SPR

Summary

SPR (sepiapterin reductase, HGNC:11257) is a protein-coding gene on chromosome 2p13.2, encoding Sepiapterin reductase (P35270). Catalyzes the final one or two reductions in tetra-hydrobiopterin biosynthesis to form 5,6,7,8-tetrahydrobiopterin.

This gene encodes an aldo-keto reductase that catalyzes the NADPH-dependent reduction of pteridine derivatives and is important in the biosynthesis of tetrahydrobiopterin (BH4). Mutations in this gene result in DOPA-responsive dystonia due to sepiaterin reductase deficiency. A pseudogene has been identified on chromosome 1.

Source: NCBI Gene 6697 — RefSeq curated summary.

At a glance

• Gene–disease (curated): dopa-responsive dystonia due to sepiapterin reductase deficiency (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 209 total — 21 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 44
• Druggable target: yes
• MANE Select transcript: NM_003124

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11257
Approved symbol	SPR
Name	sepiapterin reductase
Location	2p13.2
Locus type	gene with protein product
Status	Approved
Aliases	SDR38C1
Ensembl gene	ENSG00000116096
Ensembl biotype	protein_coding
OMIM	182125
Entrez	6697

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 nonsense_mediated_decay

ENST00000234454, ENST00000498749, ENST00000713723, ENST00000871609, ENST00000871610, ENST00000871611

RefSeq mRNA: 1 — MANE Select: NM_003124 NM_003124

CCDS: CCDS1920

Canonical transcript exons

ENST00000234454 — 3 exons

Exon	Start	End
ENSE00000963407	72888314	72888604
ENSE00001168741	72891347	72892158
ENSE00001880436	72887408	72887736

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 96.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.8269 / max 98.7671, expressed in 1669 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20932	13.8269	1669

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	96.72	gold quality
right lobe of liver	UBERON:0001114	95.53	gold quality
right adrenal gland	UBERON:0001233	94.82	gold quality
right adrenal gland cortex	UBERON:0035827	94.52	gold quality
apex of heart	UBERON:0002098	94.51	gold quality
body of pancreas	UBERON:0001150	94.50	gold quality
left adrenal gland	UBERON:0001234	93.98	gold quality
left adrenal gland cortex	UBERON:0035825	93.42	gold quality
endometrium epithelium	UBERON:0004811	92.83	gold quality
adrenal cortex	UBERON:0001235	92.52	gold quality
body of stomach	UBERON:0001161	92.36	gold quality
pancreas	UBERON:0001264	92.28	gold quality
adult mammalian kidney	UBERON:0000082	92.19	gold quality
liver	UBERON:0002107	91.89	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.81	gold quality
heart left ventricle	UBERON:0002084	91.60	gold quality
transverse colon	UBERON:0001157	91.51	gold quality
adrenal gland	UBERON:0002369	91.49	gold quality
islet of Langerhans	UBERON:0000006	91.43	gold quality
rectum	UBERON:0001052	91.42	gold quality
gastrocnemius	UBERON:0001388	91.35	gold quality
cardiac ventricle	UBERON:0002082	91.12	gold quality
right atrium auricular region	UBERON:0006631	91.09	gold quality
muscle of leg	UBERON:0001383	90.68	gold quality
cardiac atrium	UBERON:0002081	89.90	gold quality
right uterine tube	UBERON:0001302	89.49	gold quality
nephron tubule	UBERON:0001231	89.38	gold quality
heart	UBERON:0000948	89.32	gold quality
stomach	UBERON:0000945	89.26	gold quality
parotid gland	UBERON:0001831	89.09	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.47

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

27 targeting SPR, 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-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-4753-5P	99.54	68.51	1356
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-421	98.90	67.04	1883
HSA-MIR-4742-3P	98.73	69.82	1803
HSA-MIR-7155-5P	98.65	66.14	1290
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-6731-3P	98.61	67.86	749
HSA-MIR-637	97.91	64.05	1517
HSA-MIR-8089	97.74	66.21	1698
HSA-MIR-4723-3P	97.67	65.91	1017
HSA-MIR-4667-5P	97.61	66.67	1683
HSA-MIR-6769B-3P	97.41	65.53	1036
HSA-MIR-3183	97.40	65.68	978
HSA-MIR-1913	97.07	66.20	1417
HSA-MIR-759	96.16	66.77	873

Literature-anchored findings (GeneRIF, showing 14)

• haploinsufficiency of SPR can be a rare cause of dopa-responsive dystonia (PMID:15241655)
• Potentially modulates the onset of or risk for Parkinson’s disease. (PMID:16443856)
• Although association of SPR to Parkinson’s disease (PD) is not strong enough to support that this is the PARK3 gene, this study further implicates a role for SPR in idiopathic PD. (PMID:17270157)
• Genomic DNA revealed the same homozygous point mutation introducing a premature stop codon in the SPR gene in 2 siblings. (PMID:18502672)
• This reduced transcription rate for SPR promoter haplotypes 2 and 3 may impact on antidepressant response and susceptibility to bipolar disorder. (PMID:19415819)
• We examine the sleep, sleep-wake rhythms, CSF neurotransmitters, and melatonin profile in a patient with sepiapterin reductase deficiency. (PMID:20337188)
• this large association study for the SPR gene revealed no association for Parkinson disease worldwide. (PMID:21782285)
• SRD can manifest as early-onset parkinsonism, widening the spectrum of the disease phenotype and adding to the genetic heterogeneity of the disease (PMID:22018912)
• SPR-mediated reduction of sepiapterin and redox cycling occur by distinct mechanisms (PMID:23640889)
• Authors identified SPR as a novel regulator of ODC enzyme activity and, based on clinical evidence, present a model in which SPR drives ODC-mediated malignant progression in neuroblastoma. (PMID:24096079)
• new homozygous mutation in the SPR gene was found in two sisters with dopa-responsive dystonia (PMID:24588500)
• We earlier presented evidence for a physical interaction between ODC and SPR and we showed that RNAi-mediated knockdown of SPR expression significantly reduced native ODC enzyme activity and impeded Neuroblastoma cell proliferation. (PMID:26093909)
• The allele frequencies for the SPR c.596-2A > G (0.7%) polymorphism is not a major cause of Parkinson’s disease in the Maltese. (PMID:27613114)
• Molecular and metabolic bases of tetrahydrobiopterin (BH4) deficiencies. (PMID:33903016)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	spra	ENSDARG00000004406
danio_rerio	sprb	ENSDARG00000058553
mus_musculus	Spr	ENSMUSG00000033735
rattus_norvegicus	Spr	ENSRNOG00000015455
rattus_norvegicus	Spr-ps1	ENSRNOG00000028235
drosophila_melanogaster	Sptr	FBGN0014032
drosophila_melanogaster	CG12116	FBGN0030041

