Details for: TPH1

Gene ID: 7166

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: TPH1

Ensembl ID: ENSG00000129167

Description: tryptophan hydroxylase 1

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • enteroendocrine cell of small intestine CL0009006
    CSI 10.56
    rCSI 23.25%
    PRS 99.95
  • lung neuroendocrine cell CL1000223
    CSI 10.32
    rCSI 15.26%
    PRS 99.94
  • enteroendocrine cell CL0000164
    CSI 9.46
    rCSI 12.93%
    PRS 99.74
  • type EC enteroendocrine cell CL0000577
    CSI 6.58
    rCSI 23.37%
    PRS 99.95
  • neuroendocrine cell CL0000165
    CSI 5.02
    rCSI 19.42%
    PRS 100
  • enteroendocrine cell of colon CL0009042
    CSI 4.1
    rCSI 19.21%
    PRS 100
  • diffuse bipolar 3b cell CL4033030
    CSI 1.79
    rCSI 11.87%
    PRS 99.9

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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  • Node Color (Target Cell CSI, relative to current network):
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    • High
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  • Node Size: Proportional to Target Cell CSI magnitude
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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary Tryptophan hydroxylase 1 ([TPH1](/details-gene/7166)) is a protein-coding gene located on chromosome 11 that encodes the rate-limiting enzyme in the biosynthesis of serotonin (5-hydroxytryptamine) in peripheral tissues. As a monooxygenase, it catalyzes the conversion of L-tryptophan to 5-hydroxytryptophan. Its expression is highly specific, with the highest significance observed in [enteroendocrine cell](/details-cell/CL0000164)s of the gastrointestinal tract, particularly the [small intestine](/details-cell/CL0009006), and in [lung neuroendocrine cell](/details-cell/CL1000223)s. This expression pattern underscores its primary role as the source of the vast majority of the body's serotonin, which functions as a hormone and signaling molecule in diverse physiological processes outside the central nervous system, including gut motility, hemostasis, and bone metabolism. Its clinical relevance is linked to disorders involving peripheral serotonin dysregulation ([191060](https://omim.org/entry/191060)). ## Cellular Roles and Expression Landscape **Overall**, the expression profile of [TPH1](/details-gene/7166) is characterized by its exceptionally high specificity for neuroendocrine cell lineages responsible for peripheral serotonin synthesis. The gene shows the highest significance in [enteroendocrine cell of small intestine](/details-cell/CL0009006) (CSI: 10.56) and [lung neuroendocrine cell](/details-cell/CL1000223) (CSI: 10.32), followed by broader categories such as [enteroendocrine cell](/details-cell/CL0000164) (CSI: 9.46) and [neuroendocrine cell](/details-cell/CL0000165) (CSI: 5.02). Specifically, it is a key marker for [type EC enteroendocrine cell](/details-cell/CL0000577)s (CSI: 6.58), which are the primary producers of serotonin in the gut. This highly restricted expression pattern highlights the division of labor between [TPH1](/details-gene/7166) and its paralog, TPH2, which performs the same function in the central nervous system. The data confirm that [TPH1](/details-gene/7166) is the master regulator of serotonin production in the gut-lung axis. Its role in these tissues is foundational, providing the serotonin that regulates local physiological processes and enters circulation to be taken up by platelets, where it influences hemostasis. ## Pathways and Molecular Function The molecular function of [TPH1](/details-gene/7166) is defined by its `Tryptophan 5-monooxygenase activity` ([GO:0004510](https://www.ebi.ac.uk/QuickGO/term/GO:0004510)), which requires `Iron ion binding` ([GO:0005506](https://www.ebi.ac.uk/QuickGO/term/GO:0005506)) for its catalytic action [Link](https://doi.org/10.1021/bi026561f). This activity is the first and rate-limiting step in the `Serotonin biosynthetic process` ([GO:0042427](https://www.ebi.ac.uk/QuickGO/term/GO:0042427)), as detailed in the Reactome pathway `Serotonin and melatonin biosynthesis` ([R-HSA-209931](https://reactome.org/content/detail/R-HSA-209931)). The biological consequences of [TPH1](/details-gene/7166) activity are extensive, consistent with the pleiotropic effects of peripheral serotonin. Its involvement in the `Regulation of hemostasis` ([GO:1900046](https://www.ebi.ac.uk/QuickGO/term/GO:1900046)) and `Platelet degranulation` ([GO:0002576](https://www.ebi.ac.uk/QuickGO/term/GO:0002576)) is directly linked to the uptake of gut-derived serotonin by circulating platelets. Furthermore, functional annotations point to a systemic regulatory role in skeletal homeostasis, including `Bone remodeling` ([GO:0046849](https://www.ebi.ac.uk/QuickGO/term/GO:0046849)) and `Negative regulation of ossification` ([GO:0030279](https://www.ebi.ac.uk/QuickGO/term/GO:0030279)), where gut-derived serotonin acts as a hormone to inhibit bone formation. The gene's involvement in broader metabolic pathways, such as `Metabolism of amine-derived hormones` ([R-HSA-209776](https://reactome.org/content/detail/R-HSA-209776)), solidifies its central role in systemic endocrine signaling. ## Research Directions The highly specific expression of [TPH1](/details-gene/7166) in peripheral tissues makes it a key node for understanding and manipulating physiological processes governed by serotonin outside the brain. ### Proposed Hypotheses 1. **Differential regulation in the gut-lung axis:** Given its high significance in both [enteroendocrine cell](/details-cell/CL0000164)s and [lung neuroendocrine cell](/details-cell/CL1000223)s, it is hypothesized that the transcriptional and post-translational regulation of [TPH1](/details-gene/7166) is distinct in these two tissues, allowing for independent control of local serotonin levels in response to different stimuli (e.g., luminal contents in the gut vs. hypoxia in the lung). 2. **Role in metabolic syndrome:** Based on its function in `Positive regulation of fat cell differentiation` ([GO:0045600](https://www.ebi.ac.uk/QuickGO/term/GO:0045600)), we hypothesize that increased [TPH1](/details-gene/7166) activity in the gut contributes to adipogenesis and that its inhibition could be a therapeutic strategy to mitigate diet-induced obesity and associated metabolic dysfunctions. ### Key Experimental Approach To test the hypothesis that gut-derived serotonin negatively regulates bone mass, a key experiment would involve the generation of a gut-specific [TPH1](/details-gene/7166) knockout mouse model. Using a Cre-Lox system with a Villin-Cre driver, [TPH1](/details-gene/7166) could be specifically ablated in the intestinal epithelium. The resulting phenotype could be assessed by measuring serum serotonin levels (which should be drastically reduced) and performing micro-CT and histomorphometric analysis of long bones and vertebrae to quantify changes in bone mineral density, trabecular architecture, and osteoblast/osteoclast activity. This would definitively link the activity of [TPH1](/details-gene/7166) in a specific cell population ([enteroendocrine cell](/details-cell/CL0000164)s) to a systemic physiological outcome. ### Therapeutic Potential [TPH1](/details-gene/7166) is an attractive therapeutic target for diseases driven by excess peripheral serotonin. As an enzyme, it is highly druggable by small molecule inhibitors. The key advantage of targeting [TPH1](/details-gene/7166) is the ability to reduce peripheral serotonin without affecting brain serotonin levels, as inhibitors can be designed not to cross the blood-brain barrier, thus sparing the function of its CNS-specific paralog, TPH2. Therefore, **inhibition** of [TPH1](/details-gene/7166) is a promising strategy for conditions like carcinoid syndrome, irritable bowel syndrome with diarrhea (IBS-D), and pulmonary arterial hypertension.

