TH

Summary

TH (tyrosine hydroxylase, HGNC:11782) is a protein-coding gene on chromosome 11p15.5, encoding Tyrosine 3-monooxygenase (P07101). Catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-Dopa), the rate-limiting step in the biosynthesis of catecholamines, dopamine, noradrenaline, and adrenaline.

The protein encoded by this gene is involved in the conversion of tyrosine to dopamine. It is the rate-limiting enzyme in the synthesis of catecholamines, hence plays a key role in the physiology of adrenergic neurons. Mutations in this gene have been associated with autosomal recessive Segawa syndrome. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.

Source: NCBI Gene 7054 — RefSeq curated summary.

At a glance

• Gene–disease (curated): tyrosine hydroxylase deficiency (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 17
• Clinical variants (ClinVar): 1,242 total — 52 pathogenic, 116 likely-pathogenic
• Phenotypes (HPO): 40
• Druggable target: yes
• MANE Select transcript: NM_000360

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11782
Approved symbol	TH
Name	tyrosine hydroxylase
Location	11p15.5
Locus type	gene with protein product
Status	Approved
Aliases	DYT5b
Ensembl gene	ENSG00000180176
Ensembl biotype	protein_coding
OMIM	191290
Entrez	7054

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 8 protein_coding, 3 nonsense_mediated_decay, 3 retained_intron

ENST00000324155, ENST00000333684, ENST00000352909, ENST00000381168, ENST00000381175, ENST00000381178, ENST00000412076, ENST00000416223, ENST00000461172, ENST00000469226, ENST00000479437, ENST00000853117, ENST00000941211, ENST00000941212

RefSeq mRNA: 3 — MANE Select: NM_000360 NM_000360, NM_199292, NM_199293

CCDS: CCDS31338, CCDS7730, CCDS7731

Canonical transcript exons

ENST00000352909 — 13 exons

Exon	Start	End
ENSE00001285442	2169650	2169871
ENSE00001607448	2165232	2165365
ENSE00001851822	2171697	2171815
ENSE00003527173	2166887	2167032
ENSE00003545349	2166002	2166058
ENSE00003550033	2165668	2165763
ENSE00003559971	2168491	2168665
ENSE00003565862	2167866	2167933
ENSE00003584238	2168091	2168179
ENSE00003585927	2167435	2167485
ENSE00003596261	2166480	2166549
ENSE00003662445	2166633	2166768
ENSE00003901440	2163929	2164392

Expression profiles

Bgee: expression breadth ubiquitous, 147 present calls, max score 94.90.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.8528 / max 461.9579, expressed in 169 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118191	1.6340	142
118190	0.1876	29
206160	0.0311	14

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
substantia nigra pars reticulata	UBERON:0001966	94.90	gold quality
substantia nigra pars compacta	UBERON:0001965	93.18	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.74	gold quality
substantia nigra	UBERON:0002038	86.19	gold quality
midbrain	UBERON:0001891	83.30	gold quality
right adrenal gland	UBERON:0001233	76.77	gold quality
adrenal gland	UBERON:0002369	76.75	gold quality
hypothalamus	UBERON:0001898	76.68	gold quality
left adrenal gland	UBERON:0001234	76.31	gold quality
left adrenal gland cortex	UBERON:0035825	74.95	gold quality
adrenal cortex	UBERON:0001235	72.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.04	gold quality
caudate nucleus	UBERON:0001873	71.74	gold quality
right lobe of liver	UBERON:0001114	68.38	gold quality
nucleus accumbens	UBERON:0001882	68.11	gold quality
ventral tegmental area	UBERON:0002691	65.65	gold quality
superior vestibular nucleus	UBERON:0007227	62.16	gold quality
right adrenal gland cortex	UBERON:0035827	60.53	gold quality
pituitary gland	UBERON:0000007	59.44	gold quality
putamen	UBERON:0001874	59.14	gold quality
inferior olivary complex	UBERON:0002127	58.36	silver quality
endocervix	UBERON:0000458	57.95	gold quality
adenohypophysis	UBERON:0002196	57.94	gold quality
adrenal tissue	UBERON:0018303	57.70	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	57.41	gold quality
liver	UBERON:0002107	56.68	gold quality
prefrontal cortex	UBERON:0000451	56.45	gold quality
forebrain	UBERON:0001890	56.10	gold quality
decidua	UBERON:0002450	55.99	gold quality
gall bladder	UBERON:0002110	55.11	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-25	yes	2758.94
E-GEOD-93593	yes	8.03
E-HCAD-10	yes	4.28
E-ANND-3	no	1.77

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, AP1, AR, ARNT, ASCL1, ATF1, ATF2, ATF4, ATF5, BCL6, BMAL1, CEBPG, CLOCK, CREB1, CREM, CTF1, EGR1, ELK1, ENO1, EOMES, ESR1, ESR2, ETV1, FOS, FOSB, FOSL2, FOXA1, FOXA2, FOXN1, GATA3, GSC2, HAND1, HAND2, HIF1A, HMX1, HOXA4, HOXA5, JUN, JUNB, JUND

miRNA regulators (miRDB)

9 targeting TH, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-6885-5P	98.71	64.33	902
HSA-MIR-6827-5P	98.46	64.88	1256
HSA-MIR-3665	97.73	65.08	975
HSA-MIR-4786-5P	97.45	67.89	924
HSA-MIR-433-5P	94.67	64.82	99

