Tryptophan metabolism (WP465)

Homo sapiens

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This pathway describes the metabolism of tryptophan, an essential amino acid. Originally adapted from: [https://www.genome.jp/kegg-bin/show_pathway?hsa00380 KEGG], and expanded with information from [https://doi.org/10.1016/j.chom.2018.05.003 Agus 2018], [https://doi.org/10.1177%2F1178646919852996 Dehhaghi 2019], and [https://doi.org/10.1093/advances/nmz127 Gao 2020]. "The tryptophan (Trp) metabolism follows three major pathways in the gastrointestinal tract: 1. direct transformation of Trp, including ligands of the aryl hydrocarbon receptor (AhR), by the gut microbiota; 2. through the kynurenine pathway in both immune and epithelial cells via indoleamine 2,3-dioxygenase (IDO) 1; 3. the serotonin (5-hydroxytryptamine [5-HT]) production pathway in enterochromaffin cells via Trp hydroxylase 1 (TpH1)." [https://doi.org/10.1016/j.chom.2018.05.003 Agus 2018]. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP465 CPTAC Assay Portal].

Authors

Lynn M. Ferrante , Alex Pico , Kristina Hanspers , Adrien Defay , Egon Willighagen , Denise Slenter , Friederike Ehrhart , and Finterly Hu

Activity

last edited

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Cited In

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Organisms

Homo sapiens

Communities

Annotations

Pathway Ontology

tryptophan metabolic pathway tryptophan biosynthetic pathway tryptophan degradation pathway kynurenine metabolic pathway aryl hydrocarbon receptor signaling pathway classic metabolic pathway signaling pathway regulatory pathway indoleamine and related compounds biosynthetic pathway indoleamine and related compounds metabolic pathway

