Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004757 sepiapterin reductase (NADP+) activity	IBA GO_REF:0000033	ACCEPT	Summary: This is the core molecular function of SPR. The enzyme catalyzes the NADP+-dependent reduction of sepiapterin and related pteridine substrates. PMID:1883349 cloned human SPR and established it as "an enzyme involved in tetrahydrobiopterin biosynthesis." UniProt confirms EC 1.1.1.153 with experimental evidence and kinetic characterization. Reason: This annotation precisely describes the core enzymatic function of SPR. The IBA annotation is well-supported by phylogenetic analysis and confirmed by extensive experimental evidence including kinetic characterization. Supporting Evidence: PMID:1883349 Cloning and sequencing of cDNA encoding human sepiapterin reductase--an enzyme involved in tetrahydrobiopterin biosynthesis. UniProt:P35270 file:human/SPR/SPR-deep-research-falcon.md model: Edison Scientific Literature
GO:0006729 tetrahydrobiopterin biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: SPR catalyzes the terminal reduction steps in BH4 biosynthesis, making this the core biological process. The deep research confirms SPR operates downstream of GCH1 and PTS in de novo BH4 biosynthesis and participates in BH4 salvage from sepiapterin. SPR deficiency causes BH4 deficiency leading to dopamine and serotonin deficiencies (PMID:11443547). Reason: This is the primary biological process in which SPR functions. As the terminal reductase in BH4 biosynthesis, this annotation is accurate and represents the core function. Well supported by IBA phylogenetic evidence and extensive literature. Supporting Evidence: PMID:1883349 Cloning and sequencing of cDNA encoding human sepiapterin reductase--an enzyme involved in tetrahydrobiopterin biosynthesis. PMID:9792819 Genomic organization and chromosomal localization of the human sepiapterin reductase gene.
GO:0004757 sepiapterin reductase (NADP+) activity	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation based on InterPro domain (IPR006393 Sepiapterin_red) and Rhea reaction mappings. Consistent with the IBA annotation and experimental evidence. Reason: This IEA annotation is accurate and consistent with the experimentally verified IBA annotation. The InterPro domain IPR006393 specifically identifies sepiapterin reductase family members. Supporting Evidence: UniProt:P35270
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation based on UniProt subcellular location vocabulary. UniProt entry states "SUBCELLULAR LOCATION: Cytoplasm." This is consistent with the cytosolic IDA annotation and the soluble nature of the enzyme. Reason: While cytosol (GO:0005829) is more specific and experimentally verified, cytoplasm is not incorrect. The IEA is a reasonable inference from UniProt annotation. Both cytoplasm and cytosol annotations can coexist since cytosol is_a cytoplasm. Supporting Evidence: UniProt:P35270
GO:0006729 tetrahydrobiopterin biosynthetic process	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation based on InterPro domain IPR006393 (Sepiapterin_red). This is consistent with the IBA annotation and well-established function of SPR in BH4 biosynthesis. Reason: This IEA is accurate and consistent with the experimentally supported IBA annotation. The InterPro domain is specific to sepiapterin reductase family members that function in BH4 biosynthesis. Supporting Evidence: PMID:1883349 Cloning and sequencing of cDNA encoding human sepiapterin reductase--an enzyme involved in tetrahydrobiopterin biosynthesis.
GO:0016491 oxidoreductase activity	IEA GO_REF:0000043	ACCEPT	Summary: IEA based on UniProt keyword KW-0560 (Oxidoreductase). SPR is indeed an oxidoreductase (EC 1.1.1.153), catalyzing NADPH-dependent reductions. However, this is a very general term compared to the specific GO:0004757 (sepiapterin reductase activity). Reason: While this term is much less specific than GO:0004757, it is not incorrect. SPR is an oxidoreductase. The more specific term (sepiapterin reductase activity) is also annotated, so this general term can be retained as a broader classification. Supporting Evidence: UniProt:P35270
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: IDA annotation based on immunofluorescence data (HPA). SPR is a soluble cytosolic enzyme that functions in the cytoplasm where BH4 biosynthesis occurs. UniProt confirms cytoplasmic localization. Reason: Cytosol is the appropriate specific cellular component for SPR. The enzyme functions in the soluble cytoplasmic compartment where it participates in BH4 biosynthesis alongside GCH1 and PTS. IDA evidence from immunofluorescence is reliable. Supporting Evidence: UniProt:P35270
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	MARK AS OVER ANNOTATED	Summary: HTP annotation from a high-throughput mitochondrial proteome study. SPR is primarily a cytosolic enzyme and mitochondrial localization is not the primary site of function. This may represent detection in a comprehensive proteomics survey rather than functional mitochondrial localization. Reason: SPR is well-established as a cytosolic enzyme (UniProt, IDA evidence). The mitochondrial detection in this HTP study may be due to contamination or minor dual localization but does not represent the primary functional compartment. BH4 biosynthesis occurs in the cytosol. This annotation could be misleading about primary localization. Supporting Evidence: UniProt:P35270 PMID:34800366 Epub 2021 Nov 19. Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	KEEP AS NON CORE	Summary: HDA annotation from proteomic analysis of exosomes isolated from expressed prostatic secretions in urine. The study identified ~900 proteins in exosome preparations using shotgun proteomics. Reason: Detection of SPR in exosomes represents a finding from high-throughput proteomics but does not indicate a primary functional localization. Many cytosolic proteins are detected in exosomes. This is not core to SPR function but may be retained as a non-core observation. Supporting Evidence: PMID:23533145 2013 Apr 23. In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: HDA annotation from large-scale proteomics of urinary exosomes. The study identified 1132 proteins in human urinary exosomes using LC-MS/MS. Reason: Similar to the other exosome annotation - detection in a proteomics survey does not indicate primary functional localization. Can be retained as non-core observation. Supporting Evidence: PMID:19056867 2008 Dec 3. Large-scale proteomics and phosphoproteomics of urinary exosomes.
GO:0005829 cytosol	TAS Reactome:R-HSA-1497853	ACCEPT	Summary: TAS annotation from Reactome pathway annotation for SPR phosphorylation by CaMK2. The reaction occurs in the cytosol. However, note that UniProt indicates the Ser-213 phosphorylation by CaMK2 does not change kinetic parameters. Reason: Cytosol localization is accurate for SPR. Reactome pathway curation places SPR in cytosol consistent with its role in BH4 biosynthesis. Supporting Evidence: Reactome:R-HSA-1497853
GO:0005829 cytosol	TAS Reactome:R-HSA-1475414	ACCEPT	Summary: TAS annotation from Reactome for the de novo BH4 synthesis reaction where SPR reduces DHNTP (6-pyruvoyltetrahydropterin precursor) to BH4. Reason: Cytosol localization is appropriate for the de novo BH4 synthesis pathway. Supporting Evidence: Reactome:R-HSA-1475414
GO:0005829 cytosol	TAS Reactome:R-HSA-1497869	ACCEPT	Summary: TAS annotation from Reactome for the BH4 salvage pathway where SPR reduces sepiapterin to BH2. Reason: Cytosol localization is appropriate for the BH4 salvage pathway reaction. Supporting Evidence: Reactome:R-HSA-1497869
GO:0004757 sepiapterin reductase (NADP+) activity	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to experimentally verified orthologs (with reference to mouse SPR UniProtKB:P18297). Mouse SPR is well characterized. Reason: The ISS annotation is valid and consistent with the direct experimental evidence for human SPR (EC 1.1.1.153). Human and mouse SPR share 74% sequence identity (PMID:1883349). Supporting Evidence: PMID:1883349 Cloning and sequencing of cDNA encoding human sepiapterin reductase--an enzyme involved in tetrahydrobiopterin biosynthesis.
GO:0006729 tetrahydrobiopterin biosynthetic process	TAS PMID:1883349 Cloning and sequencing of cDNA encoding human sepiapterin re...	ACCEPT	Summary: TAS annotation based on the original cloning paper by Ichinose et al. (1991). The paper cloned human SPR cDNA and established its role in BH4 biosynthesis. Reason: This is the foundational paper establishing SPR function in BH4 biosynthesis. TAS evidence is appropriate for this well-established role. Supporting Evidence: PMID:1883349 Cloning and sequencing of cDNA encoding human sepiapterin reductase--an enzyme involved in tetrahydrobiopterin biosynthesis.
GO:0006809 nitric oxide biosynthetic process	IDA PMID:15197144 Functional tetrahydrobiopterin synthesis in human platelets	MODIFY	Summary: IDA annotation based on Franscini et al. (2004) study of BH4 synthesis in human platelets. The study demonstrated functional BH4 synthesis in platelets and discussed its importance for NO synthase activity. BH4 is an essential cofactor for NOS enzymes. However, SPR does not directly synthesize NO - it synthesizes BH4 which is required as a cofactor by NOS. Reason: This annotation represents an indirect relationship. SPR synthesizes BH4, which is required as a cofactor for NOS. SPR does not directly participate in NO biosynthesis. The annotation is somewhat over-extended. The core function is BH4 biosynthesis. If the connection to NO synthesis is to be retained, it should be as a more general regulatory term or kept as non-core. Proposed replacements: tetrahydrobiopterin biosynthetic process Supporting Evidence: PMID:15197144 Functional tetrahydrobiopterin synthesis in human platelets. PMID:9792819 Genomic organization and chromosomal localization of the human sepiapterin reductase gene.
GO:0008106 alcohol dehydrogenase (NADP+) activity	TAS PMID:1883349 Cloning and sequencing of cDNA encoding human sepiapterin re...	REMOVE	Summary: TAS annotation based on the cloning paper. The paper noted homology between SPR and other short-chain dehydrogenases. However, GO:0008106 refers to a different enzymatic activity (alcohol dehydrogenase converting ethanol to acetaldehyde), not sepiapterin reductase activity. This appears to be an incorrect mapping. Reason: This is an incorrect annotation. SPR does not have alcohol dehydrogenase activity as defined by GO:0008106 (primary alcohols to aldehydes). SPR is specifically a sepiapterin reductase (EC 1.1.1.153), not an alcohol dehydrogenase (EC 1.1.1.2). The original paper mentions sequence homology to SDR family members but does not demonstrate alcohol dehydrogenase activity. The correct MF term is GO:0004757. Supporting Evidence: UniProt:P35270 PMID:1883349 Cloning and sequencing of cDNA encoding human sepiapterin reductase--an enzyme involved in tetrahydrobiopterin biosynthesis.
GO:0050661 NADP binding	TAS PMID:1883349 Cloning and sequencing of cDNA encoding human sepiapterin re...	ACCEPT	Summary: TAS annotation based on the cloning paper. SPR uses NADPH as cofactor. UniProt confirms NADP(+) binding sites at multiple residues. Crystal structure (PDB 1Z6Z) shows NADP bound. Reason: NADP binding is a valid molecular function of SPR. The enzyme uses NADPH as the reducing cofactor for its reductase activity. Crystal structure confirms NADP binding. This represents a true, experimentally verified function. Supporting Evidence: UniProt:P35270 KM=14.3 uM for sepiapterin UniProt:P35270 KM=10 uM for NADPH {ECO:0000269\|PubMed:10350607, ECO:0000269\|PubMed:11825621} PMID:1883349 Cloning and sequencing of cDNA encoding human sepiapterin reductase--an enzyme involved in tetrahydrobiopterin biosynthesis.
GO:0004757 sepiapterin reductase (NADP+) activity	TAS PMID:9792819 Genomic organization and chromosomal localization of the hum...	ACCEPT	Summary: TAS annotation based on Ohye et al. (1998) genomic organization paper. The paper states SPR "catalyzes the final step of the biosynthetic pathway of tetrahydrobiopterin." Reason: The annotation is accurate. The paper explicitly describes SPR's enzymatic function in BH4 biosynthesis. Supporting Evidence: PMID:9792819 Genomic organization and chromosomal localization of the human sepiapterin reductase gene.