Literature-anchored findings (GeneRIF, showing 40)

• Gene expression found upregulated by Glial cell line-derived neurotrophic factor in human neuroblastoma cell lines (PMID:12358785)
• A review of investigations on the possible contribution and potential role of the TYH microsatellite HUMTH01 in neuropathological conditions represents an example of approaches needed to validate genetic targets in the post-genomic era. (PMID:12428766)
• The ultrastsructural localization of this enzyme in human BPMCs is regulated by cell stimulation and related to the functional activity of the enzyme. (PMID:12457228)
• Tyrosine hydroxylase neurons constitute a subpopulation of non-pyramidal cells that are morphologically and neurochemically heterogenous. (PMID:12571119)
• Gene expression is a sensitive and semiquantitative marker for minimal residual disease detection of neuroblastoma (PMID:12576454)
• results support a direct function for tyrosine hydroxylase in the melanosome via a concerted action with tyrosinase to promote pigmentation. (PMID:12631248)
• This study does not support the involvement of tyrosine hydroxylase, catechol-O-methyl transferase and Wolfram syndrome 1 polymorphisms in mood disorders. (PMID:12782971)
• tyrosine hydroxylase deficiency results not in predominating dystonia, a largely nondegenerative condition, but in a progressive often lethal neurometabolic disorder, which can be improved but not cured by L-dopa (PMID:12891655)
• In summary, our results provide a novel regulatory frame in which modulation of chromatin structure by histone deacetylase may contribute to transcriptional regulation of the tyrosine hydroxylase. (PMID:14651963)
• These data suggest that the repressor element may play an important role in neuron cell-specific expression of the tyrosine hydroxylase gene. (PMID:14651989)
• tyrosine hydroxylase polymorphism is associated with Tobacco Use Disorder (PMID:15077008)
• the denatured state properties of the AAAHs (TH, TPH and PAH) contribute significantly to the stability of these enzymes and their tolerance towards missense mutations (PMID:15135070)
• Physiological effects of four mutations (T245P, T283M, R306H, T463M) in human TyrH that cause a mild form of DOPA-responsive dystonia are primarily due to the decreased stability of the mutant proteins rather than decreases in their intrinsic activities. (PMID:15468323)
• The mutation rate of TH gene in Chinese patients with AR-DRD is low, hence suggesting the genetic heterogeneity and a new locus for autosomal recessive dopa-responsive dystonia. (PMID:15476168)
• Val-81-Met polymorphism of tyrosine hydroxylase may have a role in early-onset alscoholism. (PMID:15722952)
• choroid contains abundant NPY and TH nerve fibers related to chroroidal vascular structures (PMID:15736042)
• Human TH minimal promoters may provide opportunity for selection of TH-positive human embryonic and adult stem cells for brain transplantation experiments in animal models for Parkinson’s disease. (PMID:15744773)
• High stability hTH1 mutants can be generated by the loss of a PEST motif in their N-termini and the structural change in the catalytic domain, which would promise an efficient production of dopamine in mammalian cells expressing N-terminus deleted hTH1. (PMID:15898085)
• The CpG-rich sequence located outside the 5’ promoter region of the human tyrosine hydroxylase (TH) gene appears to influence the functional effect of the adjacent intronic HUMTH01 microsatellite. (PMID:15953356)
• TH gene expression in neuronal progenitor cells does not depend on Nurr1 and a better understanding may have implications for the development of novel therapeutic approaches and the pathogenesis of neurological illnesses. (PMID:16252282)
• L-DOPA is produced by ectopically expressing tyrosine hydroxylase in mouse albino retinal pigment epithelium cells. (PMID:16445854)
• demonstrated that these cells possess tyrosinase as well as L-tyrosine hydroxylase (TH) activity and synthesize melanosomes (PMID:16447258)
• Presence is demonstrated, in normal adult mouse dorsal root ganglia, of a distinct subpopulation of tyrosine hydroxylase-positive, essentially calcitonin gene-related peptide (CGRP)- and isolectin B4 (IB4)-negative small/medium-sized neurons. (PMID:16516890)
• hierarchical phosphorylation provides a mechanism whereby the two major human TH isoforms (1 and 2) can be differentially regulated with only isoform 1 responding to the ERK pathway, whereas isoform 2 is more sensitive to calcium-mediated events (PMID:16644734)
• DJ-1 transcriptionally up-regulates the human tyrosine hydroxylase by inhibiting the sumoylation of pyrimidine tract-binding protein-associated splicing factor (PMID:16731528)
• NRSF/REST functions as a repressor of TH transcription in NSCs via a mechanism dependent on the TH NRSE/RE1 sites. (PMID:16764822)
• The co-expression of GTP cyclohydrolase I (GCHI) with tyrosine hydroxylase (TH) indicates that TH is indeed active in human neurosecretory neurons. (PMID:17135716)
• In human chromaffin cells, activation of CRF1 receptors induced tyrosine hydroxylase, whereas activation of CRF2 suppressed it. (PMID:17194738)
• Chromatin remodeling might play a relevant role ine conferring tissue specific gene expression of the human tyrosine hydroxylate gene. (PMID:17195153)
• Results demonstrate for the first time existence of hTH isoforms Delta2,8,9 & Delta1b,2,8,9. Their general distribution in neuroblastoma and adrenal glands and translation into protein suggest a significant functional role for these novel hTH isoforms. (PMID:17391063)
• TH activity may be severely limited by oxygen availability even at moderate hypoxic conditions (PMID:17520326)
• Homozygous tyrosine hydroxylase gene promoter mutation is associated with encephalopathy (PMID:17698383)
• Catecholamine secretion is influenced by genetic variation in the adrenergic pathway encoding catecholamine synthesis at the rate-limiting step, TH. which may suggest new strategies to approach diagnosis and treatment of hypertension. (PMID:17698732)
• The extent of nestin-positive neuronal cells correlated with the appearance of tyrosine hydroxylase positive neurons. (PMID:17784840)
• TH allele tended towards association with higher severity of suicidal behaviour in bipolar patient. (PMID:17869399)
• Not all of the glomus cells in the carotid body express detectable TH levels either in normal or in some abnormal conditions (PMID:17926059)
• study does not support the involvement of tyrosine hydroxylase gene variants as major contributors to suicide, whereas dopa decarboxylase variants could mediate some features related to suicide and be involved in violent suicidal behavior (PMID:17948905)
• Tyrosine hydroxylase gene polymorphism is associated with gastric cancer (PMID:17972051)
• Reduced striatal tyrosine hydroxylase in incidental Lewy body disease. (PMID:17985144)
• The mRNA expression levels of IL-1beta, TNF-alpha and TH was higher in paranoid schizophrenic patients than those in normal controls. (PMID:17988588)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	th	ENSDARG00000030621
mus_musculus	Th	ENSMUSG00000000214
rattus_norvegicus	Th	ENSRNOG00000020410
drosophila_melanogaster	ple	FBGN0005626
caenorhabditis_elegans		WBGENE00000296