Cell Type Ontology

serotonin secreting cell enterochromaffin-like cell type EC enteroendocrine cell

Participants
Query Drugst.One

Label Type Compact URI Comment
2-Oxoadipate Metabolite chemspider:19951093 2-Oxoadipate
Anthranilate Metabolite chemspider:4573598 Anthranilate
Indole-3-acetate Metabolite chemspider:779 AKA IAA, Indole Acetic Acid; Indole acetic acid is converted to skatole by Lactobacillus, Clostridium, Bacteroides, and others.
5-hydroxykynurenamine Metabolite chebi:62214 5-Hydroxykynurenamine
(S)-3-Hydroxybutyryl-CoA Metabolite kegg.compound:C01144 (S)-3-Hydroxybutanoyl-CoA
5-Methoxyindoleacetate Metabolite chemspider:14533147 5-Methoxyindoleacetate
2-Aminomuconate Metabolite kegg.compound:C03824 2-Aminomuconate
3-Hydroxy-L-kynurenine Metabolite kegg.compound:C03227 AKA 3-Hydroxy-L-kynurenine, 3H-KYN
N-formylanthranilate Metabolite wikidata:Q27103061 Formylanthranilate
2-Aminomuconate Metabolite kegg.compound:C02220 2-Aminomuconate
4,8-Dihydroxyquinoline Metabolite chebi:28883 4,8-Dihydroxyquinoline
Cinnavalininate Metabolite kegg.compound:C05640 Cinnavalininate
3-Hydroxykynurenamine Metabolite hmdb:HMDB0060281 3-Hydroxykynurenamine
Indole-3-acetaldehyde Metabolite chemspider:778 AKA IAAId
Formyl-5-hydroxykynurenamine Metabolite hmdb:HMDB0012948
2-Amino-3-carboxymuconate Metabolite kegg.compound:C04409 2-Amino-3-carboxymuconate
Serotonin Metabolite chemspider:5013 AKA 3-(2-Aminoethyl)-1H-indol-5-ol
3-Hydroxyanthranilate Metabolite chemspider:7822291 AKA 3-Hydroxyanthranilate, 3-HAA
Formyl-N-acetyl-5-methoxykynurenamine Metabolite kegg.compound:C05642 Formyl-N-acetyl-5-methoxykynurenamine
5-Hydroxyindoleacetate Metabolite chemspider:10637170 5-Hydroxyindoleacetate
Quinolinate Metabolite chemspider:2777129
Formylkynurenine Metabolite cas:1022-31-7 Formylkynurenine
4-(2-Amino-3-hydroxyphenyl)-2,4-dioxobutanoate Metabolite hmdb:HMDB0004083
ILA Metabolite chebi:55528 AKA Indole-3-lactic acid
skatole Metabolite chebi:9171 Indole acetic acid is converted to skatole by Lactobacillus, Clostridium, Bacteroides, and others.
Indolepyruvate Metabolite kegg.compound:C00331 AKA IPYA, IP
Acetyl-CoA Metabolite cas:72-89-9 Acetyl-CoA
alpha-tocopherol Metabolite chebi:22470
Indole Metabolite chebi:35581
5-Hydroxy-L-tryptophan Metabolite hmdb:HMDB0000472 'The neurotransmitter 5-HT is produced in the brain through the Trp hydroxylase 2 enzyme (TpH2), [...], more than 90% of the body's 5-HT is produced in the gut and particularly in enterochromaffin cells (ECs), a specialized subtype of intestinal epithelial cell.'
Butyrate Metabolite chebi:17968
L-Kynurenine Metabolite cas:343-65-7 L-Kynurenine
Melatonin Metabolite hmdb:HMDB0001389
5-Hydroxykynurenine Metabolite cas:484-78-6
Xanthurenic acid Metabolite hmdb:HMDB0000881
Indole-3-acetamide Metabolite chebi:16031 AKA IAM
N-Methylserotonin Metabolite hmdb:HMDB0004369
Tryptophol Metabolite chebi:17890
Tryptamine Metabolite cas:61-54-1
5-Hydroxy-N-formylkynurenine Metabolite hmdb:HMDB0004086
4,6-Dihydroxyquinoline Metabolite hmdb:HMDB0004077
indole-sulfonic acid Metabolite pubchem.compound:12904055
SCFAs Metabolite chebi:26666 Short-Chain-fatty-acids
L-Tryptophan Metabolite cas:73-22-3
Kynurenic Acid Metabolite chebi:18344
Acetoacetyl-CoA Metabolite kegg.compound:C00332
Indican Metabolite chebi:16700
N-Methyltryptamine Metabolite chebi:28136
Crotonoyl-CoA Metabolite kegg.compound:C00877
5-Hydroxyindoleacetaldehyde Metabolite hmdb:HMDB0004073 AKA 5-HIAA
4-aminobenzoic acid Metabolite chebi:30753
Indolyl acryloyl glycine Metabolite chebi:145761
Tyramine Metabolite chebi:15760
6-Hydroxymelatonin Metabolite cas:2208-41-5
Indole-3-aldehyde Metabolite chebi:28238 AKA IAId
Glutaryl-CoA Metabolite kegg.compound:C00527
cholate Metabolite chebi:29747
N-Acetylserotonin Metabolite cas:1210-83-9 AKA N-Acetylserotonin, NAS
picolinate Metabolite kegg.compound:C10164
IA Metabolite chebi:132244 AKA Indole acrylic acid
IPA Metabolite chebi:43580 AKA Indole-3-propionic acid
Quinaldic Acid Metabolite chebi:18386
Indole acetic glutamine Metabolite chebi:176458
IDO2 GeneProduct ncbigene:169355
GCDH GeneProduct ncbigene:2639 predicted
ALDH2 GeneProduct ncbigene:217
4.1.1.- GeneProduct eccode:4.1.1.- Unclear which specific protein acts in this reaction