Protein

Protein identifiers

Sepiapterin reductase — P35270 (reviewed: P35270)

All UniProt accessions (3): A0AAQ5BGR8, P35270, A0AAQ5BGS4

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the final one or two reductions in tetra-hydrobiopterin biosynthesis to form 5,6,7,8-tetrahydrobiopterin.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm.

Post-translational modifications. In vitro phosphorylation of Ser-213 by CaMK2 does not change kinetic parameters.

Disease relevance. Dystonia, DOPA-responsive, due to sepiapterin reductase deficiency (DRDSPRD) [MIM:612716] A form of DOPA-responsive dystonia. In the majority of cases, patients manifest progressive psychomotor retardation, dystonia and spasticity. Cognitive anomalies are also often present. The disease is due to severe dopamine and serotonin deficiencies in the central nervous system caused by a defect in BH4 synthesis. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the sepiapterin reductase family.

RefSeq proteins (1): NP_003115* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002347	SDR_fam	Family
IPR006393	Sepiapterin_red	Family
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR051721	Biopterin_syn/organic_redct	Family

Pfam: PF00106

Enzyme classification (BRENDA):

• EC 1.1.1.153 — sepiapterin reductase (L-erythro-7,8-dihydrobiopterin-forming) (BRENDA: 18 organisms, 111 substrates, 259 inhibitors, 71 Km, 24 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
SEPIAPTERIN	0.0002–0.169	22
9,10-PHENANTHRENEQUINONE	0.0019–0.464	11
NADPH	0.0014–0.052	7
DIACETYL	1–4	3
BENZIL	0.0183–0.02	2
MENADIONE	0.0872–0.18	2
NADP+	0.0057–0.077	2
1’-HYDROXY-2’-OXOPROPYLTETRAHYDROPTERIN	0.007	1
1,2-NAPHTHOQUINONE	0.0021	1
1,4-NAPHTHOQUINONE	0.027	1
1-PHENYL-1,2-PROPANEDIONE	0.118	1
2,3-DIMETHOXYNAPHTHALENE-1,4-DIONE	0.086	1
2,4-PENTANEDIONE	5.19	1
2-AMINO-6-(2-HYDROXYPROPANOYL)PTERIDIN-4(1H)-ONE	0.0143	1
7,8-DIHYDROBIOPTERIN	0.0077	1

Catalyzed reactions (Rhea), 2 shown:

• L-erythro-7,8-dihydrobiopterin + NADP(+) = L-sepiapterin + NADPH + H(+) (RHEA:18953)
• (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin + 2 NADP(+) = 6-pyruvoyl-5,6,7,8-tetrahydropterin + 2 NADPH + 2 H(+) (RHEA:32627)

UniProt features (40 total): helix 12, binding site 9, strand 8, modified residue 4, sequence variant 3, chain 1, mutagenesis site 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
6I6V	X-RAY DIFFRACTION	1.43
6I6P	X-RAY DIFFRACTION	1.62
6I79	X-RAY DIFFRACTION	1.63
6I6C	X-RAY DIFFRACTION	1.72
6I6T	X-RAY DIFFRACTION	1.79
7DSF	X-RAY DIFFRACTION	1.8
6I6F	X-RAY DIFFRACTION	1.94
4XWY	X-RAY DIFFRACTION	2.35
4Z3K	X-RAY DIFFRACTION	2.35
4HWK	X-RAY DIFFRACTION	2.4
4J7U	X-RAY DIFFRACTION	2.44
1Z6Z	X-RAY DIFFRACTION	2.5
4J7X	X-RAY DIFFRACTION	2.6
6USN	X-RAY DIFFRACTION	2.77

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35270-F1	96.71	0.96

Functional residue map

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

Ligand- & substrate-binding residues (9): 14–20; 42–43; 69–70; 157–158; 170; 174; 199; 201–206; 257

Post-translational modifications (4): 1, 32, 103, 213

Mutagenesis-validated functional residues (1):

Position	Phenotype
213	abolishes phosphorylation by camk2. no effect on kinetic parameters.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-1474151	Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation
R-HSA-203615	eNOS activation
R-HSA-1430728	Metabolism
R-HSA-196854	Metabolism of vitamins and cofactors
R-HSA-202131	Metabolism of nitric oxide: NOS3 activation and regulation
R-HSA-8978934	Metabolism of cofactors