Paralogs (3): TPH1 (ENSG00000129167), TPH2 (ENSG00000139287), PAH (ENSG00000171759)

Protein

Protein identifiers

Tyrosine 3-monooxygenase — P07101 (reviewed: P07101)

Alternative names: Tyrosine 3-hydroxylase

All UniProt accessions (5): E7EQI0, P07101, F8W8M5, H0Y670, H0Y677

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-Dopa), the rate-limiting step in the biosynthesis of catecholamines, dopamine, noradrenaline, and adrenaline. Uses tetrahydrobiopterin and molecular oxygen to convert tyrosine to L-Dopa (PubMed:15287903, PubMed:1680128, PubMed:17391063, PubMed:24753243, PubMed:34922205, PubMed:8528210, Ref.18). In addition to tyrosine, is able to catalyze the hydroxylation of phenylalanine and tryptophan with lower specificity. Positively regulates the regression of retinal hyaloid vessels during postnatal development. Lacks catalytic activity. Lacks catalytic activity.

Subunit / interactions. Homotetramer (PubMed:24947669, Ref.18). Interacts (when phosphorylated at Ser-19) with YWHAG; one YWHAG dimer binds to one TH tetramer and this interaction may influence the phosphorylation and dephosphorylation of other sites. Interacts with NT5DC2; the interaction results in reduced phosphorylation and decreased catalytic activity of TH.

Subcellular location. Cytoplasm. Perinuclear region. Nucleus. Cell projection. Axon. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle.

Tissue specificity. Mainly expressed in the brain and adrenal glands.

Post-translational modifications. Phosphorylated on Ser-19, Ser-62 and Ser-71 by several protein kinases with different site specificities. Phosphorylation at Ser-62 and Ser-71 leads to an increase of TH activity. Phosphorylation at Ser-71 activates the enzyme and also counteracts the feedback inhibition of TH by catecholamines. Phosphorylation of Ser-19 and Ser-62 triggers the proteasomal degradation of TH through the ubiquitin-proteasome pathway. Phosphorylation at Ser-62 facilitates transport of TH from the soma to the nerve terminals via the microtubule network. Phosphorylation at Ser-19 induces the high-affinity binding to the 14-3-3 protein YWHAG; this interaction may influence the phosphorylation and dephosphorylation of other sites. Ser-19 increases the phosphorylation at Ser-71 in a hierarchical manner, leading to increased activity.

Disease relevance. Segawa syndrome autosomal recessive (ARSEGS) [MIM:605407] A form of DOPA-responsive dystonia presenting in infancy or early childhood. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. Some cases present with parkinsonian symptoms in infancy. Unlike all other forms of dystonia, it is an eminently treatable condition, due to a favorable response to L-DOPA. The disease is caused by variants affecting the gene represented in this entry. May play a role in the pathogenesis of Parkinson disease (PD). A genome-wide copy number variation analysis has identified a 34 kilobase deletion over the TH gene in a PD patient but not in any controls.

Activity regulation. Inhibited in feedback fashion by the catecholamine neurotransmitters, especially by dopamine in competition with tetrahydrobiopterin. Phosphorylation of several Ser/Thr residues in the N-terminus regulates the catalytic activity. Ser-62 and Ser-71 are readily phosphorylated to activate the catalytic activity. A Cysteine modification induced by N-ethylmaleimide (NEM), inhibits tyrosine 3-monooxygenase activity through the modification of the Cys-207.

Pathway. Catecholamine biosynthesis; dopamine biosynthesis; dopamine from L-tyrosine: step 1/2.