ASMT GeneProduct ncbigene:438
IDO2 GeneProduct ensembl:ENSG00000188676
1.5.1.- GeneProduct eccode:1.5.1.- Unclear which specific protein acts in this reaction.
CYP1A1 GeneProduct ncbigene:1543
DLD GeneProduct ncbigene:1738 aka OADH
MAOA GeneProduct ncbigene:4128
DDC GeneProduct ncbigene:1644 In Agus et al, this protein is called 'AAAD', aka 'aromatic amino acid decarboxylase', which is known in UniProt at DCC; AAAD is an unrelated protein and its addition to Figure 2 of this paper is questionable [PMID:29902437]. Fig. 1 [PMID:31825083] mentions AADC, in peripheral synthesis.
CAT GeneProduct ncbigene:847
STAT1 GeneProduct ensembl:ENSG00000115415
DDC GeneProduct ncbigene:1644
DDC GeneProduct ncbigene:1644 Known under two EC numbers: aromatic-L-amino-acid/L-tryptophan decarboxylase [EC:4.1.1.28; EC:4.1.1.105]
ACAT1 GeneProduct ncbigene:38
INDO2 GeneProduct ncbigene:3620
AFMID GeneProduct ncbigene:125061
AANAT GeneProduct ncbigene:15
ALDH8A1 GeneProduct ncbigene:64577
AOX1 GeneProduct ncbigene:316
AADAT GeneProduct ncbigene:56267
ACMSD GeneProduct ncbigene:130013
KMO GeneProduct ncbigene:8564 liver PW
KYNU GeneProduct ncbigene:8942 AKA kynureninase
INMT GeneProduct ncbigene:11185
HAAO GeneProduct ncbigene:23498 AKA 3-hydroxyanthraniate 3,4-dioxygenase
AOC1 GeneProduct ncbigene:26 aka ABP1
MAOA GeneProduct ncbigene:4128 AKA Monoamine Ozydase (MAO)
IDO1 GeneProduct ensembl:ENSG00000131203
KYNU GeneProduct ncbigene:8942
ECHS1 GeneProduct ncbigene:1892
TDO2 GeneProduct ncbigene:6999 liver PW
TPH2 GeneProduct ncbigene:121278 produced in the brain; central synthesis
IDO2 GeneProduct ncbigene:169355 brain, liver and gut PW
ALDH2 Protein uniprot:P05091
IDO1 Protein uniprot:P14902 AKA indoleamine 2,3-dioxygenase, in both immune and epithelial cells [PMID: 22688187]
TpH1 Protein uniprot:P17752 AKA Trp hydroxylase 1, produced in intestinal epithelial cells; peripheral synthesis
HDAC Protein interpro:IPR000286 Family of proteins
MAOA Protein ncbigene:4128
AHR Protein hgnc.symbol:AHR
IL4I1 Protein uniprot:Q96RQ9
fldH Protein uniprot:G9EZR6 AKA phenyllactate dehydrogenase or indolelactic acid dehydrogenase (ILDH); species: Clostridium sporogenes (strain ATCC 7955 / DSM 767 / NBRC 16411 / NCIMB 8053 / NCTC 8594 / PA 3679)
ArAT Protein eccode:2.6.1.57 AKA Aromatic amino acid aminotransferase, group of proteins
KYAT1 Protein uniprot:Q16773 KAT I/glutamine transaminase K/cysteine conjugate beta-lyase 1
TMO Protein uniprot:P48775 AKA Tryptophan 2,3-dioxygenase; abbreviation TMO is not know in UniProt (TDO2 is the gene name).
TNA Protein uniprot:P31015 AKA Tryptophanase (2); Species: Symbiobacterium thermophilum (strain T / IAM 14863)
HADH Protein uniprot:Q16836
porB Protein uniprot:Q9ZKA3 AKA pyruvate : ferrodoxin oxidoreductase B; Species: Helicobacter pylori (strain J99 / ATCC 700824) (Campylobacter pylori J99)
acdA Protein uniprot:P45867 AKA acyl-CoA dehydrogenase; Species: Bacillus subtilis (strain 168)
fldH Protein uniprot:J7SHB8 AKA phenyllactate dehydrogenase or indolelactic acid dehydrogenase (ILDH); species: Clostridium sporogenes (strain ATCC 15579)
fldB Protein uniprot:Q93AL9 AKA phenyllactate dehydratase; fldBC is know as two entries in UniProt (fldB and fldC); Species: Clostridium sporogenes
fldC Protein uniprot:Q93AL8 AKA phenyllactate dehydratase; fldBC is know as two entries in UniProt (fldB and fldC); Species: Clostridium sporogenes
acdA Protein uniprot:J7TF92 AKA acyl-CoA dehydrogenase; Species: Clostridium sporogenes (strain ATCC 15579)
TNA Protein uniprot:P31014 AKA Tryptophanase (1); Species: Symbiobacterium thermophilum (strain T / IAM 14863)
TNA Protein uniprot:Q9ZNA8 AKA Tryptophanase; Species: Proteus inconstans
TNA Protein uniprot:O07674 AKA Tryptophanase; Species: Haemophilus influenzae
KYAT2 Protein uniprot:Q8N5Z0 KAT II/aminoadipate aminotransferase
KYAT3 Protein uniprot:Q6YP21 KAT III/cysteine conjugate beta-lyase 2
KYAT4 Protein uniprot:P00505 KAT IV/glutamic-oxaloacetic transaminase 2/mitochondrial aspartate aminotransferase
IDO2 Protein uniprot:Q6ZQW0 brain, liver and gut PW
STAT1 Protein uniprot:P42224
STAT1 Protein uniprot:P42224 FN-gamma–dependent phosphorylation of STAT1

