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
• GWAS associations: 4
• Clinical variants (ClinVar): 210 total — 21 pathogenic, 5 likely-pathogenic
• GTEx eGene: eQTL in 12 tissues, sQTL in 2 (q < 0.05)
• Phenotypes (HPO): 44
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.53 (unconstrained)
• 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: 10 — 7 protein_coding, 3 nonsense_mediated_decay

MANE Select: ENST00000234454

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 3: 1

ENST00000234454, ENST00000498749, ENST00000713723, ENST00000871609, ENST00000871610, ENST00000871611, ENST00000981064, ENST00000981065, ENST00001119773, ENST00001144680

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.

Highest expression (Bgee): mucosa of transverse colon, lobe of liver, adrenal gland, adrenal gland cortex, apex of heart.

Genetic regulation across tissues (GTEx eQTL / sQTL)

SPR is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 12 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

14 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	8.4e-05	+0.40	2:72035218:G:A
Heart Left Ventricle	eqtl	2.7e-03	+0.55	2:72052709:TAAGG:T
Muscle Skeletal	eqtl	4.0e-03	+0.13	2:72855134:G:A
Breast Mammary Tissue	eqtl	4.0e-03	-0.09	2:73131576:G:A
Nerve Tibial	eqtl	4.3e-03	-0.17	2:73689625:C:T
Stomach	sqtl	7.0e-03	+1.74	2:72517932:C:T
Skin Sun Exposed Lower leg	eqtl	9.1e-03	-0.09	2:73264555:G:A
Esophagus Mucosa	eqtl	9.6e-03	-0.49	2:73115020:A:G
Cells Cultured fibroblasts	eqtl	1.8e-02	-0.47	2:73122003:C:CCAT
Thyroid	eqtl	2.2e-02	+0.33	2:72919745:CTT:C
Muscle Skeletal	sqtl	3.3e-02	-0.57	2:72968364:T:C
Colon Sigmoid	eqtl	3.5e-02	-0.11	2:72280511:T:C
Prostate	eqtl	4.2e-02	-0.13	2:71937782:G:C
Brain Frontal Cortex BA9	eqtl	4.6e-02	-0.18	2:72887223:A:C

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
20932	13.8269	1669

Top tissues by expression

showing 100 of 289 tissues 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
muscle organ	UBERON:0001630	88.77	gold quality
colon	UBERON:0001155	88.63	gold quality
pancreatic ductal cell	CL:0002079	88.62	silver quality
large intestine	UBERON:0000059	88.52	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.35	gold quality
lower esophagus	UBERON:0013473	88.33	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.29	gold quality
ileal mucosa	UBERON:0000331	88.11	gold quality
thoracic aorta	UBERON:0001515	87.71	gold quality
omental fat pad	UBERON:0010414	87.69	gold quality
ascending aorta	UBERON:0001496	87.67	gold quality
peritoneum	UBERON:0002358	87.64	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	87.64	gold quality
intestine	UBERON:0000160	87.49	gold quality
adipose tissue of abdominal region	UBERON:0007808	87.39	gold quality
sigmoid colon	UBERON:0001159	87.38	gold quality
metanephros cortex	UBERON:0010533	87.32	gold quality
kidney	UBERON:0002113	87.22	gold quality
fundus of stomach	UBERON:0001160	87.07	gold quality
triceps brachii	UBERON:0001509	87.06	gold quality
cortex of kidney	UBERON:0001225	87.03	gold quality
saliva-secreting gland	UBERON:0001044	86.97	gold quality
descending thoracic aorta	UBERON:0002345	86.91	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.71	gold quality
choroid plexus epithelium	UBERON:0003911	86.46	gold quality
right lobe of thyroid gland	UBERON:0001119	86.43	gold quality
minor salivary gland	UBERON:0001830	86.37	gold quality
left coronary artery	UBERON:0001626	86.25	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.24	gold quality
esophagus	UBERON:0001043	86.14	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	86.00	gold quality
duodenum	UBERON:0002114	85.96	gold quality
kidney epithelium	UBERON:0004819	85.93	gold quality
prostate gland	UBERON:0002367	85.86	gold quality
gluteal muscle	UBERON:0002000	85.76	silver quality
small intestine	UBERON:0002108	85.72	gold quality
aorta	UBERON:0000947	85.70	gold quality
coronary artery	UBERON:0001621	85.61	gold quality
colonic mucosa	UBERON:0000317	85.31	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.24	gold quality
left lobe of thyroid gland	UBERON:0001120	85.10	gold quality
skeletal muscle tissue	UBERON:0001134	85.05	gold quality
esophagus mucosa	UBERON:0002469	84.91	gold quality
mouth mucosa	UBERON:0003729	84.78	gold quality
adipose tissue	UBERON:0001013	84.61	gold quality
right coronary artery	UBERON:0001625	84.60	gold quality
thyroid gland	UBERON:0002046	84.42	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	84.41	silver quality
popliteal artery	UBERON:0002250	84.31	gold quality
renal glomerulus	UBERON:0000074	84.30	gold quality
tibial artery	UBERON:0007610	84.27	gold quality
muscle tissue	UBERON:0002385	84.20	gold quality
metanephric glomerulus	UBERON:0004736	84.19	gold quality
endocervix	UBERON:0000458	84.18	gold quality
connective tissue	UBERON:0002384	84.18	gold quality
epithelium of bronchus	UBERON:0002031	83.90	gold quality
bronchial epithelial cell	CL:0002328	83.88	gold quality
metanephros	UBERON:0000081	83.64	gold quality
diaphragm	UBERON:0001103	83.64	gold quality
right lung	UBERON:0002167	83.56	gold quality
subcutaneous adipose tissue	UBERON:0002190	83.53	gold quality
bronchus	UBERON:0002185	83.44	gold quality
oocyte	CL:0000023	83.33	gold quality
quadriceps femoris	UBERON:0001377	83.31	silver quality
upper lobe of left lung	UBERON:0008952	83.28	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	83.25	gold quality
mucosa of sigmoid colon	UBERON:0004993	83.11	gold quality
vastus lateralis	UBERON:0001379	83.05	silver quality
gall bladder	UBERON:0002110	83.03	gold quality
stromal cell of endometrium	CL:0002255	83.02	gold 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

