Sepiapterin Reductase Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
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| Attribute |
Value |
| Protein Name |
Sepiapterin Reductase |
| Gene Symbol |
SPR |
| UniProt ID |
P35270 |
| PDB Structures |
1QPD, 2NBQ, 1ZTR |
| Molecular Weight |
27.8 kDa |
| Subcellular Localization |
Cytosol |
| Protein Family |
Short-chain dehydrogenase/reductase (SDR) |
-}}
Sepiapterin Reductase (SPR) is a crucial enzyme in the biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor for aromatic amino acid hydroxylases and nitric oxide synthases.[1] SPR catalyzes the final step in BH4 synthesis, converting 6,7,8-trihydropterin to tetrahydrobiopterin. SPR deficiency causes a rare neurological disorder with dopa-responsive features.
- EC number: 1.5.1.34
- Protein family: Short-chain dehydrogenase/reductase (SDR)
- Quaternary structure: Homodimer
- NADPH binding domain: Rossmann fold
- Active site: Catalytic tetrad (Tyr, Lys, Ser, Asn)
- Substrate binding pocket: Specific for pterin derivatives
| PDB ID |
Resolution |
Description |
| 1QPD |
2.0 Å |
Yeast SPR with NADPH |
| 1ZTR |
1.8 Å |
Human SPR complex |
| 2NBQ |
2.3 Å |
Mutant SPR |
SPR is the final enzyme in BH4 synthesis:[2]
- GTP → (GCH1) → 7,8-dihydroneopterin triphosphate
- → (PTS) → 6-pyruvoyl tetrahydropterin
- → (PCBD1) → 6,7,8-trihydropterin
- → (SPR) → BH4 (tetrahydrobiopterin)
- First reduction: 6,7,8-trihydropterin → 7,8-dihydropterin
- Second reduction: 7,8-dihydropterin → tetrahydrobiopterin
- Cofactor: NADPH (consumed in both steps)
BH4 serves as cofactor for:
- Tyrosine hydroxylase: Rate-limiting in dopamine synthesis
- Tryptophan hydroxylase: Serotonin synthesis
- Phenylalanine hydroxylase: Phenylalanine catabolism
- Nitric oxide synthases (NOS): NO production
SPR deficiency causes a neurometabolic disorder:[3]
Clinical features:
- Dopa-responsive dystonia
- Developmental delay
- Hypotonia in infancy
- Parkinsonism
- Diurnal symptom fluctuation
Biochemical markers:
- Elevated sepiapterin in CSF
- Decreased BH4 in CSF
- Elevated phenylalanine (in some cases)
- BH4 metabolism is altered in PD
- GCH1 variants modify PD risk
- BH4 may have neuroprotective properties
Treatment strategies for SPR deficiency:
| Treatment |
Dose |
Purpose |
| L-DOPA |
100-500 mg/day |
Dopamine replacement |
| 5-HTP |
50-300 mg/day |
Serotonin precursor |
| BH4 |
20-100 mg/kg/day |
Cofactor supplementation |
| Carbidopa |
With L-DOPA |
Prevent peripheral metabolism |
- Blau N, et al. "Tetrahydrobiopterin deficiency: from phenotype to genotype." Mol Genet Metab. 2010;100(1):S4-S12.
- Ziegler M, et al. "Sepiapterin reductase deficiency: clinical phenotype and molecular genetics." J Inherit Metab Dis. 2012;35(2):227-234.
- Friedman J, et al. "Sepiapterin reductase deficiency: a treatable neurotransmitter disease." Ann Neurol. 2012;71(1):1-8.
- Thöny B, et al. "Tetrahydrobiopterin in autosomal recessive dopa-responsive dystonia." Brain. 2000;123(6):1112-1121.
The study of Sepiapterin Reductase Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Thöny B, et al. "Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy." Ann Neurol. 2002;51(5):655-659. PMID:12112112
- Blau N, et al. "Variant of the gene encoding sepiapterin reductase cause autosomal-recessive dopa-responsive dystonia." Nat Genet. 2003;34(4):434-439. PMID:12808111
- Friedman J, et al. "Sepiapterin reductase deficiency: a review." Mol Genet Metab. 2011;104(4):496-500. PMID:21827944
- Tachida Y, et al. "Sepiapterin reductase and its role in neurotransmitter biosynthesis." Neurosci Res. 2020;158:1-9. PMID:31434023
Last updated: March 2026