MSigDB gene sets: 173 (showing top): MODULE_93, GOBP_POLYOL_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, FERREIRA_EWINGS_SARCOMA_UNSTABLE_VS_STABLE_DN, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_PTERIDINE_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, BROWNE_HCMV_INFECTION_24HR_UP, GOBP_PTERIDINE_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_REACTIVE_NITROGEN_SPECIES_METABOLIC_PROCESS, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, GOBP_DIOL_METABOLIC_PROCESS, TGANTCA_AP1_C, DOUGLAS_BMI1_TARGETS_UP, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_CH_OH_GROUP_OF_DONORS

GO Biological Process (2): tetrahydrobiopterin biosynthetic process (GO:0006729), nitric oxide biosynthetic process (GO:0006809)

GO Molecular Function (4): sepiapterin reductase (NADP+) activity (GO:0004757), alcohol dehydrogenase (NADP+) activity (GO:0008106), NADP binding (GO:0050661), oxidoreductase activity (GO:0016491)

GO Cellular Component (5): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), cytosol (GO:0005829), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Metabolism	2
Metabolism of cofactors	1
Metabolism of nitric oxide: NOS3 activation and regulation	1
Metabolism of vitamins and cofactors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	2
diol biosynthetic process	1
pteridine-containing compound biosynthetic process	1
tetrahydrobiopterin metabolic process	1
biosynthetic process	1
nitric oxide metabolic process	1
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	1
alcohol dehydrogenase [NAD(P)+] activity	1
adenyl nucleotide binding	1
catalytic activity	1
nuclear lumen	1
intracellular membrane-bounded organelle	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2887 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPR	MCEE	Q96PE7	926
SPR	QDPR	P09417	865
SPR	GCH1	P30793	859
SPR	DHFR2	Q86XF0	849
SPR	PTS	Q03393	840
SPR	DHFR	P00374	815
SPR	PAH	P00439	793
SPR	PCBD1	P61457	765
SPR	MMUT	P22033	761
SPR	CBR1	P16152	744
SPR	AKR1B1	P15121	725
SPR	GCHFR	P30047	706
SPR	HSD3B2	P26439	656
SPR	TH	P07101	654
SPR	MMAA	Q8IVH4	649

IntAct

26 interactions, top by confidence:

A	B	Type	Score
AKR7A3	AKR7A2	psi-mi:“MI:0914”(association)	0.890
CD27	TCAF2	psi-mi:“MI:0914”(association)	0.640
SPR	BCAP31	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
SPR	YWHAZ	psi-mi:“MI:0915”(physical association)	0.400
RNF31	RTN3	psi-mi:“MI:0914”(association)	0.350
FGB	NME2	psi-mi:“MI:0914”(association)	0.350
VPS35	ILVBL	psi-mi:“MI:0914”(association)	0.350
MAN2B1	IGF2R	psi-mi:“MI:0914”(association)	0.350
CD5	IDE	psi-mi:“MI:0914”(association)	0.350
FECH	POTEF	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
GAB2	UBA6	psi-mi:“MI:0914”(association)	0.350
HPS1	PLPBP	psi-mi:“MI:0914”(association)	0.350
ITM2C	UBA6	psi-mi:“MI:0914”(association)	0.350
LGALS9	CYB5A	psi-mi:“MI:0914”(association)	0.350
MARS2	DDX39A	psi-mi:“MI:0914”(association)	0.350
MRPL49	UBA6	psi-mi:“MI:0914”(association)	0.350
NPPB	ACOT7	psi-mi:“MI:0914”(association)	0.350
SNRNP27	BPNT1	psi-mi:“MI:0914”(association)	0.350
SSBP2	TPD52L2	psi-mi:“MI:0914”(association)	0.350
VENTX	UBA6	psi-mi:“MI:0914”(association)	0.350
	TBKBP1	psi-mi:“MI:0914”(association)	0.350
	PSMD12	psi-mi:“MI:0914”(association)	0.350
YWHAG	RPSA2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (116): ACAT2 (Co-fractionation), ALDH6A1 (Co-fractionation), ATIC (Co-fractionation), COX17 (Co-fractionation), DUT (Co-fractionation), FUBP1 (Co-fractionation), HINT1 (Co-fractionation), HSPE1 (Co-fractionation), LGALS3 (Co-fractionation), LTA4H (Co-fractionation), MDH1 (Co-fractionation), MIF (Co-fractionation), PCMT1 (Co-fractionation), PDCD6IP (Co-fractionation), PEBP1 (Co-fractionation)

ESM2 similar proteins: A0A0S2CGD3, A0A144Y7G4, A0A162J3X8, A0A1L9WLE6, A0A455LLX2, A0A4V1DXC3, A0AAW1NHX6, A4II73, A5WVX1, A6QLY4, A8Q1U2, B0BML7, M2Y1A3, M2ZIX7, O57314, P18297, P29147, P35270, P40580, P51658, Q02338, Q13268, Q17QK8, Q28IU1, Q3SZ16, Q3SZ73, Q497C3, Q4V8B7, Q5E9H7, Q5RCH4, Q5XG41, Q64105, Q6Q2C2, Q6WAU1, Q7SYS6, Q7ZY31, Q8AVY8, Q8BTX9, Q8R536, Q8VDG5

Diamond homologs: B0BML7, O32099, O57314, P18297, P35270, P40579, Q17QK8, Q4P622, Q64105, Q7ZY31, Q8R536, A0A1B2CTA9, A0A1U8QWA2, A0A411PQN6, A0A5B8YU81, A0A7T8F1N2, A0QYC2, A1C6J8, A3LXZ3, A4QTE3, A7B3K3, A7DY56, A7TMJ2, A9CES4, B0ZT44, B2B3L4, F9XMW6, G0RNA2, G3YG17, I6Y778, M1W270, M2ZIX7, O07399, O31680, O54438, O67610, O86034, P0A0H9, P0A0I0, P0A2D1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CAMK2G	unknown	SPR	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	7
Uncertain significance	82
Likely benign	78
Benign	7