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Spinal cord	tissue	80.8
Medulla oblongata	tissue	72.2
Pons	tissue	65.4
Substantia nigra	tissue	64.2
Cerebral cortex	tissue	62.4	medium
Somatosensory cortex	tissue	62.4
Superior colliculi	tissue	61.1
Liver	tissue	60.1	high
Thalamus	tissue	57.2
Midbrain	tissue	56.7
Periaqueductal gray	tissue	55.6
Hypothalamus	tissue	54.7
Basal ganglia	tissue	51.5	medium
Hippocampal formation	tissue	51.5
Putamen	tissue	50.1
Pancreas	tissue	49.7	high
Septum	tissue	49.7
Ventral forebrain	tissue	47.5
Occipital cortex	tissue	47.5
Temporal cortex	tissue	42.7
Entorhinal cortex	tissue	42.6
Motor cortex	tissue	42.3
Prefrontal cortex	tissue	40.5
Retrosplenial and cingulate cortex	tissue	38.3
Choroid plexus	tissue	37.9
Parathyroid gland	tissue	36.1
Epididymis	tissue	34.8	high
Kidney	tissue	34.4	high
Skeletal muscle	tissue	34.2	medium
Retrosplenial cortex	tissue	34.1
Cerebellum	tissue	34.0	medium
Insular cortex	tissue	33.8
Amygdala	tissue	33.7
Colon	tissue	32.8	high
Rectum	tissue	30.5	high
Salivary gland	tissue	29.4	high
Corpus callosum	tissue	27.6
Frontal cortex	tissue	26.5
Heart muscle	tissue	25.3	medium
Olfactory bulb	tissue	25.0
Fallopian tube	tissue	24.7	high
Tongue	tissue	23.8
Stomach 1	tissue	22.6	high
Duodenum	tissue	22.0	high
Prostate	tissue	21.8	high
Caudate putamen	tissue	21.0
Small intestine	tissue	20.7	high
Adrenal gland	tissue	19.3	high
Locus coeruleus	tissue	18.1
Thyroid gland	tissue	18.0	high
Adipose tissue	tissue	17.9	medium
Breast	tissue	16.3	high
Seminal vesicle	tissue	15.7	high
Vagina	tissue	13.9	medium
Lung	tissue	13.7	high
Nucleus accumbens	tissue	11.2
Gallbladder	tissue	11.2	high
Cervix	tissue	11.0	high
Pituitary gland	tissue	10.7
Smooth muscle	tissue	10.7	medium

Brain sub-regions (HPA Brain Atlas): detected in 291; highest nTPM — Ventral spinal cord (80.8), Dorsal spinal cord (63.0), Dorsal hippocampus (51.5), Ventral hippocampus (48.3), Subiculum (44.2).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting SPR by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

27 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 5.91e-06, LOEUF 1.53, missense Z -0.7 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000234454 — one region, missense o/e 0.94.