Genular Protein ID: 52168686

Symbol: TPH1_HUMAN

Name: Tryptophan 5-hydroxylase 1

UniProtKB Accession Codes:

P17752 D3DQX6 O95188 O95189 Q16736 Q3KPG8

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 2 CTD 1 ChEBI 14 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 4 DrugCentral 1 EC 1 EMBL 7 Ensembl 2 EvolutionaryTrace 1 ExpressionAtlas 1 GO 14 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 10 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 NCBIfam 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 20 PDBsum 20 PIR 1 PIRSF 1 PRINTS 1 PRO 1 PROSITE 3 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 2 RefSeq 1 Rhea 1 SABIO-RK 1 SIGNOR 1 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 2377472

Title: Complete coding sequence of human tryptophan hydroxylase.

PubMed ID: 2377472

DOI: 10.1093/nar/18.14.4257

PubMed ID: 7986090

Title: Cloning and expression of rabbit and human brain tryptophan hydroxylase cDNA in Escherichia coli.

PubMed ID: 7986090

DOI: 10.1006/abbi.1994.1523

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 9751214

Title: Alternative splicing at the 3'-cDNA of human tryptophan hydroxylase.

PubMed ID: 9751214

DOI: 10.1046/j.1471-4159.1998.71041769.x

PubMed ID: 12379098

Title: Three-dimensional structure of human tryptophan hydroxylase and its implications for the biosynthesis of the neurotransmitters serotonin and melatonin.

PubMed ID: 12379098

DOI: 10.1021/bi026561f

Sequence Information:

  • Length: 444
  • Mass: 50985
  • Checksum: DFAD501446953A91
  • Sequence:
    • MIEDNKENKD HSLERGRASL IFSLKNEVGG LIKALKIFQE KHVNLLHIES RKSKRRNSEF 
EIFVDCDINR EQLNDIFHLL KSHTNVLSVN LPDNFTLKED GMETVPWFPK KISDLDHCAN 
RVLMYGSELD ADHPGFKDNV YRKRRKYFAD LAMNYKHGDP IPKVEFTEEE IKTWGTVFQE 
LNKLYPTHAC REYLKNLPLL SKYCGYREDN IPQLEDVSNF LKERTGFSIR PVAGYLSPRD 
FLSGLAFRVF HCTQYVRHSS DPFYTPEPDT CHELLGHVPL LAEPSFAQFS QEIGLASLGA 
SEEAVQKLAT CYFFTVEFGL CKQDGQLRVF GAGLLSSISE LKHALSGHAK VKPFDPKITC 
KQECLITTFQ DVYFVSESFE DAKEKMREFT KTIKRPFGVK YNPYTRSIQI LKDTKSITSA 
MNELQHDLDV VSDALAKVSR KPSI