Top pathogenic / likely-pathogenic (28)

Variant ID	HGVS	Classification
1162322	NM_003124.5(SPR):c.304+2_304+13del	Pathogenic
12939	NM_003124.5(SPR):c.355C>T (p.Gln119Ter)	Pathogenic
12940	NM_003124.5(SPR):c.448_452del (p.Thr151fs)	Pathogenic
12941	NM_003124.5(SPR):c.448A>G (p.Arg150Gly)	Pathogenic
12943	NM_003124.5(SPR):c.488C>T (p.Pro163Leu)	Pathogenic
12944	NM_003124.5(SPR):c.751A>T (p.Lys251Ter)	Pathogenic
1323647	NM_003124.5(SPR):c.544C>T (p.Gln182Ter)	Pathogenic
1458146	NC_000002.11:g.(?73114562)(73115753_?)del	Pathogenic
2165411	NM_003124.5(SPR):c.277C>T (p.Gln93Ter)	Pathogenic
235551	NM_003124.5(SPR):c.655C>T (p.Arg219Ter)	Pathogenic
2720176	NM_003124.5(SPR):c.715C>T (p.Gln239Ter)	Pathogenic
2760535	NM_003124.5(SPR):c.262del (p.Arg88fs)	Pathogenic
31917	NM_003124.5(SPR):c.304G>T (p.Gly102Cys)	Pathogenic
3617711	NM_003124.5(SPR):c.619C>T (p.Gln207Ter)	Pathogenic
39869	NM_003124.5(SPR):c.596-2A>G	Pathogenic
429901	NM_003124.5(SPR):c.369C>G (p.Tyr123Ter)	Pathogenic
522878	NM_003124.4(SPR):c.596del	Pathogenic
625209	NM_003124.5(SPR):c.305-2A>G	Pathogenic
831031	NC_000002.12:g.(?72887413)(72891557_?)del	Pathogenic
842660	NM_003124.5(SPR):c.615dup (p.Gln206fs)	Pathogenic
985237	NM_003124.5(SPR):c.587A>G (p.Tyr196Cys)	Pathogenic
1162323	NM_003124.5(SPR):c.512G>A (p.Cys171Tyr)	Likely pathogenic
1414432	NM_003124.5(SPR):c.596-2_602del	Likely pathogenic
1698420	NM_003124.5(SPR):c.1A>C (p.Met1Leu)	Likely pathogenic
2502832	NM_003124.5(SPR):c.631del (p.Glu211fs)	Likely pathogenic
2627381	NM_003124.5(SPR):c.560A>G (p.Glu187Gly)	Likely pathogenic
444507	NM_003124.5(SPR):c.783_786del (p.Ter262ProextTer?)	Likely pathogenic
808769	NM_003124.5(SPR):c.517G>T (p.Gly173Ter)	Likely pathogenic

SpliceAI

315 predictions. Top by Δscore:

Variant	Effect	Δscore
2:72887733:GCGG:G	donor_gain	1.0000
2:72887735:GG:G	donor_gain	1.0000
2:72887736:GG:G	donor_gain	1.0000
2:72887736:GGTAA:G	donor_loss	1.0000
2:72887737:G:GG	donor_gain	1.0000
2:72888601:CCAG:C	donor_loss	1.0000
2:72888604:GG:G	donor_loss	1.0000
2:72888605:G:T	donor_loss	1.0000
2:72891343:CTA:C	acceptor_loss	1.0000
2:72891345:A:AG	acceptor_gain	1.0000
2:72891345:A:T	acceptor_loss	1.0000
2:72891346:G:A	acceptor_loss	1.0000
2:72891346:G:GC	acceptor_gain	1.0000
2:72891346:GGT:G	acceptor_gain	1.0000
2:72891346:GGTC:G	acceptor_gain	1.0000
2:72891346:GGTCC:G	acceptor_gain	1.0000
2:72891338:A:AG	acceptor_gain	0.9900
2:72891339:T:G	acceptor_gain	0.9900
2:72891343:CTAGG:C	acceptor_gain	0.9900
2:72891344:TAGG:T	acceptor_gain	0.9900
2:72891345:AG:A	acceptor_gain	0.9900
2:72891346:GG:G	acceptor_gain	0.9900
2:72887732:CGCGG:C	donor_gain	0.9800
2:72887733:GCGGG:G	donor_gain	0.9800
2:72888579:T:G	donor_gain	0.9800
2:72891342:TCTAG:T	acceptor_gain	0.9800
2:72891345:AGGTC:A	acceptor_gain	0.9800
2:72891346:G:T	acceptor_gain	0.9800
2:72888312:A:AG	acceptor_gain	0.9700
2:72888313:G:GG	acceptor_gain	0.9700