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

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:103078) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 22 distinct phenotype terms.

Mouse phenotype (MP)	Records
postnatal growth retardation	2
premature death	2
abnormal biopterin level	2
abnormal neopterin level	2
decreased dopamine level	2
decreased serotonin level	2
decreased noradrenaline level	2
increased neutrophil cell number	1
tremors	1
decreased body weight	1
decreased locomotor activity	1
abnormal synaptic neurotransmitter level	1
abnormal dopaminergic neuron morphology	1
abnormal locomotor activation	1
decreased circulating insulin-like growth factor I level	1
bradykinesia	1
abnormal enzyme/coenzyme level	1
increased grip strength	1
preweaning lethality, complete penetrance	1
prenatal lethality, incomplete penetrance	1
increased circulating phenylalanine level	1
decreased phenylalanine level	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Meriones unguiculatus	Q8R536	86.6%	Diamond
Xenopus tropicalis	B0BML7	86.5%	Diamond
Xenopus laevis	Q7ZY31	86.5%	Diamond
Bos taurus	Q17QK8	81.5%	Diamond
Trichoderma reesei QM6a	G0RNA2	54.4%	Diamond
Saccharomyces cerevisiae S288C	P40579	52.3%	Diamond
Dictyostelium discoideum	Q54GP3	43.1%	Diamond
Bacillus subtilis subsp. subtilis str. 168	O32099	42.6%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
EMX1	protein-coding	2016
EXOC6B	protein-coding	23233
SFXN5	protein-coding	94097
CYP26B1	protein-coding	56603

Protein

Protein identifiers

Sepiapterin reductase — P35270 (reviewed: P35270)

All UniProt accessions (4): A0AAQ5BGR8, A0AAQ5BGS4, B4DSF0, P35270

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)

• 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 (42 total): helix 14, 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 by resolution:

PDB	Title	Method	Resolution (Å)
6I6V	SEPIAPTERIN REDUCTASE IN COMPLEX WITH COMPOUND 6	X-RAY DIFFRACTION	1.43
6I6P	SEPIAPTERIN REDUCTASE IN COMPLEX WITH COMPOUND 3	X-RAY DIFFRACTION	1.62
6I79	SEPIAPTERIN REDUCTASE IN COMPLEX WITH COMPOUND 4	X-RAY DIFFRACTION	1.63
6I6C	SEPIAPTERIN REDUCTASE IN COMPLEX WITH COMPOUND 2	X-RAY DIFFRACTION	1.72
6I6T	SEPIAPTERIN REDUCTASE IN COMPLEX WITH COMPOUND 5	X-RAY DIFFRACTION	1.79
7DSF	The Crystal Structure of human SPR from Biortus.	X-RAY DIFFRACTION	1.8
6I6F	SEPIAPTERIN REDUCTASE IN COMPLEX WITH COMPOUND 1	X-RAY DIFFRACTION	1.94
4XWY	Crystal structure of human sepiapterin reductase in complex with an N-acetylserotinin …	X-RAY DIFFRACTION	2.35
4Z3K	Human sepiapterin reductase in complex with the cofactor NADP+ and the trypthophan …	X-RAY DIFFRACTION	2.35
4HWK	Crystal structure of human sepiapterin reductase in complex with sulfapyridine	X-RAY DIFFRACTION	2.4
4J7U	Crystal structure of human sepiapterin reductase in complex with sulfathiazole	X-RAY DIFFRACTION	2.44
1Z6Z	Crystal Structure of Human Sepiapterin Reductase in complex with NADP+	X-RAY DIFFRACTION	2.5
4J7X	Crystal structure of human sepiapterin reductase in complex with sulfasalazine	X-RAY DIFFRACTION	2.6
6USN	Co-crystal structure of SPR with compound 5	X-RAY DIFFRACTION	2.77

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Oxidoreductases, Metabolic proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital disorders of metabolism, Congenital disorders of cofactor/vitamin metabolism

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; nucleoplasm

Antibody reliability (HPA): IH uncertain · IF supported

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)

Position	Role
14–20	NADP(+)
42–43	NADP(+)
69–70	NADP(+)
157–158	substrate
170	substrate
174	NADP(+)
199	substrate
201–206	NADP(+)
257	substrate

Post-translational modifications (4)