Core Functions

Core enzymatic function. SPR catalyzes the NADPH-dependent reduction of sepiapterin and 6-pyruvoyl-tetrahydropterin intermediates to form tetrahydrobiopterin. EC 1.1.1.153. Kinetic parameters: Km 14.3 uM sepiapterin, Km 10 uM NADPH, kcat 1.1 s-1. Crystal structure solved (PDB:6I6V at 1.43 A). Homodimer.

Molecular Function:

sepiapterin reductase (NADP+) activity

NADP cofactor binding function. SPR binds NADPH as the reducing cofactor. Multiple NADP binding sites identified by X-ray crystallography (PDB:1Z6Z, 6I6V). Km for NADPH is 10 uM. Member of short-chain dehydrogenase/reductase (SDR) superfamily.

Molecular Function:

NADP binding

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

IBA annotations for sepiapterin reductase activity and BH4 biosynthesis are well-supported by phylogenetic evidence

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

Cytosol localization confirmed by immunofluorescence

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10350607

Functionally important residues tyrosine-171 and serine-158 in sepiapterin reductase

SPR is the terminal enzyme in the BH4 biosynthetic pathway

"sepiapterin reductase (SPR), which is a member of the NADP(H)-preferring short-chain dehydrogenase/reductase (SDR) family and acts as the terminal enzyme in the biosynthetic pathway of tetrahydrobiopterin cofactor (BH4)"
Ser-158, Tyr-171, and Lys-175 are essential for catalytic activity

"Ser-158, Tyr-171, and Lys-175 contributed to the catalytic activity of SPR, and both Tyr-171 and Ser-158 are simultaneously necessary on proton transfer to the carbonyl functional groups of substrate"

PMID:11443547

Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency without hyperphenylalaninemia

SPR mutations cause progressive psychomotor retardation with dystonia and monoamine deficiency

"two patients with progressive psychomotor retardation, dystonia, severe dopamine and serotonin deficiencies (low levels of 5-hydroxyindoleacetic and homovanillic acids), and abnormal pterin pattern"
SPR deficiency causes BH4-dependent neurotransmitter deficiency without hyperphenylalaninemia

"autosomal recessive SR deficiency leads to BH(4) and to neurotransmitter deficiencies without hyperphenylalaninemia and may not be detected by neonatal screening for phenylketonuria"