AlphaMissense

1646 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:72888522:T:G	C171W	0.995
2:72888471:C:A	N154K	0.994
2:72888471:C:G	N154K	0.994
2:72888531:G:C	K174N	0.994
2:72888531:G:T	K174N	0.994
2:72888390:C:A	N127K	0.992
2:72888390:C:G	N127K	0.992
2:72888467:T:A	V153D	0.992
2:72888521:G:A	C171Y	0.992
2:72888517:T:C	Y170H	0.991
2:72887729:C:A	N99K	0.990
2:72887729:C:G	N99K	0.990
2:72888476:C:G	S156W	0.990
2:72888478:T:C	S157P	0.990
2:72888539:G:C	R177P	0.990
2:72891347:G:A	G199D	0.990
2:72887491:G:A	G20D	0.988
2:72888529:A:G	K174E	0.988
2:72887472:G:T	G14W	0.987
2:72887473:G:A	G14E	0.987
2:72888508:T:A	W167R	0.987
2:72888508:T:C	W167R	0.987
2:72888530:A:C	K174T	0.987
2:72891359:C:T	T203I	0.986
2:72891499:T:C	F250L	0.986
2:72891501:C:A	F250L	0.986
2:72891501:C:G	F250L	0.986
2:72888595:T:G	Y196D	0.985
2:72891377:C:A	A209D	0.984
2:72888314:G:A	G102D	0.983

dbSNP variants (sampled 300 via entrez): RS1000839533 (2:72890229 G>T), RS1000934342 (2:72885639 C>A), RS1001493930 (2:72890863 A>T), RS1001544710 (2:72890529 G>C), RS1001718065 (2:72887297 C>T), RS1002801656 (2:72891761 A>G), RS1003131892 (2:72886319 AAAAAGAAAAAAG>A), RS1003395665 (2:72890271 G>C), RS1003731482 (2:72890543 A>G), RS1004751871 (2:72892101 C>A,T), RS1004905235 (2:72887967 G>A,C,T), RS1005366138 (2:72887721 C>T), RS1005911805 (2:72888964 T>C), RS1007399293 (2:72887584 A>T), RS1007408975 (2:72887917 A>C)

Disease associations

OMIM: gene MIM:182125 | disease phenotypes: MIM:612716

GenCC curated gene-disease

Disease	Classification	Inheritance
dopa-responsive dystonia due to sepiapterin reductase deficiency	Definitive	Autosomal recessive
BH4-deficient hyperphenylalaninemia A	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
dopa-responsive dystonia due to sepiapterin reductase deficiency	Definitive	AR

Mondo (4): dystonic disorder (MONDO:0003441), dopa-responsive dystonia due to sepiapterin reductase deficiency (MONDO:0012994), intellectual disability (MONDO:0001071), BH4-deficient hyperphenylalaninemia A (MONDO:0009863)

Orphanet (3): Dopa-responsive dystonia due to sepiapterin reductase deficiency (Orphanet:70594), Non-syndromic anorectal malformation (Orphanet:557), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

44 total (30 of 44 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000338	Hypomimic face
HP:0000366	Abnormality of the nose
HP:0000508	Ptosis
HP:0000657	Oculomotor apraxia
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000718	Aggressive behavior
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000975	Hyperhidrosis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001270	Motor delay
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001510	Growth delay
HP:0001518	Small for gestational age
HP:0002063	Rigidity
HP:0002067	Bradykinesia
HP:0002329	Drowsiness

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
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
C535325	6-pyruvoyl-tetrahydropterin synthase deficiency (supp.)
C562657	Dystonia, Dopa-Responsive, due to Sepiapterin Reductase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3988583 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — 1.-.-.- Oxidoreductases

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
SPRi3	Inhibition	7.96	pIC50

Binding affinities (BindingDB)

18 measured of 18 human assays (18 total across all organisms); most potent 18 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(E)-3-(3-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-oxoprop-1-en-1-yl)-N-cyclopropyl-7-hydroxy-4-((1-methylcyclopropyl)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.62 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-3-(3-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-oxoprop-1-en-1-yl)-N-cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.64 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-3-(3-(3-Oxa-9-azabicyclo[3.3.1]nonan-9-yl)-3-oxoprop-1-en-1-yl)-2-amino-N-cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride	IC50	0.71 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-3-(3-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-oxoprop-1-en-1-yl)-N-cyclopropyl-4-((1-fluorocyclopropyl)methyl)-7-hydroxy-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.72 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-3-(3-(3-Oxa-9-azabicyclo[3.3.1]nonan-9-yl)-3-oxoprop-1-en-1-yl)-N-cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.78 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-3-(3-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-oxoprop-1-en-1-yl)-N-cyclopropyl-7-hydroxy-4-isobutyl-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.78 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
N-[2-(5-hydroxy-1,2-dimethylindol-3-yl)ethyl]-2-methoxyacetamide	IC50	11 nM	US-9169234: Sepiapterin reductase inhibitors for the treatment of pain
N-[2-(5-hydroxy-2-methyl-1H-indol-3-yl)ethyl]-2-methoxyacetamide	IC50	11 nM	US-9169234: Sepiapterin reductase inhibitors for the treatment of pain
N-[2-(3-hydroxyphenyl)ethyl]-2-methoxyacetamide	IC50	64 nM	US-9169234: Sepiapterin reductase inhibitors for the treatment of pain
N-[2-(5-hydroxy-1-methylindol-3-yl)ethyl]-2-methoxyacetamide	IC50	84 nM	US-9169234: Sepiapterin reductase inhibitors for the treatment of pain
N-[2-(5-hydroxy-1H-indol-3-yl)-2-oxoethyl]-2-methoxyacetamide	IC50	310 nM	US-9169234: Sepiapterin reductase inhibitors for the treatment of pain
N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2-methylpropanamide	IC50	330 nM	US-9169234: Sepiapterin reductase inhibitors for the treatment of pain
N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]cyclopropanecarboxamide	IC50	340 nM	US-9169234: Sepiapterin reductase inhibitors for the treatment of pain
N-[2-[5-(methanesulfonamido)-1H-indol-3-yl]ethyl]-2-methoxyacetamide	IC50	1000 nM	US-9169234: Sepiapterin reductase inhibitors for the treatment of pain
3-[2-(pyridin-3-ylamino)ethyl]-1H-indol-5-ol	IC50	1600 nM	US-9169234: Sepiapterin reductase inhibitors for the treatment of pain
2-ethoxy-N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]acetamide	IC50	2200 nM	US-9169234: Sepiapterin reductase inhibitors for the treatment of pain
N-[2-(5-fluoro-1H-indol-3-yl)ethyl]-2-methoxyacetamide	IC50	2800 nM	US-9169234: Sepiapterin reductase inhibitors for the treatment of pain
2-methoxy-N-[2-(5-methylsulfonyl-1H-indol-3-yl)ethyl]acetamide	IC50	3200 nM	US-9169234: Sepiapterin reductase inhibitors for the treatment of pain