References

  1. KEGG Pathway: rno00380
  2. Structure, expression, and function of kynurenine aminotransferases in human and rodent brains. Han Q, Cai T, Tagle DA, Li J. Cell Mol Life Sci. 2010 Feb;67(3):353–68. PubMed Europe PMC Scholia
  3. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Clarke G, Grenham S, Scully P, Fitzgerald P, Moloney RD, Shanahan F, et al. Mol Psychiatry. 2013 Jun;18(6):666–73. PubMed Europe PMC Scholia
  4. Serotonin signalling in the gut--functions, dysfunctions and therapeutic targets. Mawe GM, Hoffman JM. Nat Rev Gastroenterol Hepatol. 2013 Aug;10(8):473–86. PubMed Europe PMC Scholia
  5. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, et al. Cell. 2015 Apr 9;161(2):264–76. PubMed Europe PMC Scholia
  6. Impact of the Gut Microbiota on Intestinal Immunity Mediated by Tryptophan Metabolism. Gao J, Xu K, Liu H, Liu G, Bai M, Peng C, et al. Front Cell Infect Microbiol. 2018 Feb 6;8:13. PubMed Europe PMC Scholia
  7. Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease. Agus A, Planchais J, Sokol H. Cell Host Microbe. 2018 Jun 13;23(6):716–24. PubMed Europe PMC Scholia
  8. Helicobacter pylori in human health and disease: Mechanisms for local gastric and systemic effects. Bravo D, Hoare A, Soto C, Valenzuela MA, Quest AF. World J Gastroenterol. 2018 Jul 28;24(28):3071–89. PubMed Europe PMC Scholia
  9. Butyrate Produced by Commensal Bacteria Down-Regulates Indolamine 2,3-Dioxygenase 1 (IDO-1) Expression via a Dual Mechanism in Human Intestinal Epithelial Cells. Martin-Gallausiaux C, Larraufie P, Jarry A, Béguet-Crespel F, Marinelli L, Ledue F, et al. Front Immunol. 2018 Dec 11;9:2838. PubMed Europe PMC Scholia
  10. Microorganisms, Tryptophan Metabolism, and Kynurenine Pathway: A Complex Interconnected Loop Influencing Human Health Status. Dehhaghi M, Kazemi Shariat Panahi H, Guillemin GJ. Int J Tryptophan Res. 2019 Jun 19;12:1178646919852996. PubMed Europe PMC Scholia
  11. Tryptophan Metabolism: A Link Between the Gut Microbiota and Brain. Gao K, Mu CL, Farzi A, Zhu WY. Adv Nutr. 2020 May 1;11(3):709–23. PubMed Europe PMC Scholia