Similarity. Belongs to the biopterin-dependent aromatic amino acid hydroxylase family.

Isoforms (6)

UniProt ID	Names	Canonical?
P07101-1	3, TH type 4	yes
P07101-2	1, TH type 3
P07101-3	2, HTH-1, hTH-Delta1b,2, TH type 1
P07101-4	4, hTH-Delta2, TH type 2
P07101-5	5, hTH-Delta2,8,9
P07101-6	6, hTH-Delta1b,2,8,9

RefSeq proteins (3): NP_000351, NP_954986, NP_954987 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001273	ArAA_hydroxylase	Family
IPR005962	Tyr_3_mOase	Family
IPR018301	ArAA_hydroxylase_Fe/CU_BS	Binding_site
IPR019773	Tyrosine_3-monooxygenase-like	Family
IPR019774	Aromatic-AA_hydroxylase_C	Domain
IPR021164	Tyrosine_hydroxylase_CS	Conserved_site
IPR036329	Aro-AA_hydroxylase_C_sf	Homologous_superfamily
IPR036951	ArAA_hydroxylase_sf	Homologous_superfamily
IPR041903	Eu_TyrOH_cat	Domain
IPR045865	ACT-like_dom_sf	Homologous_superfamily
IPR049321	TH_ACT	Domain

Pfam: PF00351, PF12549, PF21417

Enzyme classification (BRENDA):

• EC 1.14.16.2 — tyrosine 3-monooxygenase (BRENDA: 49 organisms, 105 substrates, 117 inhibitors, 229 Km, 27 kcat entries)

Substrate kinetics (BRENDA)

17 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-TYROSINE	0.001–2.39	74
TETRAHYDROBIOPTERIN	0.0041–0.507	38
(RS)-6-METHYL-5,6,7,8-TETRAHYDROPTERIN	0.023–0.051	20
TYROSINE	0.0061–0.5	19
L-PHENYLALANINE	0.0016–5	18
6,7-DIMETHYL-2-AMINO-4-HYDROXY-5,6,7,8-TETRAHYDO	0.0001–0.045	15
PHENYLALANINE	0.0013–0.3	8
TETRAHYDROPTERIN	0.01–0.63	6
6-METHYL-5,6,7,8-TETRAHYDROPTERIN	0.033–0.95	5
6-METHYLTETRAHYDROPTERIN	0.051–0.409	4
L-TYR	0.051–0.33	3
L-DOPA	0.056–0.146	2
2-AMINO-4-HYDROXY-6-METHYL-5,6,7,8-TETRAHYDROPTE	0.058	1
6,7-DIMETHYL-2-AMINO-4-HYDROXY-5,6,7,8-TETRAHYDR	0.34	1
6-METHYL-5,6,7,8-TETRAHYDROBIOPTERIN	0.15	1

Catalyzed reactions (Rhea), 1 shown:

• (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin + L-tyrosine + O2 = (4aS,6R)-4a-hydroxy-L-erythro-5,6,7,8-tetrahydrobiopterin + L-dopa (RHEA:18201)

UniProt features (92 total): sequence variant 41, helix 15, strand 10, turn 5, modified residue 4, splice variant 4, mutagenesis site 4, binding site 3, sequence conflict 2, chain 1, region of interest 1, compositionally biased region 1, site 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
2XSN	X-RAY DIFFRACTION	2.68
4J6S	X-RAY DIFFRACTION	3.08
6ZZU	ELECTRON MICROSCOPY	3.5
6ZVP	ELECTRON MICROSCOPY	4
7A2G	ELECTRON MICROSCOPY	4.1
6ZN2	ELECTRON MICROSCOPY	4.3
7PIM	ELECTRON MICROSCOPY	4.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07101-F1	81.75	0.59

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 455 (important for substrate specificity)

Ligand- & substrate-binding residues (3): 361; 366; 406

Post-translational modifications (4): 502, 19, 62, 71

Mutagenesis-validated functional residues (4):

Position	Phenotype
62	affects subcellular localization. accumulates mainly in the soma of the neuroblastoma cells.
62	does not affect subcellular localization. distributed throughout the soma and neurites.
71	suppresses feedback inhibition induced by dopamine. suppresses feedback inhibition induced by dopamine; when associated
207	suppresses the decrease in tyrosine 3-monooxygenase activity induced by nem modification. suppresses feedback inhibition

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-209905	Catecholamine biosynthesis

MSigDB gene sets: 266 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, ATF_B, GOBP_MEMORY, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_RESPONSE_TO_ETHANOL, GOBP_COGNITION, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_BEHAVIOR, HARRIS_HYPOXIA, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_NEUROGENESIS, CREBP1_Q2, GOBP_CELL_CELL_SIGNALING

GO Biological Process (26): response to hypoxia (GO:0001666), synaptic transmission, dopaminergic (GO:0001963), heart morphogenesis (GO:0003007), dopamine biosynthetic process from tyrosine (GO:0006585), heart development (GO:0007507), visual perception (GO:0007601), learning (GO:0007612), memory (GO:0007613), mating behavior (GO:0007617), locomotory behavior (GO:0007626), regulation of heart contraction (GO:0008016), anatomical structure morphogenesis (GO:0009653), animal organ morphogenesis (GO:0009887), dopamine biosynthetic process (GO:0042416), epinephrine biosynthetic process (GO:0042418), norepinephrine biosynthetic process (GO:0042421), serotonin biosynthetic process (GO:0042427), eye photoreceptor cell development (GO:0042462), eating behavior (GO:0042755), pigmentation (GO:0043473), response to ethanol (GO:0045471), embryonic camera-type eye morphogenesis (GO:0048596), cognition (GO:0050890), hyaloid vascular plexus regression (GO:1990384), aromatic amino acid metabolic process (GO:0009072), catecholamine biosynthetic process (GO:0042423)