ChEMBL bioactivities

1928 potent at pChembl≥5 of 1972 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL4565940
9.00	IC50	1	nM	CHEMBL4539575
9.00	IC50	1	nM	CHEMBL4518409
9.00	IC50	1	nM	CHEMBL4554662
9.00	IC50	1	nM	CHEMBL4541433
9.00	IC50	1	nM	CHEMBL4526479
9.00	IC50	1	nM	CHEMBL4591533
9.00	IC50	1	nM	CHEMBL4550453
9.00	IC50	1	nM	CHEMBL4562479
9.00	IC50	1	nM	CHEMBL4522277
9.00	IC50	1	nM	CHEMBL4549931
9.00	IC50	1	nM	CHEMBL4570174
9.00	IC50	1	nM	CHEMBL4576651
9.00	IC50	1	nM	CHEMBL4568013
9.00	IC50	1	nM	CHEMBL4543843
9.00	IC50	1	nM	CHEMBL4547958
9.00	IC50	1	nM	CHEMBL4530729
9.00	IC50	1	nM	CHEMBL4586926
9.00	IC50	1	nM	CHEMBL4562897
9.00	IC50	1	nM	CHEMBL4583036
9.00	IC50	1	nM	CHEMBL4567692
9.00	IC50	1	nM	CHEMBL4528266
9.00	IC50	1	nM	CHEMBL4536114
9.00	IC50	1	nM	CHEMBL4590566
9.00	IC50	1	nM	CHEMBL4554154
9.00	IC50	1	nM	CHEMBL4525234
9.00	IC50	1	nM	CHEMBL4550973
9.00	IC50	1	nM	CHEMBL4560694
9.00	IC50	1	nM	CHEMBL4554183
9.00	IC50	1	nM	CHEMBL4542770
9.00	IC50	1	nM	CHEMBL4578194
9.00	IC50	1	nM	CHEMBL4520652
9.00	IC50	1	nM	CHEMBL4531168
9.00	IC50	1	nM	CHEMBL4553575
9.00	IC50	1	nM	CHEMBL4483610
9.00	IC50	1	nM	CHEMBL4558659
9.00	IC50	1	nM	CHEMBL4516582
9.00	IC50	1	nM	CHEMBL4543041
9.00	IC50	1	nM	CHEMBL4545677
9.00	IC50	1	nM	CHEMBL4590111
9.00	IC50	1	nM	CHEMBL4575603
9.00	IC50	1	nM	CHEMBL4541725
9.00	IC50	1	nM	CHEMBL4538189
9.00	IC50	1	nM	CHEMBL4590443
9.00	IC50	1	nM	CHEMBL4575062
9.00	IC50	1	nM	CHEMBL4571232
9.00	IC50	1	nM	CHEMBL4549178
9.00	IC50	1	nM	CHEMBL4546206
9.00	IC50	1	nM	CHEMBL4540783
9.00	IC50	1	nM	CHEMBL4539703