Type	Positions
N-acetylmethionine	1
Phosphoserine	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

2 curated (TAS) of 6; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

6 pathways:

ID	Pathway	Evidence
R-HSA-1474151	Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation	curated
R-HSA-203615	eNOS activation	curated
R-HSA-1430728	Metabolism	—
R-HSA-8978934	Metabolism of cofactors	—
R-HSA-202131	Metabolism of nitric oxide: NOS3 activation and regulation	—
R-HSA-196854	Metabolism of vitamins and 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 (4): mitochondrion (GO:0005739), cytosol (GO:0005829), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

4 top-level categories:

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

14 GO namespaces:

Category	Terms
cytoplasm	2
cellular anatomical structure	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
intracellular membrane-bounded organelle	1
extracellular vesicle	1
intracellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 4 of 10 annotations. The rest are phylogenetic / computational / electronic (IEA).

4 experimentally-supported GO terms:

GO term	NS	Evidence
nitric oxide biosynthetic process	BP	direct assay
cytosol	CC	direct assay
extracellular exosome	CC	high-throughput assay
mitochondrion	CC	high-throughput

Protein interactions and networks

STRING

showing 15 of 1,282 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPR	MCEE	Q96PE7	924
SPR	QDPR	P09417	871
SPR	DHFR2	Q86XF0	857
SPR	GCH1	P30793	840
SPR	PTS	Q03393	836
SPR	DHFR	P00374	807
SPR	PAH	P00439	789
SPR	CBR1	P16152	769
SPR	PCBD1	P61457	760
SPR	MMUT	P22033	754
SPR	AKR1B1	P15121	716
SPR	GCHFR	P30047	670
SPR	MMAA	Q8IVH4	661
SPR	HSD3B2	P26439	645
SPR	DBH	P09172	622

IntAct

Human interaction partners of SPR in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

2 partners by confidence:

Partner	Interaction type	MIscore	Records
BCAP31	physical association	0.400	1
YWHAZ	physical association	0.400	1

BioGRID (116 interactions; top human partners by supporting records): C21orf33 (Co-fractionation; 2 records), AAR2 (Affinity Capture-MS), ABHD11 (Co-fractionation), ABL1 (Affinity Capture-MS), ABL2 (Affinity Capture-MS), ACAT2 (Co-fractionation), ACO2 (Co-fractionation), ADH5 (Co-fractionation), AHCYL1 (Co-fractionation), ALDH6A1 (Co-fractionation), ASS1 (Co-fractionation), ATG5 (Proximity Label-MS), ATIC (Co-fractionation), AURKA (Affinity Capture-MS), BROX (Co-fractionation)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
CAMK2G	unknown	SPR	phosphorylation

Disease & clinical

Genetic variants

Variant evidence for SPR: 210 ClinVar records (26 pathogenic / likely pathogenic); 4 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	5
Uncertain significance	83
Likely benign	78
Benign	7

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 26 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
12944	NM_003124.5(SPR):c.751A>T (p.Lys251Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	11
235551	NM_003124.5(SPR):c.655C>T (p.Arg219Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	10
12941	NM_003124.5(SPR):c.448A>G (p.Arg150Gly)	Pathogenic	criteria provided, multiple submitters, no conflicts	9
1323647	NM_003124.5(SPR):c.544C>T (p.Gln182Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2720176	NM_003124.5(SPR):c.715C>T (p.Gln239Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1162323	NM_003124.5(SPR):c.512G>A (p.Cys171Tyr)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
39869	NM_003124.5(SPR):c.596-2A>G	Pathogenic	criteria provided, single submitter	4
625209	NM_003124.5(SPR):c.305-2A>G	Pathogenic	criteria provided, single submitter	2
429901	NM_003124.5(SPR):c.369C>G (p.Tyr123Ter)	Pathogenic	criteria provided, single submitter	1
522878	NM_003124.4(SPR):c.596del	Pathogenic	criteria provided, single submitter	1
842660	NM_003124.5(SPR):c.615dup (p.Gln206fs)	Pathogenic	criteria provided, single submitter	1
985237	NM_003124.5(SPR):c.587A>G (p.Tyr196Cys)	Pathogenic	criteria provided, single submitter	1
1162322	NM_003124.5(SPR):c.304+2_304+13del	Pathogenic	criteria provided, single submitter	1
2165411	NM_003124.5(SPR):c.277C>T (p.Gln93Ter)	Pathogenic	criteria provided, single submitter	1
2760535	NM_003124.5(SPR):c.262del (p.Arg88fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore SPR’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 27 predictions of 166):

Position(s)	Effect	Δscore	Sites
2:72887737–72887738	donor_loss	1.0000	5
2:72888605–72888606	donor_loss	1.0000	5
2:72891345–72891346	acceptor_loss	1.0000	4
2:72887738	donor_loss	0.9900
2:72891339	acceptor_gain	0.9900
2:72891345–72891346	acceptor_loss	0.9900	2
2:72888579	donor_gain	0.9800
2:72888528	donor_gain	0.9600
2:72888312–72888313	acceptor_loss	0.9500	6
2:72887739	donor_gain	0.9300

AlphaMissense

568 missense substitutions predicted likely pathogenic (of 1,646 scored), across 164 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M205	9	0.888	0.981
D257	8	0.915	0.976
N127	8	0.913	0.992
F19	8	0.810	0.968
K174	7	0.962	0.994
W167	7	0.929	0.987
F250	7	0.928	0.986
N100	7	0.917	0.982
N154	7	0.860	0.994
F164	7	0.852	0.968
E187	7	0.840	0.954
F258	7	0.828	0.981
D69	7	0.802	0.863
H255	7	0.790	0.952
D178	7	0.778	0.881
D202	7	0.702	0.794
D106	7	0.663	0.784
G14	6	0.968	0.987
G199	6	0.961	0.990
Y170	6	0.935	0.991

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Glioblastoma Multiforme (validation)	favorable	0.000196
Breast Invasive Carcinoma (TCGA)	favorable	0.000718

Disease associations

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

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
dopa-responsive dystonia due to sepiapterin reductase deficiency	Definitive	Autosomal recessive	6
BH4-deficient hyperphenylalaninemia A	Strong	Autosomal recessive

ClinGen Gene-Disease Validity

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

1 validity classifications:

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

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (16 panels, 13 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

16 panels:

Panel	Rating
Ataxia and cerebellar anomalies - childhood onset	green
Brain channelopathy	green
DDG2P	green
Dystonia, chorea or related movement disorder, childhood onset	green
Early onset dystonia	green
Hereditary ataxia and cerebellar anomalies, childhood onset	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Neurotransmitter disorders	green
Parkinson Disease and Complex Parkinsonism	green
Undiagnosed metabolic disorders	green
Early onset or syndromic epilepsy	amber
Paediatric disorders	amber
Unexplained death in infancy and sudden unexplained death in childhood	amber

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

Orphanet (2): Dopa-responsive dystonia due to sepiapterin reductase deficiency (Orphanet:70594), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

44 phenotypes (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
HP:0002359	Frequent falls
HP:0002360	Sleep disturbance
HP:0002509	Limb hypertonia
HP:0003593	Infantile onset
HP:0004923	Hyperphenylalaninemia
HP:0005968	Temperature instability
HP:0008297	Transient hyperphenylalaninemia
HP:0008936	Axial hypotonia
HP:0010553	Oculogyric crisis
HP:0040206	Abnormal circulating neopterin concentration
HP:0040210	Abnormal circulating biopterin concentration
HP:0100021	Cerebral palsy
HP:0100543	Cognitive impairment
HP:6000563	Reduced sepiapterin reductase activity in cultured fibroblasts

GWAS associations

4 associations:

Study	Trait	p-value
GCST007094_72	Diastolic blood pressure	2e-9
GCST007099_181	Systolic blood pressure	4e-6
GCST010725_54	Malaria	5e-6
GCST010725_35	Malaria	7e-6

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure

MeSH disease descriptors

4 disease descriptors:

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 (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Oxidoreductases

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

Ligand	Action	Affinity	Parameter
SPRi3	Inhibition	7.96	pIC50

Binding affinities (BindingDB)