GO Molecular Function (9): tyrosine 3-monooxygenase activity (GO:0004511), iron ion binding (GO:0005506), enzyme binding (GO:0019899), identical protein binding (GO:0042802), monooxygenase activity (GO:0004497), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced pteridine as one donor, and incorporation of one atom of oxygen (GO:0016714), metal ion binding (GO:0046872)

GO Cellular Component (14): nucleus (GO:0005634), cytoplasm (GO:0005737), smooth endoplasmic reticulum (GO:0005790), cytosol (GO:0005829), synaptic vesicle (GO:0008021), cytoplasmic side of plasma membrane (GO:0009898), axon (GO:0030424), cytoplasmic vesicle (GO:0031410), melanosome membrane (GO:0033162), neuron projection (GO:0043005), perikaryon (GO:0043204), perinuclear region of cytoplasm (GO:0048471), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of amine-derived hormones	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
catecholamine biosynthetic process	3
cytoplasm	3
animal organ development	2
learning or memory	2
protein binding	2
response to stress	1
response to decreased oxygen levels	1
chemical synaptic transmission	1
heart development	1
animal organ morphogenesis	1
dopamine biosynthetic process	1
circulatory system development	1
sensory perception of light stimulus	1
reproductive behavior	1
behavior	1
heart contraction	1
regulation of blood circulation	1
developmental process	1
anatomical structure development	1
anatomical structure morphogenesis	1
dopamine metabolic process	1
epinephrine metabolic process	1
norepinephrine metabolic process	1
serotonin metabolic process	1
indole-containing compound biosynthetic process	1
phenol-containing compound biosynthetic process	1
primary amino compound biosynthetic process	1
eye photoreceptor cell differentiation	1
photoreceptor cell development	1
feeding behavior	1
biological_process	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced pteridine as one donor, and incorporation of one atom of oxygen	1
transition metal ion binding	1
oxidoreductase activity	1
binding	1
catalytic activity	1
monooxygenase activity	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen	1
cation binding	1

Protein interactions and networks

STRING

3474 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TH	SNCA	P37840	975
TH	DBH	P09172	970
TH	SLC18A2	Q05940	964
TH	PNMT	P11086	948
TH	SLC6A3	Q01959	944
TH	DDC	P20711	944
TH	GCH1	P30793	915
TH	CHAT	P28329	881
TH	GDNF	P39905	847
TH	YWHAG	P35214	843
TH	BDNF	P23560	838
TH	NR4A2	P43354	837
TH	TAC1	P20366	836
TH	DRD2	P14416	834
TH	GAL	P22466	829

IntAct

10 interactions, top by confidence:

A	B	Type	Score
YWHAZ	TH	psi-mi:“MI:0914”(association)	0.530
TH	YWHAZ	psi-mi:“MI:0914”(association)	0.530
CEP192	WASL	psi-mi:“MI:0914”(association)	0.350
TH	MAP3K7	psi-mi:“MI:0914”(association)	0.350
VCP	FAM171A2	psi-mi:“MI:0914”(association)	0.350
YWHAH	TH	psi-mi:“MI:0914”(association)	0.350
TH	YWHAG	psi-mi:“MI:0914”(association)	0.350
TH	YWHAZ	psi-mi:“MI:0914”(association)	0.350

BioGRID (42): KDM3B (Affinity Capture-MS), NFIC (Affinity Capture-MS), RELL1 (Affinity Capture-MS), DNAJC12 (Affinity Capture-MS), ZBTB34 (Affinity Capture-MS), MTFR2 (Affinity Capture-MS), MAP3K7 (Affinity Capture-MS), TAOK2 (Affinity Capture-MS), TAB1 (Affinity Capture-MS), TH (Co-localization), TH (Co-localization), TH (Co-localization), TH (Co-localization), TH (Two-hybrid), TH (Two-hybrid)

ESM2 similar proteins: A0A060X6Z0, A8HQD7, A8X3V8, E5KBU3, E5KBU4, G8BAW7, O17446, O42091, O80452, P00365, P00439, P04176, P04177, P07101, P09810, P11982, P15274, P16331, P17276, P17289, P17290, P17532, P17752, P18459, P23225, P24529, P34466, P50998, P70080, P90925, P90986, Q0EAB8, Q0U2R3, Q10289, Q2HZ26, Q2KIH7, Q4W9F7, Q4WED9, Q54XS1, Q6BIV1

Diamond homologs: A0A060X6Z0, A8HQD7, A8X3V8, E5KBU3, E5KBU4, F5BFC8, O17446, O42091, P00439, P04176, P04177, P07101, P09810, P11982, P16331, P17276, P17289, P17290, P17532, P17752, P18459, P24529, P30967, P43334, P70080, P90925, P90986, Q0EAB8, Q2HZ26, Q2KIH7, Q54XS1, Q76IQ3, Q8CGU9, Q8CGV2, Q8IWU9, Q8XU39, Q92142, Q98D72, Q9A7V7, Q9KLB8

SIGNOR signaling

23 interactions.