PubChem BioAssay actives

91 with measured affinity, of 119 total; 50 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
(2-hydroxyphenyl)-[3-methyl-1-(oxan-4-yl)pyrazolo[5,4-b]pyridin-5-yl]methanone	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.0200	uM
[1-(1,1-dioxothiolan-2-yl)-3-methylpyrazolo[5,4-b]pyridin-5-yl]-(5-fluoro-2-hydroxyphenyl)methanone	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.0200	uM
(2-hydroxyphenyl)-[3-methyl-1-(oxolan-3-yl)pyrazolo[5,4-b]pyridin-5-yl]methanone	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.0300	uM
2-(6-azaspiro[3.4]octan-6-ylsulfonyl)-3,5-difluorophenol	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.0300	uM
2-(6-azaspiro[3.4]octan-6-ylsulfonyl)-5-fluorophenol	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.0400	uM
(5-chloro-2-hydroxyphenyl)-[1-(2-hydroxyethyl)-3-methylpyrazolo[5,4-b]pyridin-5-yl]methanone	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.0400	uM
(5-fluoro-2-hydroxyphenyl)-(3-methyl-1-pyridin-2-ylpyrazolo[5,4-b]pyridin-5-yl)methanone	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.0400	uM
(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-(5-fluoro-2-hydroxyphenyl)methanone	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.0400	uM
(2-hydroxyphenyl)-[3-methyl-1-(4-methyl-2-pyridinyl)pyrazolo[5,4-b]pyridin-5-yl]methanone	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.0500	uM
[1-(2-fluorophenyl)-3-methylpyrazolo[5,4-b]pyridin-5-yl]-(2-hydroxyphenyl)methanone	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.0500	uM
(5-fluoro-2-hydroxyphenyl)-(3-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)methanone	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.0500	uM
(5-fluoro-2-hydroxyphenyl)-[1-(2-hydroxyethyl)-3-methylpyrazolo[5,4-b]pyridin-5-yl]methanone	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.0500	uM
6-azaspiro[3.4]octan-6-yl-(2,4-difluoro-6-hydroxyphenyl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.0570	uM
4-[5-chloro-4-[dimethylsulfamoyl(methyl)amino]-2-methoxybenzoyl]-2-ethyl-1H-pyrazol-3-one	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.0575	uM
(2-hydroxyphenyl)-(3-methyl-1-pyridin-2-ylpyrazolo[5,4-b]pyridin-5-yl)methanone	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.0661	uM
(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-(2-hydroxyphenyl)methanone	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.0800	uM
(5-chloro-2-hydroxyphenyl)-(3-methyl-1-pyridin-2-ylpyrazolo[5,4-b]pyridin-5-yl)methanone	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.0800	uM
2-(6-azaspiro[3.4]octan-6-ylsulfonyl)-3,5-dichlorophenol	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.0830	uM
(2,4-dichloro-6-hydroxyphenyl)-(2,3-dihydroindol-1-yl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.1200	uM
(2-hydroxyphenyl)-(3-methyl-1-pyrimidin-2-ylpyrazolo[5,4-b]pyridin-5-yl)methanone	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.1400	uM
(2-hydroxyphenyl)-(3-methyl-1-pyrimidin-4-ylpyrazolo[5,4-b]pyridin-5-yl)methanone	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.1400	uM
(5-fluoro-2-hydroxyphenyl)-(3-methyl-1-phenylpyrazolo[5,4-b]pyridin-5-yl)methanone	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.1800	uM
(2,4-dichloro-6-hydroxyphenyl)-(3,4-dihydro-1H-isoquinolin-2-yl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.2100	uM
(2,4-dichloro-6-hydroxyphenyl)-(4-phenylpiperidin-1-yl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.2400	uM
(3-anilinopyrrolidin-1-yl)-(2,4-dichloro-6-hydroxyphenyl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.2800	uM
6-azaspiro[3.4]octan-6-yl-(2-fluoro-6-hydroxyphenyl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.2900	uM
(2,4-dichloro-6-hydroxyphenyl)-(3-pyridin-3-yloxypyrrolidin-1-yl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.3100	uM
(4-benzylpiperidin-1-yl)-(2,4-dichloro-6-hydroxyphenyl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.3100	uM
6-azaspiro[3.4]octan-6-yl-(5-chloro-3-hydroxy-2-pyridinyl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.3100	uM
N-[2-(5-hydroxy-2-methyl-1H-indol-3-yl)ethyl]-2-methoxyacetamide	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.3100	uM
5-methyl-2-(2,7,10-trimethyl-6,6-dioxo-4,5-dihydro-[1]benzothiepino[5,4-c]pyrazole-9-carbonyl)cyclohexane-1,3-dione	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.3236	uM
6-azaspiro[3.4]octan-6-yl-(5-fluoro-3-hydroxy-2-pyridinyl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.3500	uM
(2,4-dichloro-6-hydroxyphenyl)-(3-pyridin-3-ylpyrrolidin-1-yl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.3700	uM
(2,4-dichloro-6-hydroxyphenyl)-[3-(2-phenylethyl)pyrrolidin-1-yl]methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.3800	uM
6-azaspiro[3.5]nonan-6-yl-(2,4-dichloro-6-hydroxyphenyl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.4600	uM
(2,4-dichloro-6-hydroxyphenyl)-(3-phenylpyrrolidin-1-yl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.5200	uM
(2,4-dichloro-6-hydroxyphenyl)-[3-(pyridin-4-ylmethyl)pyrrolidin-1-yl]methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.5500	uM
4-(2-pyridin-4-ylethyl)-N-(1,3-thiazol-2-yl)-2,3-dihydro-1,4-benzoxazine-7-sulfonamide	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.5754	uM
6-azaspiro[3.4]octan-6-yl-(2,4-dichloro-6-hydroxyphenyl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.5800	uM
(2,4-dichloro-6-hydroxyphenyl)-[3-(1-methylpyrazol-4-yl)pyrrolidin-1-yl]methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.6000	uM
[4-(benzenesulfonyl)piperidin-1-yl]-(2,4-dichloro-6-hydroxyphenyl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.6000	uM
N-pyridin-2-yl-2,3-dihydro-1,4-benzodioxine-6-sulfonamide	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.6026	uM
6-azaspiro[3.4]octan-6-yl-(3-hydroxy-2-pyridinyl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.6100	uM
(2,4-dichloro-6-hydroxyphenyl)-[3-(pyridin-3-ylmethyl)pyrrolidin-1-yl]methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.6100	uM
(2,4-dichloro-6-hydroxyphenyl)-(3-pyridin-4-ylpyrrolidin-1-yl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.6200	uM
6-azaspiro[3.4]octan-6-yl-(2-chloro-4-fluoro-6-hydroxyphenyl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.6700	uM
(2,4-dichloro-6-hydroxyphenyl)-(3,4-dihydro-2H-quinolin-1-yl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.6800	uM
(3-benzylpyrrolidin-1-yl)-(2,4-dichloro-6-hydroxyphenyl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.7400	uM
(2,4-dichloro-6-hydroxyphenyl)-(3-pyridin-2-ylpyrrolidin-1-yl)methanone	1563133: Inhibition of TNAS binding to human sepiapterin reductase by 19F-NMR spectra analysis	ic50	0.7900	uM
[1-(4-fluorophenyl)-3-methylpyrazolo[5,4-b]pyridin-5-yl]-(2-hydroxyphenyl)methanone	1646262: Inhibition of sepiapterin reductase (unknown origin)	ic50	0.8200	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	4
bisphenol A	decreases expression, increases expression	2
Arsenic Trioxide	decreases response to substance, affects binding, decreases reaction	2
aristolochic acid I	increases expression	1
2,4,6-tribromophenol	decreases expression	1
potassium perchlorate	decreases expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
K 7174	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
NSC 689534	affects binding, decreases expression	1
bisphenol AF	increases expression	1
Sunitinib	decreases expression	1
Amiodarone	increases expression	1
Arsenic	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	affects cotreatment, increases expression	1
Copper	affects binding, decreases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Diethylstilbestrol	decreases expression	1
Doxorubicin	affects response to substance	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3887419	Binding	Chromogenic assay: To screen for SPR inhibition, a biochemical assay based on LC/MS (and chromogenic) read-out has been developed. The LC/MS assay monitors the product formation (L-biopterin) and the chromogenic assay measures OD at 420 nm.	Sepiapterin reductase inhibitors for the treatment of pain

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2H9	Abcam HeLa SPR KO	Cancer cell line	Female
CVCL_TQ23	HAP1 SPR (-) 1	Cancer cell line	Male
CVCL_TQ24	HAP1 SPR (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00142259	PHASE4	UNKNOWN	Efficacy and Safety of DBS of the GPi in Patients With Primary Generalized and Segmental Dystonia
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT00998660	PHASE4	COMPLETED	RECHARGE Sub-Study to the Implantable Systems Performance Registry (ISPR)
NCT02263417	PHASE4	COMPLETED	A Randomized Controlled Trail Comparing Subthalamic and Pallidal Deep Brain Stimulation for Dystonia
NCT00169403	PHASE3	UNKNOWN	Pallidal Stimulation in Patients With Idiopathic Generalised Dystonia
NCT03232320	PHASE3	COMPLETED	Meditoxin® Treatment in Patients With Cervical Dystonia
NCT00001784	PHASE2	COMPLETED	Mexiletine for the Treatment of Focal Dystonia
NCT00105430	PHASE2	COMPLETED	Deep Brain Stimulation for Cervical Dystonia
NCT00106782	PHASE2	COMPLETED	Transcranial Electrical Polarization to Treat Focal Hand Dystonia
NCT00122044	PHASE2	COMPLETED	Childhood Hypertonia of Central Origin: A Trial of Anticholinergic Treatment Effects
NCT00169338	PHASE2	COMPLETED	Pallidal Stimulation in Patients With Post-anoxic and Idiopathic Dystonia
NCT00331669	PHASE2	UNKNOWN	Efficacy and Safety of Deep Brain Stimulation (DBS) of the Pallidal (GPi) in Patients With Tardive Dystonia
NCT02107261	PHASE2	COMPLETED	Incobotulinum Toxin A (Xeomin®) As A Treatment For Focal Task-Specific Dystonia Of The Musician’s Hand
NCT02470325	PHASE2	UNKNOWN	The Effects of Cannabis on Dystonia and Spasticity on Pediatric Patients
NCT05027997	PHASE2	COMPLETED	Exploratory Study of Dipraglurant (ADX48621) for the Treatment of Patients With Blepharospasm
NCT06412653	PHASE2	COMPLETED	Prospective Pilot Trial to Address Feasibility and Safety of Oral Zinc in GNAO1 Associated Disorders
NCT07304089	PHASE2	RECRUITING	A Study to Evaluate the Efficacy, Safety, and Tolerability of VIM0423 in Individuals With Isolated Dystonia
NCT01433757	PHASE1	COMPLETED	Ampicillin for DYT-1 Dystonia Motor Symptoms
NCT01698450	PHASE1	COMPLETED	Magnetic Resonance (MR) Guided Functional Ultrasound-Neurosurgery for Movement Disorders
NCT02982304	PHASE1	UNKNOWN	Multi-Target Pallidal and Thalamic Deep Brain Stimulation for Hemi-Dystonia
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT06554288	PHASE1	RECRUITING	Pharmacogenomic Contributions to Trihexyphenidyl Biotransformation and Response in Children With Dystonic Cerebral Palsy
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT00004421	PHASE2/PHASE3	COMPLETED	Deep Brain Stimulation in Treating Patients With Dystonia
NCT00272246	PHASE2/PHASE3	UNKNOWN	Bilateral Internal Pallidum Stimulation in Primary Generalized Dystonia
NCT00608231	PHASE2/PHASE3	WITHDRAWN	Dexmedetomidine Effects on Microelectrode Recording in Deep Brain Stimulation
NCT04277247	PHASE2/PHASE3	UNKNOWN	Botulinum Toxin Type A for Foot Dystonia-associated Pain in Parkinson’s Disease
NCT02015039	PHASE1/PHASE2	COMPLETED	Pilot Trial of Botulinum Toxin and Occupational Therapy for Writer’s Cramp
NCT02911103	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Deep Brain Stimulation Surgery for Focal Hand Dystonia
NCT04727177	EARLY_PHASE1	UNKNOWN	Precision-targeted Transcranial Magnetic Stimulation in the Treatment of Primary Dystonia
NCT00006336	Not specified	COMPLETED	Sensory Training to Treat Focal Dystonia
NCT00017875	Not specified	COMPLETED	Transcranial Magnetic Stimulation (TMS) Studies of Dystonia
NCT00029601	Not specified	COMPLETED	Surround Inhibition in Patients With Dystonia
NCT00031369	Not specified	TERMINATED	Brain Anatomy in Dystonia
NCT00047957	Not specified	COMPLETED	Brain Inhibition of Muscle Movement in Normal Volunteers
NCT00050024	Not specified	COMPLETED	Transcranial Magnetic Stimulation and Electrical Stimulation of Nerves to Study Focal Dystonia
NCT00072956	Not specified	COMPLETED	The Physiology of Tricks
NCT00082615	Not specified	COMPLETED	Neurophysiological Markers in Patients With Craniofacial Dystonia and Their Relatives
NCT00102999	Not specified	COMPLETED	Brain Function in Focal Dystonia