653 measured of 702 human assays (702 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-Cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-3-((pyridin-3-yloxy)methyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.18 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
N-Cyclopropyl-4-hydroxy-1-neopentyl-2,8-dioxo-1,2,7,8-tetrahydropyrido[2’,3’:3,4]pyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	0.39 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
3-((E)-3-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-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	0.48 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(R,E)-N-Cyclopropyl-7-hydroxy-4-((1-methylcyclopropyl)methyl)-3-(3-(3-methylmorpholino)-3-oxoprop-1-en-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.54 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(R,E)-N-Cyclopropyl-7-hydroxy-3-(3-(3-(methoxymethyl)morpholino)-3-oxoprop-1-en-1-yl)-4-((1-methylcyclopropyl)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.55 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(R,E)-N-Cyclopropyl-7-hydroxy-4-isobutyl-3-(3-(3-(methoxymethyl)morpholino)-3-oxoprop-1-en-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.55 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
N-Cyclopropyl-9-hydroxy-6-neopentyl-2,7-dioxo-1,2,4,5,6,7-hexahydropyrimido[1’,2’:1,5]pyrazolo[3,4-d][1,3]oxazepine-8-carboxamide	IC50	0.56 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-N-Cyclopropyl-7-hydroxy-4-isobutyl-3-(3-((2-methoxyethyl)amino)-3-oxoprop-1-en-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.57 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(S,E)-N-Cyclopropyl-7-hydroxy-4-((1-methylcyclopropyl)methyl)-3-(3-(3-methylmorpholino)-3-oxoprop-1-en-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.58 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-3-(3-(8-Oxa-3-azabicyclo[3.2.1]octan-3-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	0.58 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-N-Cyclopropyl-3-(3-(1,1-dioxidothiomorpholino)-3-oxoprop-1-en-1-yl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.58 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-2-Amino-N-cyclopropyl-7-hydroxy-4-isobutyl-3-(3-morpholino-3-oxoprop-1-en-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.59 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(S,E)-2-Amino-N-cyclopropyl-7-hydroxy-4-isobutyl-3-(3-(3-methylmorpholino)-3-oxoprop-1-en-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride	IC50	0.59 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-N-Cyclopropyl-3-(3-(cyclopropyl(methyl)amino)-3-oxoprop-1-en-1-yl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.59 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(S,E)-N-Cyclopropyl-7-hydroxy-3-(3-(2-(hydroxymethyl)morpholino)-3-oxoprop-1-en-1-yl)-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.59 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-N-Cyclopropyl-7-hydroxy-4-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-3-(3-morpholino-3-oxoprop-1-en-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.6 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-N6-Cyclopropyl-7-hydroxy-4-isobutyl-3-(3-morpholino-3-oxoprop-1-en-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxamide	IC50	0.6 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-3-(3-(8-Oxa-3-azabicyclo[3.2.1]octan-3-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	0.61 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(S,E)-N-Cyclopropyl-7-hydroxy-3-(3-(3-(methoxymethyl)morpholino)-3-oxoprop-1-en-1-yl)-4-((1-methylcyclopropyl)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.61 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
N-Cyclopropyl-4-hydroxy-1-neopentyl-2,8-dioxo-1,2,7,8,9,10-hexahydropyrido[2’,3’:3,4]pyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	0.61 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(R,E)-2-Amino-N-cyclopropyl-7-hydroxy-4-isobutyl-3-(3-(3-methylmorpholino)-3-oxoprop-1-en-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride	IC50	0.61 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-N-Cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-3-(3-oxo-3-(3-oxopyrrolidin-1-yl)prop-1-en-1-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.61 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
N-Cyclopropyl-3-((E)-3-(trans-3,4-difluoropyrrolidin-1-yl)-3-oxoprop-1-en-1-yl)-7-hydroxy-4-isobutyl-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.61 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-((1-methylcyclopropyl)methyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.62 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
N-Cyclopropyl-3-((E)-3-((3R,5R)-3,5-dimethylmorpholino)-3-oxoprop-1-en-1-yl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.62 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-N-Cyclopropyl-4-((1-fluorocyclopropyl)methyl)-7-hydroxy-3-(3-morpholino-3-oxoprop-1-en-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.63 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
N-Cyclopropyl-7-hydroxy-4-neopentyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[2’,3’:3,4]pyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.63 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
N-Cyclopropyl-4-hydroxy-1-isobutyl-2,8-dioxo-1,2,7,8,9,10-hexahydropyrido[2’,3’:3,4]pyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	0.63 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-N-Cyclopropyl-7-hydroxy-2-methyl-3-(3-morpholino-3-oxoprop-1-en-1-yl)-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.63 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
N6-Cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-N3-((tetrahydro-2H-pyran-4-yl)methyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide	IC50	0.64 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-3-(3-(4-Carbamoylpiperidin-1-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-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
3-((E)-3-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-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-((Cyanomethyl)(methyl)amino)-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	0.64 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
N6-Cyclopropyl-7-hydroxy-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2,6-dicarboxamide	IC50	0.65 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
N-Cyclopropyl-7-hydroxy-4-isobutyl-3-(morpholine-4-carbonyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.65 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
N6-Cyclopropyl-7-hydroxy-4-isobutyl-5-oxo-N3-(pyrimidin-2-ylmethyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide	IC50	0.65 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-N-Cyclopropyl-7-hydroxy-4-(2-methoxy-2-methylpropyl)-3-(3-morpholino-3-oxoprop-1-en-1-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.65 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
3-((E)-3-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-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	0.65 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
3-((E)-3-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-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	0.65 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-2-Amino-N-cyclopropyl-7-hydroxy-3-(3-morpholino-3-oxoprop-1-en-1-yl)-4-neopentyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.65 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-2-Amino-N-cyclopropyl-7-hydroxy-5-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-3-(2-(tetrahydro-2H-pyran-4-yl)vinyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride	IC50	0.65 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(S,E)-N-Cyclopropyl-7-hydroxy-3-(3-(3-(hydroxymethyl)morpholino)-3-oxoprop-1-en-1-yl)-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.65 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
N-Cyclopropyl-3-((E)-3-((3S,5S)-3,5-dimethylmorpholino)-3-oxoprop-1-en-1-yl)-7-hydroxy-4-isobutyl-2-(methylamino)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.66 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-2-Amino-N-cyclopropyl-7-hydroxy-4-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-5-oxo-3-(2-(tetrahydro-2H-pyran-4-yl)vinyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride	IC50	0.66 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-N-Cyclopropyl-7-hydroxy-3-(3-((2-hydroxy-2-methylpropyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.66 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(R,E)-N-Cyclopropyl-3-(3-(3-ethylmorpholino)-3-oxoprop-1-en-1-yl)-7-hydroxy-4-isobutyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.66 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(S,E)-7-Hydroxy-4-isobutyl-3-(3-morpholino-3-oxoprop-1-en-1-yl)-5-oxo-N-(1,1,1-trifluoropropan-2-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.66 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-N-Cyclopropyl-7-hydroxy-4-isobutyl-2-methyl-5-oxo-3-(3-oxo-3-(8-oxa-1-azaspiro[4.5]decan-1-yl)prop-1-en-1-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.66 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND
(E)-N-Cyclopropyl-7-hydroxy-3-(3-morpholino-3-oxoprop-1-en-1-yl)-4-neopentyl-5-oxo-2-ureido-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	0.67 nM	US-20240092784: CONDENSED HETEROCYCLIC COMPOUND