A	Effect	B	Mechanism
CAMK2A	up-regulates	TH	phosphorylation
“MTA1/DJ1 complex”	“up-regulates quantity by expression”	TH	“transcriptional regulation”
CTF1	“down-regulates quantity by repression”	TH	“transcriptional regulation”
TH	“down-regulates quantity”	tyrosine	“chemical modification”
TH	“up-regulates quantity”	L-dopa	“chemical modification”
Gbeta	up-regulates	TH	phosphorylation
ERK1/2	up-regulates	TH	phosphorylation
CDK5	“up-regulates activity”	TH	phosphorylation
MAPK1	up-regulates	TH	phosphorylation
MAPK3	up-regulates	TH	phosphorylation
RPS6KA3	up-regulates	TH	phosphorylation
MAPKAPK5	up-regulates	TH	phosphorylation
RPS6KA5	up-regulates	TH	phosphorylation
ARNT	“down-regulates quantity by repression”	TH	“transcriptional regulation”
NPAS1	“down-regulates quantity by repression”	TH	“transcriptional regulation”
PRKACA	“up-regulates activity”	TH	phosphorylation
MAPKAPK2	“up-regulates activity”	TH	phosphorylation
CAMK2G	“up-regulates activity”	TH	phosphorylation
SFPQ	“down-regulates quantity by repression”	TH	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1242 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	52
Likely pathogenic	116
Uncertain significance	383
Likely benign	551
Benign	43

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068293	NM_000360.4(TH):c.488-1G>A	Pathogenic
1072805	NM_000360.4(TH):c.788del (p.Gly263fs)	Pathogenic
12327	NM_000360.4(TH):c.605G>A (p.Arg202His)	Pathogenic
12331	NM_000360.4(TH):c.1105-24T>A	Pathogenic
12332	NM_000360.4(TH):c.202del (p.Leu68fs)	Pathogenic
1359133	NM_000360.4(TH):c.1138A>T (p.Lys380Ter)	Pathogenic
1371019	NM_000360.4(TH):c.281C>A (p.Ser94Ter)	Pathogenic
1390521	NM_000360.4(TH):c.1354C>T (p.Gln452Ter)	Pathogenic
1452491	NM_000360.4(TH):c.374_387dup (p.Tyr130fs)	Pathogenic
1457222	NM_000360.4(TH):c.584C>A (p.Ser195Ter)	Pathogenic
1458504	NC_000011.9:g.(?2191910)(2193087_?)del	Pathogenic
1460233	NC_000011.9:g.(?2187460)(2191953_?)del	Pathogenic
188890	NM_000360.4(TH):c.1282C>T (p.Gln428Ter)	Pathogenic
1947375	NM_000360.4(TH):c.507del (p.Val170fs)	Pathogenic
1998536	NM_000360.4(TH):c.91-833dup	Pathogenic
2019062	NM_000360.4(TH):c.982_991del (p.Cys328fs)	Pathogenic
2025524	NM_000360.4(TH):c.837del (p.Lys280fs)	Pathogenic
2033133	NM_000360.4(TH):c.778del (p.Arg260fs)	Pathogenic
2039753	NM_000360.4(TH):c.1341T>A (p.Tyr447Ter)	Pathogenic
2052457	NM_000360.4(TH):c.1252dup (p.Ala418fs)	Pathogenic
208620	NM_000360.4(TH):c.283del (p.Ala95fs)	Pathogenic
2093216	NM_000360.4(TH):c.138dup (p.Lys47fs)	Pathogenic
2105184	NM_000360.4(TH):c.263del (p.Pro88fs)	Pathogenic
2114831	NM_000360.4(TH):c.739_743dup (p.Cys248fs)	Pathogenic
2427667	NC_000011.9:g.(?2186878)(2193016_?)del	Pathogenic
2427668	NC_000011.9:g.(?2187222)(2188272_?)del	Pathogenic
2695432	NM_000360.4(TH):c.91-835AC[3]	Pathogenic
2700013	NM_000360.4(TH):c.796G>T (p.Glu266Ter)	Pathogenic
2729268	NM_000360.4(TH):c.898del (p.Leu300fs)	Pathogenic
2735235	NM_000360.4(TH):c.592del (p.Val198fs)	Pathogenic

SpliceAI

2284 predictions. Top by Δscore:

Variant	Effect	Δscore
11:2164388:AGCTC:A	acceptor_gain	1.0000
11:2164390:CTC:C	acceptor_gain	1.0000
11:2164391:TC:T	acceptor_gain	1.0000
11:2164392:CC:C	acceptor_gain	1.0000
11:2164393:C:CC	acceptor_gain	1.0000
11:2164393:CTGG:C	acceptor_loss	1.0000
11:2164394:T:C	acceptor_loss	1.0000
11:2165227:CCCA:C	donor_loss	1.0000
11:2165228:CCAC:C	donor_loss	1.0000
11:2165229:CAC:C	donor_loss	1.0000
11:2165230:ACCT:A	donor_loss	1.0000
11:2165241:T:TA	donor_gain	1.0000
11:2165366:C:CC	acceptor_gain	1.0000
11:2165759:TACAG:T	acceptor_gain	1.0000
11:2165760:ACAG:A	acceptor_gain	1.0000
11:2165761:CAG:C	acceptor_gain	1.0000
11:2165761:CAGC:C	acceptor_gain	1.0000
11:2165762:AGCT:A	acceptor_loss	1.0000
11:2165764:C:CA	acceptor_loss	1.0000
11:2165764:C:CC	acceptor_gain	1.0000
11:2165997:CCCA:C	donor_loss	1.0000
11:2165998:CCA:C	donor_loss	1.0000
11:2165999:CACC:C	donor_loss	1.0000
11:2166000:A:AG	donor_loss	1.0000
11:2166475:CGTA:C	donor_loss	1.0000
11:2166476:GTACC:G	donor_loss	1.0000
11:2166477:TAC:T	donor_loss	1.0000
11:2166479:C:G	donor_loss	1.0000
11:2166555:C:CT	acceptor_gain	1.0000
11:2166631:A:AC	donor_gain	1.0000

AlphaMissense

3205 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:2165740:G:C	F407L	1.000
11:2165740:G:T	F407L	1.000
11:2165742:A:G	F407L	1.000
11:2166713:G:C	F330L	1.000
11:2166713:G:T	F330L	1.000
11:2166715:A:G	F330L	1.000
11:2167902:C:A	R234M	1.000
11:2167902:C:G	R234T	1.000
11:2165702:C:T	G420D	0.999
11:2165738:C:T	G408E	0.999
11:2165743:C:A	E406D	0.999
11:2165743:C:G	E406D	0.999
11:2165744:T:A	E406V	0.999
11:2165752:G:C	F403L	0.999
11:2165752:G:T	F403L	0.999
11:2165754:A:G	F403L	0.999
11:2166051:C:T	G383D	0.999
11:2166522:G:C	H366Q	0.999
11:2166522:G:T	H366Q	0.999
11:2166524:G:C	H366D	0.999
11:2166526:C:T	G365E	0.999
11:2166539:G:C	H361D	0.999
11:2166539:G:T	H361N	0.999
11:2166548:C:G	D358H	0.999
11:2166633:G:T	P357Q	0.999
11:2166667:G:T	R346S	0.999
11:2166686:G:C	F339L	0.999
11:2166686:G:T	F339L	0.999
11:2166688:A:G	F339L	0.999
11:2166704:G:C	S333R	0.999

dbSNP variants (sampled 300 via entrez): RS1000192759 (11:2173494 A>G), RS1000582034 (11:2172273 T>C), RS1001077137 (11:2163508 C>T), RS1001302873 (11:2172056 T>G), RS1001423810 (11:2168291 G>A,T), RS1002356459 (11:2169665 A>G), RS1002471580 (11:2167875 T>C,G), RS1002826159 (11:2167642 C>A,G,T), RS1003213179 (11:2170938 G>T), RS1003627589 (11:2170566 G>A), RS1003880422 (11:2166716 G>A,T), RS1003966156 (11:2169248 T>A,G), RS1004018356 (11:2173755 G>A), RS1004063635 (11:2170315 C>T), RS1004254508 (11:2169450 C>T)

Disease associations

OMIM: gene MIM:191290 | disease phenotypes: MIM:605407, MIM:181500, MIM:128230

GenCC curated gene-disease

Disease	Classification	Inheritance
TH-deficient dopa-responsive dystonia	Definitive	Autosomal recessive
tyrosine hydroxylase deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
tyrosine hydroxylase deficiency	Definitive	AR

Mondo (7): TH-deficient dopa-responsive dystonia (MONDO:0011551), schizophrenia (MONDO:0005090), generalized dystonia (MONDO:0000476), intellectual disability (MONDO:0001071), dystonic disorder (MONDO:0003441), dystonia 5 (MONDO:0007495), tyrosine hydroxylase deficiency (MONDO:0100064)

Orphanet (5): Autosomal recessive dopa-responsive dystonia (Orphanet:101150), Generalized isolated dystonia (Orphanet:376724), Autosomal dominant dopa-responsive dystonia (Orphanet:98808), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

40 total (30 of 40 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000298	Mask-like facies
HP:0000508	Ptosis
HP:0000737	Irritability
HP:0000750	Delayed speech and language development
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001256	Mild intellectual disability
HP:0001270	Motor delay
HP:0001290	Generalized hypotonia
HP:0001300	Parkinsonism
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001348	Brisk reflexes
HP:0001761	Pes cavus
HP:0001762	Talipes equinovarus
HP:0001945	Fever
HP:0002019	Constipation
HP:0002063	Rigidity
HP:0002066	Gait ataxia
HP:0002067	Bradykinesia
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002174	Postural tremor
HP:0002375	Hypokinesia
HP:0002395	Lower limb hyperreflexia
HP:0002448	Progressive encephalopathy
HP:0002451	Limb dystonia
HP:0002548	Parkinsonism with favorable response to dopaminergic medication
HP:0003487	Babinski sign