PMID:15197144

Functional tetrahydrobiopterin synthesis in human platelets

Human platelets have functional de novo BH4 synthesis
SPR mRNA and enzymatic activity present in freshly isolated platelets
BH4 is essential cofactor for NO synthase activity

PMID:1883349

Cloning and sequencing of cDNA encoding human sepiapterin reductase--an enzyme involved in tetrahydrobiopterin biosynthesis

First cloning of human SPR cDNA
261 amino acids, 28,047 Da molecular mass
74% identity with rat SPR
Homology to SDR family members

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes

SPR detected in urinary exosome proteome (1132 proteins identified)

PMID:23533145

In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine

SPR detected among ~900 proteins in EPS-urine exosomes

PMID:34800366

Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context

SPR detected in mitochondrial proteome study (HTP)

PMID:9792819

Genomic organization and chromosomal localization of the human sepiapterin reductase gene

SPR gene has 3 exons spanning ~4 kb
Located on chromosome 2p13
SPR catalyzes final step of BH4 biosynthesis

Reactome:R-HSA-1475414

PTHP is reduced to BH4 by sepiapterin reductase (SPR)

SPR reduces DHNTP to BH4 in de novo pathway

Reactome:R-HSA-1497853

Sepiapterin reductase (SPR) is phosphorylated by Ca2+/calmodulin-dependent protein kinase II

SPR Ser-213 phosphorylated by CaMK2
UniProt indicates phosphorylation does not change kinetic parameters

Reactome:R-HSA-1497869

Salvage - Sepiapterin is reduced to q-BH2

SPR reduces sepiapterin to BH2 in salvage pathway

file:human/SPR/SPR-deep-research-falcon.md

Deep research report on SPR

Suggested Experiments

Experiment: Measure SPR activity and BH4 levels in patient cells with novel SPR variants to establish genotype-phenotype correlations for SRD. Currently ~60 SRD cases described. Understanding variant effects on enzyme function could improve diagnosis and treatment.

📚 Additional Documentation

Deep Research Falcon

(SPR-deep-research-falcon.md)

provider: falcon
model: Edison Scientific Literature
cached: false
start_time: '2025-12-28T12:19:33.388121'
end_time: '2025-12-28T12:25:07.902112'
duration_seconds: 334.51
template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: SPR
gene_symbol: SPR
uniprot_accession: P35270
protein_description: 'RecName: Full=Sepiapterin reductase; Short=SPR; EC=1.1.1.153
{ECO:0000269|PubMed:10350607, ECO:0000269|PubMed:11443547};'
gene_info: Name=SPR;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the sepiapterin reductase family. .
protein_domains: Biopterin_syn/organic_redct. (IPR051721); NAD(P)-bd_dom_sf. (IPR036291);
SDR_fam. (IPR002347); Sepiapterin_red. (IPR006393); adh_short (PF00106)
provider_config:
timeout: 600
max_retries: 3
parameters:
allowed_domains: []
temperature: 0.1
citation_count: 18

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P35270
Protein Description: RecName: Full=Sepiapterin reductase; Short=SPR; EC=1.1.1.153 {ECO:0000269|PubMed:10350607, ECO:0000269|PubMed:11443547};
Gene Information: Name=SPR;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the sepiapterin reductase family. .
Key Domains: Biopterin_syn/organic_redct. (IPR051721); NAD(P)-bd_dom_sf. (IPR036291); SDR_fam. (IPR002347); Sepiapterin_red. (IPR006393); adh_short (PF00106)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "SPR" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'SPR' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene SPR (gene ID: SPR, UniProt: P35270) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P35270
Protein Description: RecName: Full=Sepiapterin reductase; Short=SPR; EC=1.1.1.153 {ECO:0000269|PubMed:10350607, ECO:0000269|PubMed:11443547};
Gene Information: Name=SPR;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the sepiapterin reductase family. .
Key Domains: Biopterin_syn/organic_redct. (IPR051721); NAD(P)-bd_dom_sf. (IPR036291); SDR_fam. (IPR002347); Sepiapterin_red. (IPR006393); adh_short (PF00106)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "SPR" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene SPR (gene ID: SPR, UniProt: P35270) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Plan status (abbreviated)
- We verified identity and pathway context for human SPR (P35270) and compiled targeted evidence from 2023–2024 sources on mechanism, disease relevance, and translational developments. Key claims below are grounded in the cited items.

Comprehensive research report: human SPR (UniProt P35270)

1) Key concepts and definitions
- Identity and biochemical role: SPR encodes sepiapterin reductase (EC 1.1.1.153), a short-chain dehydrogenase/reductase that catalyzes the terminal reductions in de novo and salvage biosynthesis of tetrahydrobiopterin (BH4). In de novo synthesis, GTP is converted via GCH1 and 6-pyruvoyltetrahydropterin synthase (PTS) to 6-pyruvoyl-tetrahydropterin, which SPR reduces through 1′- and 2′-oxo-tetrahydropterin intermediates to BH4. In the salvage route, sepiapterin is converted via SPR-dependent steps to BH2/BH4. Alternative aldo-keto/carbonyl reductases can form 1′/2′-oxo intermediates, but interconversion and completion of the terminal steps are uniquely dependent on SPR, explaining tissue- and species-dependent redundancy. These features place SPR as the final dedicated reductase in the GCH1–PTS–SPR axis that sets cellular BH4 levels for aromatic amino acid hydroxylases and nitric oxide synthases (NOS) (review synthesis; mechanistic details summarized in 2023 perspective). URL: https://doi.org/10.3389/fphar.2023.1173599 (May 2023) (cronin2023peripheralizedsepiapterinreductase pages 3-4).
- Structural/enzymatic family: SPR is a member of the short-chain dehydrogenase/reductase (SDR) superfamily and uses reduced nicotinamide cofactors in its reductive catalysis; its positioning in BH4 biosynthesis is consistently depicted alongside GCH1 and PTS in contemporary ferroptosis and neuroscience reviews (general pathway context). URLs: https://doi.org/10.1007/s10571-022-01197-5 (Feb 2023); https://doi.org/10.7555/jbr.37.20230224 (Mar 2024) (, ).

2) Recent developments and latest research (2023–2024)
- Peripheralized SPR inhibition for analgesia: A 2023 review marshals preclinical and human genetic data that excessive peripheral BH4 drives pain hypersensitivity and argues that peripherally restricted SPR inhibitors could reduce pain while sparing central monoamine synthesis. The review integrates evidence that BH4-pathway upregulation in injured DRG neurons and immune cells (mast cells, macrophages, T cells) contributes to nociception, and that reducing BH4 in these peripheral compartments alleviates neuropathic, inflammatory, and postoperative pain phenotypes. URL: https://doi.org/10.3389/fphar.2023.1173599 (May 2023) (cronin2023peripheralizedsepiapterinreductase pages 3-4).
- Mast cell BH4–serotonin axis in postoperative pain: 2024 Science Immunology work shows that mast cells supply BH4 (via Gch1) to support serotonin production by Tph1 after surgical injury; mast-cell-specific ablation of Gch1 or Tph1 reduces postoperative hypersensitivity. The study references pharmacological SPR inhibition (e.g., QM385) as a BH4-pathway tool and implicates neuroimmune substance P–driven BH4/serotonin release. URL: https://doi.org/10.1126/sciimmunol.adh0545 (Aug 2024) (cronin2023peripheralizedsepiapterinreductase pages 3-4).
- BH4–ferroptosis connection highlighting GCH1–PTS–SPR axis: Multiple 2023–2024 reviews on ferroptosis summarize BH4 as an endogenous, GPX4-independent lipid antioxidant system; BH4 biosynthesis by GCH1–PTS–SPR is depicted as a ferroptosis defense module. These works explicitly place SPR at the terminal step of BH4 production in these antioxidant programs. URLs: https://doi.org/10.1007/s10571-022-01197-5 (Feb 2023); https://doi.org/10.7555/jbr.37.20230224 (Mar 2024) (, ).
- Brain BH4 replenishment with sepiapterin: A 2024 preprint re-evaluates peripheral sepiapterin and reports dose-dependent brain BH4 elevation to 3–4× baseline for >6 hours at practical doses, arguing for BBB permeation and cellular uptake of sepiapterin under threshold dosing conditions. URL: https://doi.org/10.21203/rs.3.rs-4111864/v2 (Oct 2024) ().

3) Current applications and real-world implementations
- Clinical diagnostics and care for SPR deficiency (SRD): Contemporary clinical guidance (GeneReviews update, 2025) and a 2024 peer-reviewed case report detail that SRD typically lacks hyperphenylalaninemia and is therefore usually missed by standard newborn screening. Diagnosis relies on CSF neurotransmitter/pterin profiling—low HVA and 5-HIAA, normal-to-slightly increased neopterin, and elevated total biopterin, BH2, and sepiapterin—and molecular confirmation of biallelic SPR variants. Standard-of-care therapy emphasizes levodopa (with carbidopa/benserazide) and often adjunctive 5-HTP; early initiation improves outcomes. URLs: NCBI Bookshelf GeneReviews entry “Sepiapterin reductase deficiency” (updated Sep 18, 2025; accessible overview at https://www.ncbi.nlm.nih.gov/books/); https://doi.org/10.1159/000534587 (Nov 2024) (friedman2025sepiapterinreductasedeficiency pages 1-3, friedman2025sepiapterinreductasedeficiencyb pages 1-3, friedman2025sepiapterinreductasedeficiencya pages 1-3, erdal2024sepiapterinreductasedeficiency pages 1-2).
- Genomic implementation: Targeted NGS/tNGS workflows for hyperphenylalaninemia now include BH4-pathway genes and SPR in the differential to discriminate PAH vs. non-PAH causes and to streamline BH4 disorder diagnosis. URL: https://doi.org/10.3390/biomedicines11071899 (Jul 2023) ().

4) Expert opinions and analysis from authoritative sources
- Pain and safety rationale for SPR inhibitors: Experts argue that peripheral SPR inhibition may provide a “therapeutic window” by reducing excessive BH4 in peripheral nociceptors and immune cells while avoiding CNS BH4 rundown that risks monoamine deficiency, citing human genetics (e.g., GCH1/SPR deficiency phenotypes), cell-specific BH4 compensation, and salvage-route redundancy. URL: https://doi.org/10.3389/fphar.2023.1173599 (May 2023) (cronin2023peripheralizedsepiapterinreductase pages 3-4).
- Clinical consensus on SRD management: Authoritative clinical summaries emphasize that SRD is an autosomal recessive BH4 deficiency with predominant CNS monoamine deficiency, recommend CSF-guided titration of levodopa and consideration of 5-HTP, and caution about agents that impair BH4 or monoamine pathways (e.g., methotrexate, nitrous oxide). NCBI Bookshelf (updated 2025) (friedman2025sepiapterinreductasedeficiency pages 1-3, friedman2025sepiapterinreductasedeficiencyb pages 1-3, friedman2025sepiapterinreductasedeficiencya pages 1-3).

5) Relevant statistics and data (recent studies)
- Case counts: A 2024 peer-reviewed case report notes SRD has been described in “nearly 60 cases so far,” underscoring rarity and diagnostic challenges outside specialized testing. URL: https://doi.org/10.1159/000534587 (Nov 2024) (erdal2024sepiapterinreductasedeficiency pages 1-2).
- Biochemical diagnostics: Characteristic CSF profile—decreased HVA and 5-HIAA with elevated BH2/sepiapterin; urine sepiapterin can be increased—reinforced by GeneReviews updates (2025) and the 2024 case, consistent across cohorts. NCBI Bookshelf; https://doi.org/10.1159/000534587 (friedman2025sepiapterinreductasedeficiency pages 1-3, friedman2025sepiapterinreductasedeficiencyb pages 1-3, friedman2025sepiapterinreductasedeficiencya pages 1-3, erdal2024sepiapterinreductasedeficiency pages 1-2).
- Effect sizes in pain models: Reviews collate that genetic or targeted knockdown of BH4-pathway enzymes in peripheral neurons/mast cells reduces postoperative and inflammatory pain behaviors; mechanistically, mast-cell-specific Gch1 or Tph1 deletion substantially reduces postoperative hypersensitivity, identifying the mast cell BH4–serotonin axis as a driver. URL: https://doi.org/10.1126/sciimmunol.adh0545 (Aug 2024); synthesis in https://doi.org/10.3389/fphar.2023.1173599 (May 2023) (cronin2023peripheralizedsepiapterinreductase pages 3-4).
- Brain BH4 augmentation by sepiapterin: Preclinical dosing achieved 3–4× baseline brain BH4 for over 6 hours following peripheral administration above a defined threshold, supporting translational potential while highlighting saturability/transport constraints. URL: https://doi.org/10.21203/rs.3.rs-4111864/v2 (Oct 2024) ().

6) Pathways, mechanism, and cellular context
- Pathway integration: SPR operates downstream of GCH1 and PTS in de novo BH4 biosynthesis and participates in BH4 salvage from sepiapterin; BH4 is then consumed by tyrosine/tryptophan/phenylalanine hydroxylases and NOS, and is regenerated by QDPR (DHPR) with DHFR participating in BH2→BH4 reduction—a network represented in 2023–2024 ferroptosis/neurovascular reviews. URLs: https://doi.org/10.1007/s10571-022-01197-5 (Feb 2023); https://doi.org/10.7555/jbr.37.20230224 (Mar 2024) (, ).
- Relation to ferroptosis: The GCH1–PTS–SPR axis supplies BH4 as an endogenous inhibitor of lipid peroxidation, functioning alongside GPX4, FSP1–CoQ10, and DHODH–CoQH2 systems; increasing BH4 or preserving the pathway resists ferroptosis, while inhibition sensitizes to lipid-ROS. URLs: https://doi.org/10.7555/jbr.37.20230224 (Mar 2024); https://doi.org/10.1007/s10571-022-01197-5 (Feb 2023) (, ).

7) Subcellular localization
- Contemporary disease- and pathway-focused sources consistently treat SPR as a cytosolic enzyme operating in the soluble BH4 biosynthetic machinery with GCH1 and PTS; while explicit localization assays are not the focus of the 2023–2024 items, the enzyme’s integration in cytosolic BH4 production for cytosolic hydroxylases/NOS is implied in these reviews. URLs: https://doi.org/10.7555/jbr.37.20230224 (Mar 2024); https://doi.org/10.1007/s10571-022-01197-5 (Feb 2023) (, ).

8) Clinical genetics and counseling for SRD
- Genetics: SRD is autosomal recessive; biallelic pathogenic variants in SPR at 2p13.2 cause decreased BH4 synthesis and CNS accumulation of BH2 and sepiapterin. Carrier status is presumed in parents; once familial variants are identified, carrier, prenatal, and preimplantation testing are feasible. URL: NCBI Bookshelf GeneReviews (updated 2025) (friedman2025sepiapterinreductasedeficiencyb pages 15-18, friedman2025sepiapterinreductasedeficiencya pages 15-18, friedman2025sepiapterinreductasedeficiency pages 15-18).
- Treatment guidance and precautions: Titrated levodopa (with decarboxylase inhibitor) is first-line; 5-HTP is often added. GeneReviews advises avoiding drugs that impair BH4 or monoamine metabolism (e.g., methotrexate, nitrous oxide, dopamine antagonists) during management. NCBI Bookshelf (updated 2025) (friedman2025sepiapterinreductasedeficiency pages 1-3, friedman2025sepiapterinreductasedeficiencyb pages 1-3, friedman2025sepiapterinreductasedeficiencya pages 1-3).

Quality note on identity verification and ambiguity
- The gene symbol SPR in this report refers to Homo sapiens sepiapterin reductase (UniProt P35270), an SDR-family NAD(P)H-dependent oxidoreductase catalyzing the terminal steps of BH4 biosynthesis/salvage. All cited sources are consistent with this identity; no conflicting gene symbols from other organisms were used (cronin2023peripheralizedsepiapterinreductase pages 3-4).

References (URLs and dates)
- Cronin SJ.F. et al. Peripheralized sepiapterin reductase inhibition as a safe analgesic therapy. Frontiers in Pharmacology. May 2023. https://doi.org/10.3389/fphar.2023.1173599 (cronin2023peripheralizedsepiapterinreductase pages 3-4).
- Starkl P. et al. Mast cell–derived BH4 and serotonin are critical mediators of postoperative pain. Science Immunology. Aug 2024. https://doi.org/10.1126/sciimmunol.adh0545 (evidence integrated via 2023–2024 synthesis) (cronin2023peripheralizedsepiapterinreductase pages 3-4).
- Zhao Y. et al. The Role of Ferroptosis in Blood–Brain Barrier Injury. Cellular and Molecular Neurobiology. Feb 2023. https://doi.org/10.1007/s10571-022-01197-5 ().
- Zhang X. et al. Ferroptosis: Iron-mediated cell death linked to disease pathogenesis. Journal of Biomedical Research. Mar 2024. https://doi.org/10.7555/jbr.37.20230224 ().
- Ohashi A. et al. Peripheral administration of sepiapterin replenishes brain tetrahydrobiopterin. Preprint. Oct 2024. https://doi.org/10.21203/rs.3.rs-4111864/v2 ().
- Friedman J., Galosi S. Sepiapterin reductase deficiency. GeneReviews, NCBI Bookshelf. Updated Sep 18, 2025. https://www.ncbi.nlm.nih.gov/books/ (friedman2025sepiapterinreductasedeficiency pages 1-3, friedman2025sepiapterinreductasedeficiencyb pages 15-18, friedman2025sepiapterinreductasedeficiencyb pages 1-3, friedman2025sepiapterinreductasedeficiencya pages 15-18, friedman2025sepiapterinreductasedeficiencya pages 1-3, friedman2025sepiapterinreductasedeficiency pages 15-18).
- Erdal AE. et al. Sepiapterin Reductase Deficiency Misdiagnosed as Neurological Sequelae of Meningitis. Molecular Syndromology. Nov 2024. https://doi.org/10.1159/000534587 (erdal2024sepiapterinreductasedeficiency pages 1-2).
- Tendi EA. et al. Detection of Single-Nucleotide and Copy Number Defects Underlying Hyperphenylalaninemia by Next-Generation Sequencing. Biomedicines. Jul 2023. https://doi.org/10.3390/biomedicines11071899 ().

References

(cronin2023peripheralizedsepiapterinreductase pages 3-4): Shane J. F. Cronin, Nick A. Andrews, and Alban Latremoliere. Peripheralized sepiapterin reductase inhibition as a safe analgesic therapy. Frontiers in Pharmacology, May 2023. URL: https://doi.org/10.3389/fphar.2023.1173599, doi:10.3389/fphar.2023.1173599. This article has 5 citations and is from a poor quality or predatory journal.
(friedman2025sepiapterinreductasedeficiency pages 1-3): J Friedman and S Galosi. Sepiapterin reductase deficiency. Unknown journal, 2025.
(friedman2025sepiapterinreductasedeficiencyb pages 1-3): J Friedman and S Galosi. Sepiapterin reductase deficiency. Unknown journal, 2025.
(friedman2025sepiapterinreductasedeficiencya pages 1-3): J Friedman and S Galosi. Sepiapterin reductase deficiency. Unknown journal, 2025.
(erdal2024sepiapterinreductasedeficiency pages 1-2): Aysenur Engin Erdal, Oya Kıreker Köylü, Ahmet Cevdet Ceylan, Çiğdem Seher Kasapkara, Ebru Tunçez, and Meral Topçu. Sepiapterin reductase deficiency misdiagnosed as neurological sequelae of meningitis. Molecular Syndromology, 15:130-135, Nov 2024. URL: https://doi.org/10.1159/000534587, doi:10.1159/000534587. This article has 1 citations and is from a peer-reviewed journal.
(friedman2025sepiapterinreductasedeficiencyb pages 15-18): J Friedman and S Galosi. Sepiapterin reductase deficiency. Unknown journal, 2025.
(friedman2025sepiapterinreductasedeficiencya pages 15-18): J Friedman and S Galosi. Sepiapterin reductase deficiency. Unknown journal, 2025.
(friedman2025sepiapterinreductasedeficiency pages 15-18): J Friedman and S Galosi. Sepiapterin reductase deficiency. Unknown journal, 2025.

Citations

cronin2023peripheralizedsepiapterinreductase pages 3-4
erdal2024sepiapterinreductasedeficiency pages 1-2
friedman2025sepiapterinreductasedeficiency pages 1-3
friedman2025sepiapterinreductasedeficiencyb pages 1-3
friedman2025sepiapterinreductasedeficiencya pages 1-3
friedman2025sepiapterinreductasedeficiencyb pages 15-18
friedman2025sepiapterinreductasedeficiencya pages 15-18
friedman2025sepiapterinreductasedeficiency pages 15-18
https://doi.org/10.3389/fphar.2023.1173599
https://doi.org/10.1007/s10571-022-01197-5
https://doi.org/10.7555/jbr.37.20230224
https://doi.org/10.1126/sciimmunol.adh0545
https://doi.org/10.21203/rs.3.rs-4111864/v2
https://www.ncbi.nlm.nih.gov/books/
https://doi.org/10.1159/000534587
https://doi.org/10.3390/biomedicines11071899
https://doi.org/10.3389/fphar.2023.1173599,
https://doi.org/10.1159/000534587,

📄 View Raw YAML

id: P35270
gene_symbol: SPR
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Sepiapterin reductase (SPR) is a short-chain 
  dehydrogenase/reductase (SDR) family enzyme that catalyzes the terminal 
  reduction steps in the de novo and salvage biosynthesis of tetrahydrobiopterin
  (BH4). In the de novo pathway, SPR reduces 6-pyruvoyl-tetrahydropterin through
  1'-oxo and 2'-oxo intermediates to BH4. In the salvage pathway, it reduces 
  sepiapterin to 7,8-dihydrobiopterin (BH2). BH4 is an essential cofactor for 
  aromatic amino acid hydroxylases (phenylalanine, tyrosine, and tryptophan 
  hydroxylases) and nitric oxide synthases. SPR deficiency causes 
  DOPA-responsive dystonia with monoamine neurotransmitter deficiency without 
  hyperphenylalaninemia. The enzyme is a cytosolic homodimer that uses NADPH as 
  cofactor.
existing_annotations:
  - term:
      id: GO:0004757
      label: sepiapterin reductase (NADP+) activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: This is the core molecular function of SPR. The enzyme catalyzes 
        the NADP+-dependent reduction of sepiapterin and related pteridine 
        substrates. PMID:1883349 cloned human SPR and established it as "an 
        enzyme involved in tetrahydrobiopterin biosynthesis." UniProt confirms 
        EC 1.1.1.153 with experimental evidence and kinetic characterization.
      action: ACCEPT
      reason: This annotation precisely describes the core enzymatic function of
        SPR. The IBA annotation is well-supported by phylogenetic analysis and 
        confirmed by extensive experimental evidence including kinetic 
        characterization.
      supported_by:
        - reference_id: PMID:1883349
          supporting_text: Cloning and sequencing of cDNA encoding human 
            sepiapterin reductase--an enzyme involved in tetrahydrobiopterin 
            biosynthesis.
        - reference_id: UniProt:P35270
        - reference_id: file:human/SPR/SPR-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0006729
      label: tetrahydrobiopterin biosynthetic process
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: SPR catalyzes the terminal reduction steps in BH4 biosynthesis, 
        making this the core biological process. The deep research confirms SPR 
        operates downstream of GCH1 and PTS in de novo BH4 biosynthesis and 
        participates in BH4 salvage from sepiapterin. SPR deficiency causes BH4 
        deficiency leading to dopamine and serotonin deficiencies 
        (PMID:11443547).
      action: ACCEPT
      reason: This is the primary biological process in which SPR functions. As 
        the terminal reductase in BH4 biosynthesis, this annotation is accurate 
        and represents the core function. Well supported by IBA phylogenetic 
        evidence and extensive literature.
      supported_by:
        - reference_id: PMID:1883349
          supporting_text: Cloning and sequencing of cDNA encoding human 
            sepiapterin reductase--an enzyme involved in tetrahydrobiopterin 
            biosynthesis.
        - reference_id: PMID:9792819
          supporting_text: Genomic organization and chromosomal localization of 
            the human sepiapterin reductase gene.
  - term:
      id: GO:0004757
      label: sepiapterin reductase (NADP+) activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: IEA annotation based on InterPro domain (IPR006393 
        Sepiapterin_red) and Rhea reaction mappings. Consistent with the IBA 
        annotation and experimental evidence.
      action: ACCEPT
      reason: This IEA annotation is accurate and consistent with the 
        experimentally verified IBA annotation. The InterPro domain IPR006393 
        specifically identifies sepiapterin reductase family members.
      supported_by:
        - reference_id: UniProt:P35270
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: 'IEA annotation based on UniProt subcellular location vocabulary. UniProt
        entry states "SUBCELLULAR LOCATION: Cytoplasm." This is consistent with the
        cytosolic IDA annotation and the soluble nature of the enzyme.'
      action: ACCEPT
      reason: While cytosol (GO:0005829) is more specific and experimentally 
        verified, cytoplasm is not incorrect. The IEA is a reasonable inference 
        from UniProt annotation. Both cytoplasm and cytosol annotations can 
        coexist since cytosol is_a cytoplasm.
      supported_by:
        - reference_id: UniProt:P35270
  - term:
      id: GO:0006729
      label: tetrahydrobiopterin biosynthetic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: IEA annotation based on InterPro domain IPR006393 
        (Sepiapterin_red). This is consistent with the IBA annotation and 
        well-established function of SPR in BH4 biosynthesis.
      action: ACCEPT
      reason: This IEA is accurate and consistent with the experimentally 
        supported IBA annotation. The InterPro domain is specific to sepiapterin
        reductase family members that function in BH4 biosynthesis.
      supported_by:
        - reference_id: PMID:1883349
          supporting_text: Cloning and sequencing of cDNA encoding human 
            sepiapterin reductase--an enzyme involved in tetrahydrobiopterin 
            biosynthesis.
  - term:
      id: GO:0016491
      label: oxidoreductase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: IEA based on UniProt keyword KW-0560 (Oxidoreductase). SPR is 
        indeed an oxidoreductase (EC 1.1.1.153), catalyzing NADPH-dependent 
        reductions. However, this is a very general term compared to the 
        specific GO:0004757 (sepiapterin reductase activity).
      action: ACCEPT
      reason: While this term is much less specific than GO:0004757, it is not 
        incorrect. SPR is an oxidoreductase. The more specific term (sepiapterin
        reductase activity) is also annotated, so this general term can be 
        retained as a broader classification.
      supported_by:
        - reference_id: UniProt:P35270
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: IDA annotation based on immunofluorescence data (HPA). SPR is a 
        soluble cytosolic enzyme that functions in the cytoplasm where BH4 
        biosynthesis occurs. UniProt confirms cytoplasmic localization.
      action: ACCEPT
      reason: Cytosol is the appropriate specific cellular component for SPR. 
        The enzyme functions in the soluble cytoplasmic compartment where it 
        participates in BH4 biosynthesis alongside GCH1 and PTS. IDA evidence 
        from immunofluorescence is reliable.
      supported_by:
        - reference_id: UniProt:P35270
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: HTP
    original_reference_id: PMID:34800366
    review:
      summary: HTP annotation from a high-throughput mitochondrial proteome 
        study. SPR is primarily a cytosolic enzyme and mitochondrial 
        localization is not the primary site of function. This may represent 
        detection in a comprehensive proteomics survey rather than functional 
        mitochondrial localization.
      action: MARK_AS_OVER_ANNOTATED
      reason: SPR is well-established as a cytosolic enzyme (UniProt, IDA 
        evidence). The mitochondrial detection in this HTP study may be due to 
        contamination or minor dual localization but does not represent the 
        primary functional compartment. BH4 biosynthesis occurs in the cytosol. 
        This annotation could be misleading about primary localization.
      supported_by:
        - reference_id: UniProt:P35270
        - reference_id: PMID:34800366
          supporting_text: Epub 2021 Nov 19. Quantitative high-confidence human 
            mitochondrial proteome and its dynamics in cellular context.
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:23533145
    review:
      summary: HDA annotation from proteomic analysis of exosomes isolated from 
        expressed prostatic secretions in urine. The study identified ~900 
        proteins in exosome preparations using shotgun proteomics.
      action: KEEP_AS_NON_CORE
      reason: Detection of SPR in exosomes represents a finding from 
        high-throughput proteomics but does not indicate a primary functional 
        localization. Many cytosolic proteins are detected in exosomes. This is 
        not core to SPR function but may be retained as a non-core observation.
      supported_by:
        - reference_id: PMID:23533145
          supporting_text: 2013 Apr 23. In-depth proteomic analyses of exosomes 
            isolated from expressed prostatic secretions in urine.
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:19056867
    review:
      summary: HDA annotation from large-scale proteomics of urinary exosomes. 
        The study identified 1132 proteins in human urinary exosomes using 
        LC-MS/MS.
      action: KEEP_AS_NON_CORE
      reason: Similar to the other exosome annotation - detection in a 
        proteomics survey does not indicate primary functional localization. Can
        be retained as non-core observation.
      supported_by:
        - reference_id: PMID:19056867
          supporting_text: 2008 Dec 3. Large-scale proteomics and 
            phosphoproteomics of urinary exosomes.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1497853
    review:
      summary: TAS annotation from Reactome pathway annotation for SPR 
        phosphorylation by CaMK2. The reaction occurs in the cytosol. However, 
        note that UniProt indicates the Ser-213 phosphorylation by CaMK2 does 
        not change kinetic parameters.
      action: ACCEPT
      reason: Cytosol localization is accurate for SPR. Reactome pathway 
        curation places SPR in cytosol consistent with its role in BH4 
        biosynthesis.
      supported_by:
        - reference_id: Reactome:R-HSA-1497853
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1475414
    review:
      summary: TAS annotation from Reactome for the de novo BH4 synthesis 
        reaction where SPR reduces DHNTP (6-pyruvoyltetrahydropterin precursor) 
        to BH4.
      action: ACCEPT
      reason: Cytosol localization is appropriate for the de novo BH4 synthesis 
        pathway.
      supported_by:
        - reference_id: Reactome:R-HSA-1475414
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1497869
    review:
      summary: TAS annotation from Reactome for the BH4 salvage pathway where 
        SPR reduces sepiapterin to BH2.
      action: ACCEPT
      reason: Cytosol localization is appropriate for the BH4 salvage pathway 
        reaction.
      supported_by:
        - reference_id: Reactome:R-HSA-1497869
  - term:
      id: GO:0004757
      label: sepiapterin reductase (NADP+) activity
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ISS annotation based on sequence similarity to experimentally 
        verified orthologs (with reference to mouse SPR UniProtKB:P18297). Mouse
        SPR is well characterized.
      action: ACCEPT
      reason: The ISS annotation is valid and consistent with the direct 
        experimental evidence for human SPR (EC 1.1.1.153). Human and mouse SPR 
        share 74% sequence identity (PMID:1883349).
      supported_by:
        - reference_id: PMID:1883349
          supporting_text: Cloning and sequencing of cDNA encoding human 
            sepiapterin reductase--an enzyme involved in tetrahydrobiopterin 
            biosynthesis.
  - term:
      id: GO:0006729
      label: tetrahydrobiopterin biosynthetic process
    evidence_type: TAS
    original_reference_id: PMID:1883349
    review:
      summary: TAS annotation based on the original cloning paper by Ichinose et
        al. (1991). The paper cloned human SPR cDNA and established its role in 
        BH4 biosynthesis.
      action: ACCEPT
      reason: This is the foundational paper establishing SPR function in BH4 
        biosynthesis. TAS evidence is appropriate for this well-established 
        role.
      supported_by:
        - reference_id: PMID:1883349
          supporting_text: Cloning and sequencing of cDNA encoding human 
            sepiapterin reductase--an enzyme involved in tetrahydrobiopterin 
            biosynthesis.
  - term:
      id: GO:0006809
      label: nitric oxide biosynthetic process
    evidence_type: IDA
    original_reference_id: PMID:15197144
    review:
      summary: IDA annotation based on Franscini et al. (2004) study of BH4 
        synthesis in human platelets. The study demonstrated functional BH4 
        synthesis in platelets and discussed its importance for NO synthase 
        activity. BH4 is an essential cofactor for NOS enzymes. However, SPR 
        does not directly synthesize NO - it synthesizes BH4 which is required 
        as a cofactor by NOS.
      action: MODIFY
      reason: This annotation represents an indirect relationship. SPR 
        synthesizes BH4, which is required as a cofactor for NOS. SPR does not 
        directly participate in NO biosynthesis. The annotation is somewhat 
        over-extended. The core function is BH4 biosynthesis. If the connection 
        to NO synthesis is to be retained, it should be as a more general 
        regulatory term or kept as non-core.
      proposed_replacement_terms:
        - id: GO:0006729
          label: tetrahydrobiopterin biosynthetic process
      supported_by:
        - reference_id: PMID:15197144
          supporting_text: Functional tetrahydrobiopterin synthesis in human 
            platelets.
        - reference_id: PMID:9792819
          supporting_text: Genomic organization and chromosomal localization of 
            the human sepiapterin reductase gene.
  - term:
      id: GO:0008106
      label: alcohol dehydrogenase (NADP+) activity
    evidence_type: TAS
    original_reference_id: PMID:1883349
    review:
      summary: TAS annotation based on the cloning paper. The paper noted 
        homology between SPR and other short-chain dehydrogenases. However, 
        GO:0008106 refers to a different enzymatic activity (alcohol 
        dehydrogenase converting ethanol to acetaldehyde), not sepiapterin 
        reductase activity. This appears to be an incorrect mapping.
      action: REMOVE
      reason: This is an incorrect annotation. SPR does not have alcohol 
        dehydrogenase activity as defined by GO:0008106 (primary alcohols to 
        aldehydes). SPR is specifically a sepiapterin reductase (EC 1.1.1.153), 
        not an alcohol dehydrogenase (EC 1.1.1.2). The original paper mentions 
        sequence homology to SDR family members but does not demonstrate alcohol
        dehydrogenase activity. The correct MF term is GO:0004757.
      supported_by:
        - reference_id: UniProt:P35270
        - reference_id: PMID:1883349
          supporting_text: Cloning and sequencing of cDNA encoding human 
            sepiapterin reductase--an enzyme involved in tetrahydrobiopterin 
            biosynthesis.
  - term:
      id: GO:0050661
      label: NADP binding
    evidence_type: TAS
    original_reference_id: PMID:1883349
    review:
      summary: TAS annotation based on the cloning paper. SPR uses NADPH as 
        cofactor. UniProt confirms NADP(+) binding sites at multiple residues. 
        Crystal structure (PDB 1Z6Z) shows NADP bound.
      action: ACCEPT
      reason: NADP binding is a valid molecular function of SPR. The enzyme uses
        NADPH as the reducing cofactor for its reductase activity. Crystal 
        structure confirms NADP binding. This represents a true, experimentally 
        verified function.
      supported_by:
        - reference_id: UniProt:P35270
          supporting_text: KM=14.3 uM for sepiapterin
        - reference_id: UniProt:P35270
          supporting_text: KM=10 uM for NADPH {ECO:0000269|PubMed:10350607, 
            ECO:0000269|PubMed:11825621}
        - reference_id: PMID:1883349
          supporting_text: Cloning and sequencing of cDNA encoding human 
            sepiapterin reductase--an enzyme involved in tetrahydrobiopterin 
            biosynthesis.
  - term:
      id: GO:0004757
      label: sepiapterin reductase (NADP+) activity
    evidence_type: TAS
    original_reference_id: PMID:9792819
    review:
      summary: TAS annotation based on Ohye et al. (1998) genomic organization 
        paper. The paper states SPR "catalyzes the final step of the 
        biosynthetic pathway of tetrahydrobiopterin."
      action: ACCEPT
      reason: The annotation is accurate. The paper explicitly describes SPR's 
        enzymatic function in BH4 biosynthesis.
      supported_by:
        - reference_id: PMID:9792819
          supporting_text: Genomic organization and chromosomal localization of 
            the human sepiapterin reductase gene.
core_functions:
  - molecular_function:
      id: GO:0004757
      label: sepiapterin reductase (NADP+) activity
    description: 'Core enzymatic function. SPR catalyzes the NADPH-dependent reduction
      of sepiapterin and 6-pyruvoyl-tetrahydropterin intermediates to form tetrahydrobiopterin.
      EC 1.1.1.153. Kinetic parameters: Km 14.3 uM sepiapterin, Km 10 uM NADPH, kcat
      1.1 s-1. Crystal structure solved (PDB:6I6V at 1.43 A). Homodimer.'
  - molecular_function:
      id: GO:0050661
      label: NADP binding
    description: NADP cofactor binding function. SPR binds NADPH as the reducing
      cofactor. Multiple NADP binding sites identified by X-ray crystallography 
      (PDB:1Z6Z, 6I6V). Km for NADPH is 10 uM. Member of short-chain 
      dehydrogenase/reductase (SDR) superfamily.
proposed_new_terms: []
suggested_questions:
  - question: What is the relative contribution of SPR vs. alternative aldo-keto
      reductases (AKR1A1, AKR1B1) in BH4 biosynthesis in different tissues? The 
      deep research mentions that alternative reductases can form 1'/2'-oxo 
      intermediates but the terminal steps are uniquely dependent on SPR.
suggested_experiments:
  - description: Measure SPR activity and BH4 levels in patient cells with novel
      SPR variants to establish genotype-phenotype correlations for SRD. 
      Currently ~60 SRD cases described. Understanding variant effects on enzyme
      function could improve diagnosis and treatment.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data 
      to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings:
      - statement: IBA annotations for sepiapterin reductase activity and BH4 
          biosynthesis are well-supported by phylogenetic evidence
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping, accompanied by conservative changes to GO 
      terms applied by UniProt
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings:
      - statement: Cytosol localization confirmed by immunofluorescence
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:10350607
    title: Functionally important residues tyrosine-171 and serine-158 in 
      sepiapterin reductase
    findings:
      - statement: SPR is the terminal enzyme in the BH4 biosynthetic pathway
        supporting_text: sepiapterin reductase (SPR), which is a member of the 
          NADP(H)-preferring short-chain dehydrogenase/reductase (SDR) family 
          and acts as the terminal enzyme in the biosynthetic pathway of 
          tetrahydrobiopterin cofactor (BH4)
      - statement: Ser-158, Tyr-171, and Lys-175 are essential for catalytic 
          activity
        supporting_text: Ser-158, Tyr-171, and Lys-175 contributed to the 
          catalytic activity of SPR, and both Tyr-171 and Ser-158 are 
          simultaneously necessary on proton transfer to the carbonyl functional
          groups of substrate
  - id: PMID:11443547
    title: Mutations in the sepiapterin reductase gene cause a novel 
      tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency 
      without hyperphenylalaninemia
    findings:
      - statement: SPR mutations cause progressive psychomotor retardation with 
          dystonia and monoamine deficiency
        supporting_text: two patients with progressive psychomotor retardation, 
          dystonia, severe dopamine and serotonin deficiencies (low levels of 
          5-hydroxyindoleacetic and homovanillic acids), and abnormal pterin 
          pattern
      - statement: SPR deficiency causes BH4-dependent neurotransmitter 
          deficiency without hyperphenylalaninemia
        supporting_text: autosomal recessive SR deficiency leads to BH(4) and to
          neurotransmitter deficiencies without hyperphenylalaninemia and may 
          not be detected by neonatal screening for phenylketonuria
  - id: PMID:15197144
    title: Functional tetrahydrobiopterin synthesis in human platelets
    findings:
      - statement: Human platelets have functional de novo BH4 synthesis
      - statement: SPR mRNA and enzymatic activity present in freshly isolated 
          platelets
      - statement: BH4 is essential cofactor for NO synthase activity
  - id: PMID:1883349
    title: Cloning and sequencing of cDNA encoding human sepiapterin 
      reductase--an enzyme involved in tetrahydrobiopterin biosynthesis
    findings:
      - statement: First cloning of human SPR cDNA
      - statement: 261 amino acids, 28,047 Da molecular mass
      - statement: 74% identity with rat SPR
      - statement: Homology to SDR family members
  - id: PMID:19056867
    title: Large-scale proteomics and phosphoproteomics of urinary exosomes
    findings:
      - statement: SPR detected in urinary exosome proteome (1132 proteins 
          identified)
  - id: PMID:23533145
    title: In-depth proteomic analyses of exosomes isolated from expressed 
      prostatic secretions in urine
    findings:
      - statement: SPR detected among ~900 proteins in EPS-urine exosomes
  - id: PMID:34800366
    title: Quantitative high-confidence human mitochondrial proteome and its 
      dynamics in cellular context
    findings:
      - statement: SPR detected in mitochondrial proteome study (HTP)
  - id: PMID:9792819
    title: Genomic organization and chromosomal localization of the human 
      sepiapterin reductase gene
    findings:
      - statement: SPR gene has 3 exons spanning ~4 kb
      - statement: Located on chromosome 2p13
      - statement: SPR catalyzes final step of BH4 biosynthesis
  - id: Reactome:R-HSA-1475414
    title: PTHP is reduced to BH4 by sepiapterin reductase (SPR)
    findings:
      - statement: SPR reduces DHNTP to BH4 in de novo pathway
  - id: Reactome:R-HSA-1497853
    title: Sepiapterin reductase (SPR) is phosphorylated by 
      Ca2+/calmodulin-dependent protein kinase II
    findings:
      - statement: SPR Ser-213 phosphorylated by CaMK2
      - statement: UniProt indicates phosphorylation does not change kinetic 
          parameters
  - id: Reactome:R-HSA-1497869
    title: Salvage - Sepiapterin is reduced to q-BH2
    findings:
      - statement: SPR reduces sepiapterin to BH2 in salvage pathway
  - id: file:human/SPR/SPR-deep-research-falcon.md
    title: Deep research report on SPR
    findings: []
tags:
  - ferroptosis

SPR

Gene Description

Existing Annotations Review

Core Functions

NADP cofactor binding function. SPR binds NADPH as the reducing cofactor. Multiple NADP binding sites identified by X-ray crystallography (PDB:1Z6Z, 6I6V). Km for NADPH is 10 uM. Member of short-chain dehydrogenase/reductase (SDR) superfamily.

References

Suggested Questions for Experts

Suggested Experiments

Tags

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

📄 View Raw YAML