/ mouse cells
 
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Bibliography

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  1. Denise Slenter; ''Tryptophan catabolism leading to NAD+ production (Homo sapiens)''; WikiPathways https://www.wikipathways.org/index.php/Pathway:WP4210,
  2. Dalton S, Smith K, Singh K, Kaiser H, Kolhe R, Mondal AK, Khayrullin A, Isales CM, Hamrick MW, Hill WD, Fulzele S; ''Accumulation of kynurenine elevates oxidative stress and alters microRNA profile in human bone marrow stromal cells.''; Exp Gerontol, 2020 PubMed Europe PMC Scholia
  3. Castro-Portuguez R, Sutphin GL; ''Kynurenine pathway, NAD+synthesis, and mitochondrial function: Targeting tryptophan metabolism to promote longevity and healthspan.''; Exp Gerontol, 2020 PubMed Europe PMC Scholia
  4. Savitz J; ''The kynurenine pathway: a finger inevery pie.''; Mol Psychiatry, 2020 PubMed Europe PMC Scholia
  5. Alicia Usategui, Abigail López, Cristina Municio, Manuel J Del Rey, José L Pablos and Gabriel Criado; ''Role of tryptophan metabolism on senescent synovial fibroblasts''; The Journal of Immunology, 2020
  6. Lindquist C, Bjørndal B, Lund A, Slettom G, Skorve J, Nygård O, Svardal A, Berge RK; ''Increased fatty acid oxidation and mitochondrial proliferation in liver are associated with increased plasma kynurenine metabolites and nicotinamide levels in normolipidemic and carnitine-depleted rats.''; Biochim Biophys Acta Mol Cell Biol Lipids, 2020 PubMed Europe PMC Scholia
  7. ''Tryptophan metabolism, map00380''; KEGG Pathways,from https://www.genome.jp/dbget-bin/www_bget?pathway:map00380,
  8. ''''; , PubMed Europe PMC Scholia
  9. ''Kynurenine Pathway Library''; Enamine, from https://enamine.net/hit-finding/focused-libraries/view-all/immuno-oncology-library/kynurenine-pathway-library,
  10. Tan VX, Guillemin GJ; ''Kynurenine Pathway Metabolites as Biomarkers for Amyotrophic Lateral Sclerosis.''; Front Neurosci, 2019 PubMed Europe PMC Scholia
  11. Kondrikov D, Elmansi A, Bragg RT, Mobley T, Barrett T, Eisa N, Kondrikova G, Schoeinlein P, Aguilar-Perez A, Shi XM, Fulzele S, Lawrence MM, Hamrick M, Isales C, Hill W; ''Kynurenine inhibits autophagy and promotes senescence in aged bone marrow mesenchymal stem cells through the aryl hydrocarbon receptor pathway.''; Exp Gerontol, 2020 PubMed Europe PMC Scholia
  12. Sorgdrager FJH, Naudé PJW, Kema IP, Nollen EA, Deyn PP; ''''; , PubMed Europe PMC Scholia
  13. Oxenkrug GF; ''Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated psychiatric and medical disorders.''; J Neural Transm (Vienna), 2011 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
115411view11:53, 18 February 2021EgonwMade three more pathways clickable
115384view05:24, 17 February 2021KhanspersOntology Term : 'cellular senescence pathway' added !
115383view05:23, 17 February 2021KhanspersOntology Term : 'kynurenine metabolic pathway' added !
115382view05:20, 17 February 2021Khanspersadded some xrefs
115248view06:34, 8 February 2021EgonwFixed an identifier
114613view15:01, 25 January 2021Soniaa.balanNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
(S)-3-hydroxy- butanoyl-CoAMetaboliteQ27089442 (Wikidata)
3-HAAMetaboliteCHEBI:15793 (ChEBI)
3-HAOProteinP46952 (Uniprot-TrEMBL)
3-HKMetaboliteCHEBI:1547 (ChEBI)
ACMSAMetabolite5280673 (PubChem-compound)
ACMSDProteinQ8TDX5 (Uniprot-TrEMBL)
AFMIDProteinQ63HM1 (Uniprot-TrEMBL)
AMSAMetaboliteCHEBI:15745 (ChEBI)
  • Mus Musculus
  • Type your comment here
Acetyl-CoAMetaboliteHMDB01206 (HMDB)
AhR Signaling PathwayPathwayWP2873 (WikiPathways)
AhRProteinP35869 (Uniprot-TrEMBL) mice stem cells used
Anthranilic acidMetaboliteCHEBI:30754 (ChEBI)
BH4MetaboliteCHEBI:15372 (ChEBI)
CinnavalininateMetaboliteCHEBI:3715 (ChEBI)
Coenzyme AMetaboliteCHEBI:15346 (ChEBI)
Crotonyl-CoAMetaboliteCHEBI:15473 (ChEBI)
FOXO1GeneProductENSG00000150907 (Ensembl)
GCN2ProteinQ9P2K8 (Uniprot-TrEMBL)
Glutaconyl-CoAMetaboliteHMDB01290 (HMDB)
Glycolysis PathwayWP534 (WikiPathways)
IDO1 promoter GeneProduct
IDO1ProteinP14902 (Uniprot-TrEMBL)
IDO2ProteinQ6ZQW0 (Uniprot-TrEMBL)
IFNβProteinP01574 (Uniprot-TrEMBL)
IFNγProteinP01579 (Uniprot-TrEMBL)
IL-1RProteinP27930 (Uniprot-TrEMBL)
JNK Signaling PathwayPathway
KATProteinQ8N5Z0 (Uniprot-TrEMBL)
KLF5GeneProductENSG00000102554 (Ensembl)
KMOProteinO15229 (Uniprot-TrEMBL)
  • Mitochondral-associated enzyme
  • Type your comment here
Kynurenic acidMetaboliteCHEBI:18344 (ChEBI)
KynureninaseProteinQ16719 (Uniprot-TrEMBL)
KynurenineMetaboliteCHEBI:28683 (ChEBI)
Liposaccharides
MelatoninMetaboliteCHEBI:16796 (ChEBI)
N-FormylkynurenineMetaboliteCHEBI:18377 (ChEBI)
NAADMetaboliteHMDB01179 (HMDB)
NAD de novo

Synthesis

Pathway
NAD+MetaboliteCHEBI:15846 (ChEBI)
NAMNMetaboliteCHEBI:15763 (ChEBI)
NOSProteinB3VK56 (Uniprot-TrEMBL)
PGE2MetaboliteCHEBI:606564 (ChEBI)
Picolinic acidMetaboliteHMDB02243 (HMDB)
QPRTGeneProductENSG00000103485 (Ensembl)
Quinolinic acidMetaboliteHMDB00232 (HMDB)
Serotonin/Melatonin PathwayPathway
TCA CyclePathwayWP78 (WikiPathways)
TDO ProteinP48775 (Uniprot-TrEMBL)
TGFβProteinP01137; P10600; P61812
TLR 4ProteinO00206 (Uniprot-TrEMBL)
TNFProteinP01375 (Uniprot-TrEMBL)
TryptophanMetaboliteCHEBI:27897 (ChEBI)
Xanthurenic acidMetaboliteHMDB00881 (HMDB)
acetoacetyl-CoAMetaboliteQ2639429 (Wikidata)
eIF-2alphaProteinQ9BQI3 (Uniprot-TrEMBL)
glutaryl-coAMetaboliteCHEBI:15524 (ChEBI)
miR-210-3pRnaMIMAT0000267 (miRBase Sequence)
miR-493-5pRnaMIMAT0002813 (miRBase Sequence)
other miRNAs
p21ProteinP38936 (Uniprot-TrEMBL)
p53ProteinP04637 (Uniprot-TrEMBL)

Annotated Interactions

No annotated interactions
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