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST000488_11	Prostate cancer	3.000000e-33
GCST001370_17	Prostate cancer (SNP x SNP interaction)	4.000000e-06
GCST001370_18	Prostate cancer (SNP x SNP interaction)	4.000000e-06
GCST001370_43	Prostate cancer (SNP x SNP interaction)	3.000000e-06
GCST001370_45	Prostate cancer (SNP x SNP interaction)	4.000000e-06
GCST002112_1	Celiac disease	7.000000e-06
GCST002413_2	Prostate cancer (early onset)	2.000000e-08
GCST002560_9	Type 2 diabetes	1.000000e-07
GCST006196_1	Type 1 diabetes in high risk HLA genotype individuals (time to event)	3.000000e-07
GCST006197_5	Type 1 diabetes autoantibodies in high risk HLA genotype individuals (time to event)	1.000000e-07
GCST006197_8	Type 1 diabetes autoantibodies in high risk HLA genotype individuals (time to event)	6.000000e-06
GCST008464_3	Type 2 diabetes	2.000000e-08
GCST008839_232	Height	6.000000e-35
GCST011369_18	Iron status biomarkers (ferritin levels)	3.000000e-11
GCST90002383_498	Hematocrit	9.000000e-13
GCST90002384_276	Hemoglobin	7.000000e-14
GCST90026412_1	Severe autoimmune type 2 diabetes	3.000000e-07

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0000409	disease free survival
EFO:0000482	event free survival time
EFO:0004866	autoantibody measurement
EFO:0004459	ferritin measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D004422	Dystonia Musculorum Deformans	C10.228.140.079.357; C10.228.662.300.200; C10.574.500.393; C16.320.400.330
D020821	Dystonic Disorders	C10.228.662.300
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C537537	Segawa syndrome, autosomal recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1969 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10770140	Toxicity	3	opioids	Opioid-Related Disorders
rs10770141	Toxicity	3	opioids	Opioid-Related Disorders
rs2070762	Efficacy	3	methylphenidate	Attention Deficit Disorder with Hyperactivity
rs2070762	Toxicity	3	opioids	Opioid-Related Disorders

PharmGKB variants

14 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs6356	TH		0.00	0
rs10743152	TH		0.00	0
rs10770141	TH	3	3.00	1	opioids
rs2070762	TH	3	3.50	2	methylphenidate;opioids
rs6357	TH		0.00	0
rs10840490	TH		0.00	0
rs10770140	TH	3	3.00	1	opioids
rs11564713	TH		0.00	0
rs11042962	TH		0.00	0
rs7483056	TH		0.00	0
rs10840489	TH		0.00	0
rs4074905	TH		0.00	0
rs3842727	TH		0.00	0
rs4072824	TH		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Amino acid hydroxylases

ChEMBL bioactivities

3 potent at pChembl≥5 of 5 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.52	IC50	300	nM	R-N-PROPYLNORAPOMORPHINE
6.14	IC50	720	nM	IOTYROSINE
6.00	IC50	1000	nM	CHEMBL330274

PubChem BioAssay actives

3 with measured affinity, of 9 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(6aR)-6-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol	313108: Inhibition of tyrosine hydroxylase	ic50	0.3000	uM
(2S)-2-amino-3-(4-hydroxy-3-iodophenyl)propanoic acid	340328: Inhibition of tyrosine hydroxylase	ic50	0.7200	uM
(6aS)-6-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol	313108: Inhibition of tyrosine hydroxylase	ic50	1.0000	uM

CTD chemical–gene interactions

58 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tretinoin	decreases reaction, affects cotreatment, decreases expression, affects reaction, increases expression	10
Estradiol	increases expression, increases secretion, affects expression, increases reaction	4
1-Methyl-4-phenylpyridinium	decreases expression, increases expression, decreases reaction	4
Benzo(a)pyrene	increases expression, affects methylation	2
Chlorpyrifos	affects reaction, increases expression, decreases expression	2
Methamphetamine	decreases activity, decreases expression, decreases reaction, affects reaction	2
Paraquat	decreases reaction, increases expression	2
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine	decreases reaction, decreases expression	2
propionaldehyde	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases expression, decreases reaction	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
decamethrin	decreases expression	1
butyraldehyde	increases expression	1
nickel chloride	decreases reaction, increases expression	1
manganese chloride	decreases expression, increases methylation	1
aflatoxin B2	decreases methylation	1
1-methyl-4-phenyl-2,3-dihydropyridinium	decreases expression, decreases reaction	1
pentanal	decreases expression	1
ginsenoside Re	decreases activity, decreases expression, decreases reaction	1
methyllycaconitine	affects binding, decreases activity, decreases reaction, increases expression	1
fipronil	decreases expression	1
prothioconazole	increases expression	1
(+)-JQ1 compound	decreases expression	1
ortho-topolin riboside	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	increases expression	1
Arsenic Trioxide	decreases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3777462	Binding	Binding affinity to tyrosine hydroxylase (unknown origin) at 10 uM	Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies. — Eur J Med Chem

Cellosaurus cell lines

6 cell lines: 4 induced pluripotent stem cell, 1 transformed cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_5F78	SVG-TH	Transformed cell line	Male
CVCL_A8IB	ESi101-A	Induced pluripotent stem cell	Female
CVCL_A8IC	ESi102-A	Induced pluripotent stem cell	Female
CVCL_D1UL	Abcam U-87MG TH KO	Cancer cell line	Male
CVCL_D4ZP	SDQLCHi066-A	Induced pluripotent stem cell	Female
CVCL_UM01	DHMCi001-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety