Target Information

Target General Information

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Target ID

T78915 (Former ID: TTDI01969)

Target Name

Tryptophan 5-hydroxylase 1 (TPH1)

Synonyms

Tryptophan 5-monooxygenase 1; TRPH; TPRH

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Gene Name

TPH1

Target Type

Clinical trial target

[1]

Disease

[+] 2 Target-related Diseases

Psychotic disorder [ICD-11: 6A20-6A25]

Pulmonary hypertension [ICD-11: BB01]

Function

Responsible for addition of the -HO group (hydroxylation) to the 5 position to form the amino acid 5-hydroxytryptophan (5-HTP), which is the initial and rate-limiting step in the synthesis of the neurotransmitter serotonin.

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BioChemical Class

Paired donor oxygen oxidoreductase

UniProt ID

TPH1_HUMAN

EC Number

EC 1.14.16.4

Sequence

MIEDNKENKDHSLERGRASLIFSLKNEVGGLIKALKIFQEKHVNLLHIESRKSKRRNSEF
EIFVDCDINREQLNDIFHLLKSHTNVLSVNLPDNFTLKEDGMETVPWFPKKISDLDHCAN
RVLMYGSELDADHPGFKDNVYRKRRKYFADLAMNYKHGDPIPKVEFTEEEIKTWGTVFQE
LNKLYPTHACREYLKNLPLLSKYCGYREDNIPQLEDVSNFLKERTGFSIRPVAGYLSPRD
FLSGLAFRVFHCTQYVRHSSDPFYTPEPDTCHELLGHVPLLAEPSFAQFSQEIGLASLGA
SEEAVQKLATCYFFTVEFGLCKQDGQLRVFGAGLLSSISELKHALSGHAKVKPFDPKITC
KQECLITTFQDVYFVSESFEDAKEKMREFTKTIKRPFGVKYNPYTRSIQILKDTKSITSA
MNELQHDLDVVSDALAKVSRKPSI

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3D Structure

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PDB

HIT2.0 ID

T39T57

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

AGN-2979

Drug Info

Phase 2

Psychotic disorder

[1]

KAR5585

Drug Info

Phase 1

Pulmonary arterial hypertension

[2]

Mode of Action

[+] 2 Modes of Action

Modulator

[+] 1 Modulator drugs

AGN-2979

Drug Info

[1]

Inhibitor

[+] 3 Inhibitor drugs

6-fluorotryptophan

Drug Info

[3]

alpha-propyldopacetamide

Drug Info

[4]

fenclonine

Drug Info

[4]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: KAR5585

Ligand Info

Structure Description

Tryptophan 5-hydroxylase in complex with inhibitor (3~{S})-8-[2-azanyl-6-[(1~{R})-1-(4-chloranyl-2-phenyl-phenyl)-2,2,2-tris(fluoranyl)ethoxy]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-3-carboxylic acid

PDB:5L01

Method

X-ray diffraction

Resolution

1.90 Å

Mutation

[5]

PDB Sequence

TVPWFPKKIS

¹¹³

DLDHCANRVL

¹²³

MYGGFKDNVY

¹⁴¹

RKRRKYFADL

¹⁵¹

AMNYKHGDPI

¹⁶¹

PKVEFTEEEI

¹⁷¹

KTWGTVFQEL

¹⁸¹

NKLYPTHACR

¹⁹¹

EYLKNLPLLS

²⁰¹

KYCGYREDNI

²¹¹

PQLEDVSNFL

²²¹

KERTGFSIRP

²³¹

VAGYLSPRDF

²⁴¹

LSGLAFRVFH

²⁵¹

CTQYVRHSSD

²⁶¹

PFYTPEPDTC

²⁷¹

HELLGHVPLL

²⁸¹

AEPSFAQFSQ

²⁹¹

EIGLASLGAS

³⁰¹

EEAVQKLATC

³¹¹

YFFTVEFGLC

³²¹

KQDGQLRVFG

³³¹

AGLLSSISEL

³⁴¹

KHALSGHAKV

³⁵¹

KPFDPKITCK

³⁶¹

QECLITTFQD

³⁷¹

VYFVSESFED

³⁸¹

AKEKMREFTK

³⁹¹

TIK

Residue

Distance (Å)

LEU123

4.239

TYR235

3.777

LEU236

3.295

SER237

4.242

PRO238

3.818

PHE241

4.213

LEU242

4.922

ARG257

2.635

PHE263

4.586

TYR264

3.395

THR265

2.859

PRO266

3.126

GLU267

3.532

PRO268

3.615

Residue

Distance (Å)

ASP269

4.830

HIS272

3.494

ALA309

3.680

TYR312

3.735

PHE313

3.552

GLU317

3.339

PHE318

4.091

GLY333

3.680

SER336

2.532

SER337

3.541

CYS364

3.362

LEU365

4.251

ILE366

3.458

Ligand Name: 7,8-dihydrobiopterin

Ligand Info

Structure Description

Crystal structure of human tryptophan hydroxylase with bound 7,8-dihydro-L-biopterin cofactor and Fe(III)

PDB:1MLW

Method

X-ray diffraction

Resolution

1.71 Å

Mutation

[6]

PDB Sequence

SVPWFPKKIS

¹¹³

DLDHCANRVL

¹²³

MYGSELDADH

¹³³

PGFKDNVYRK

¹⁴³

RRKYFADLAM

¹⁵³

NYKHGDPIPK

¹⁶³

VEFTEEEIKT

¹⁷³

WGTVFRELNK

¹⁸³

LYPTHACREY

¹⁹³

LKNLPLLSKY

²⁰³

CGYREDNIPQ

²¹³

LEDVSNFLKE

²²³

RTGFSIRPVA

²³³

GYLSPRDFLS

²⁴³

GLAFRVFHCT

²⁵³

QYVRHSSDPF

²⁶³

YTPEPDTCHE

²⁷³

LLGHVPLLAE

²⁸³

PSFAQFSQEI

²⁹³

GLASLGASEE

³⁰³

AVQKLATCYF

³¹³

FTVEFGLCKQ

³²³

DGQLRVFGAG

³³³

LLSSISELKH

³⁴³

ALSGHAKVKP

³⁵³

FDPKITCKQE

³⁶³

CLITTFQDVY

³⁷³

FVSESFEDAK

³⁸³

EKMREFTKTI

³⁹³

Residue

Distance (Å)

VAL232

3.493

GLY234

2.996

TYR235

3.376

LEU236

2.599

SER237

3.824

PRO238

2.955

PHE241

3.370

Residue

Distance (Å)

LEU242

3.968

HIS251

4.320

GLU273

4.906

HIS277

4.675

ALA309

3.780

TYR312

3.421

GLU317

4.557

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

There is no similarity protein (E value < 0.005) for this target


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target
Tryptophan metabolism	hsa00380	Affiliated Target
Class: Metabolism => Amino acid metabolism	Pathway Hierarchy
Folate biosynthesis	hsa00790	Affiliated Target
Class: Metabolism => Metabolism of cofactors and vitamins	Pathway Hierarchy
Serotonergic synapse	hsa04726	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy

Degree	5	Degree centrality	5.37E-04	Betweenness centrality	5.14E-04
Closeness centrality	1.65E-01	Radiality	1.25E+01	Clustering coefficient	2.00E-01
Neighborhood connectivity	7.40E+00	Topological coefficient	2.92E-01	Eccentricity	11
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Affiliated Biological Pathways

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BioCyc

[+] 2 BioCyc Pathways

Superpathway of tryptophan utilization

Serotonin and melatonin biosynthesis

KEGG Pathway

[+] 3 KEGG Pathways

Tryptophan metabolism

Metabolic pathways

Serotonergic synapse

Panther Pathway

[+] 1 Panther Pathways

5-Hydroxytryptamine biosynthesis

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Tryptophan Metabolism

WikiPathways

[+] 4 WikiPathways

SIDS Susceptibility Pathways

Biogenic Amine Synthesis

Tryptophan metabolism

Metabolism of amino acids and derivatives

References

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REF 1

Antidepressant-like action of AGN 2979, a tryptophan hydroxylase activation inhibitor, in a chronic mild stress model of depression in rats. Eur Neuropsychopharmacol. 2001 Oct;11(5):351-7.

REF 2

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 3

(+)-6-fluorotryptophan, an inhibitor of tryptophan hydroxylase: sleep and wakefulness in the rat. Neuropharmacology. 1981 Apr;20(4):335-9.

REF 4

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1241).

REF 5

Optimization of spirocyclic proline tryptophan hydroxylase-1 inhibitors. Bioorg Med Chem Lett. 2017 Feb 1;27(3):413-419.

REF 6

Three-dimensional structure of human tryptophan hydroxylase and its implications for the biosynthesis of the neurotransmitters serotonin and melatonin. Biochemistry. 2002 Oct 22;41(42):12569-74.

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