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	affects binding, decreases reaction, decreases response to substance	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)

Via MONDO — disease-level, not drug-specific.

showing 60 of 172 trials:

NCT	Phase	Status	Title
NCT00142259	Phase 4	UNKNOWN	Efficacy and Safety of DBS of the GPi in Patients With Primary Generalized and Segmental Dystonia
NCT00950196	Phase 4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT00998660	Phase 4	COMPLETED	RECHARGE Sub-Study to the Implantable Systems Performance Registry (ISPR)
NCT02263417	Phase 4	COMPLETED	A Randomized Controlled Trail Comparing Subthalamic and Pallidal Deep Brain Stimulation for Dystonia
NCT00169403	Phase 3	UNKNOWN	Pallidal Stimulation in Patients With Idiopathic Generalised Dystonia
NCT03232320	Phase 3	COMPLETED	Meditoxin® Treatment in Patients With Cervical Dystonia
NCT00001784	Phase 2	COMPLETED	Mexiletine for the Treatment of Focal Dystonia
NCT00105430	Phase 2	COMPLETED	Deep Brain Stimulation for Cervical Dystonia
NCT00106782	Phase 2	COMPLETED	Transcranial Electrical Polarization to Treat Focal Hand Dystonia
NCT00122044	Phase 2	COMPLETED	Childhood Hypertonia of Central Origin: A Trial of Anticholinergic Treatment Effects
NCT00169338	Phase 2	COMPLETED	Pallidal Stimulation in Patients With Post-anoxic and Idiopathic Dystonia
NCT00331669	Phase 2	UNKNOWN	Efficacy and Safety of Deep Brain Stimulation (DBS) of the Pallidal (GPi) in Patients With Tardive Dystonia
NCT02107261	Phase 2	COMPLETED	Incobotulinum Toxin A (Xeomin®) As A Treatment For Focal Task-Specific Dystonia Of The Musician’s Hand
NCT02470325	Phase 2	UNKNOWN	The Effects of Cannabis on Dystonia and Spasticity on Pediatric Patients
NCT05027997	Phase 2	COMPLETED	Exploratory Study of Dipraglurant (ADX48621) for the Treatment of Patients With Blepharospasm
NCT06412653	Phase 2	COMPLETED	Prospective Pilot Trial to Address Feasibility and Safety of Oral Zinc in GNAO1 Associated Disorders
NCT07304089	Phase 2	RECRUITING	A Study to Evaluate the Efficacy, Safety, and Tolerability of VIM0423 in Individuals With Isolated Dystonia
NCT01433757	Phase 1	COMPLETED	Ampicillin for DYT-1 Dystonia Motor Symptoms
NCT01698450	Phase 1	COMPLETED	Magnetic Resonance (MR) Guided Functional Ultrasound-Neurosurgery for Movement Disorders
NCT02982304	Phase 1	UNKNOWN	Multi-Target Pallidal and Thalamic Deep Brain Stimulation for Hemi-Dystonia
NCT06117020	Phase 1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT06554288	Phase 1	RECRUITING	Pharmacogenomic Contributions to Trihexyphenidyl Biotransformation and Response in Children With Dystonic Cerebral Palsy
NCT03655223	Not specified	ACTIVE_NOT_RECRUITING	Early Check: Expanded Screening in Newborns
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT00004421	Phase 2/3	COMPLETED	Deep Brain Stimulation in Treating Patients With Dystonia
NCT00272246	Phase 2/3	UNKNOWN	Bilateral Internal Pallidum Stimulation in Primary Generalized Dystonia
NCT00608231	Phase 2/3	WITHDRAWN	Dexmedetomidine Effects on Microelectrode Recording in Deep Brain Stimulation
NCT04277247	Phase 2/3	UNKNOWN	Botulinum Toxin Type A for Foot Dystonia-associated Pain in Parkinson’s Disease
NCT02015039	Phase 1/2	COMPLETED	Pilot Trial of Botulinum Toxin and Occupational Therapy for Writer’s Cramp
NCT02911103	Phase 1/2	ACTIVE_NOT_RECRUITING	Deep Brain Stimulation Surgery for Focal Hand Dystonia
NCT04727177	Early Phase 1	UNKNOWN	Precision-targeted Transcranial Magnetic Stimulation in the Treatment of Primary Dystonia
NCT07626216	Early Phase 1	RECRUITING	Impact of rTMS on Abnormal Cortical fMRI in Patients With 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
NCT00285870	Not specified	COMPLETED	Quantification of Upper Extremity Hypertonia
NCT00355927	Not specified	UNKNOWN	Sedation During Microelectrode Recordings Before Deep Brain Stimulation for Movement Disorders.
NCT00361465	Not specified	COMPLETED	DYSCAR: Characterization of Dystonia
NCT00465790	Not specified	COMPLETED	Research of Biomarkers in Parkinson Disease
NCT00472914	Not specified	COMPLETED	Use of EMG to Assess Clinical Hypertonia
NCT00487383	Not specified	TERMINATED	Brain Changes in Blepharospasm
NCT00575081	Not specified	RECRUITING	Physiological Brain Atlas Development
NCT00580658	Not specified	APPROVED_FOR_MARKETING	Humanitarian Device Exemption
NCT00682513	Not specified	ACTIVE_NOT_RECRUITING	Studies of the Variable Phenotypic Presentations of Rapid-Onset Dystonia Parkinsonism and Other Movement Disorders
NCT00773604	Not specified	COMPLETED	Deep Brain Stimulation in Patients With Dystonia
NCT00792532	Not specified	COMPLETED	Use of Interventional MRI for Implantation of Deep Brain Stimulator Electrodes
NCT00878787	Not specified	COMPLETED	Theta-burst Transcranial Magnetic Stimulation
NCT00895063	Not specified	TERMINATED	Effect of Vocal Exercise After Botulinum Toxin Injection for Spasmodic Dysphonia
NCT00954408	Not specified	COMPLETED	Fatigue in Dystonia (a Single Session, Questionnaire-based Study of Fatigue in Dystonia)
NCT00971854	Not specified	UNKNOWN	Alteration of Deep Brain Stimulation Parameters for Dystonia
NCT01019343	Not specified	COMPLETED	Physiological Investigations of Movement Disorders
NCT01105845	Not specified	TERMINATED	Genetics of Motor Learning
NCT01168388	Not specified	COMPLETED	Movement Disorder Survey in East China
NCT01169324	Not specified	COMPLETED	Effect of Deep Brain Stimulation (DBS) on Sleep Architecture in Patients With Movement Disorders

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for SPR across ~30M SureChEMBL compounds — explore on Sugi Predict.