Qdpr encodes rat dihydropteridine reductase (DHPR), a cytosolic short-chain dehydrogenase/reductase-family homodimer with a Rossmann-fold dinucleotide-binding domain. It reduces quinonoid dihydrobiopterin (qBH2) back to tetrahydrobiopterin (BH4), using NADH as the preferred electron donor (NADPH is a much poorer substrate), and so regenerates the BH4 cofactor consumed by phenylalanine, tyrosine and tryptophan hydroxylases and by nitric oxide synthases. The enzyme is most active in liver and kidney and is also present in brain, where BH4 recycling supports catecholamine and serotonin synthesis; in humans, loss of DHPR causes a severe BH4-deficient form of hyperphenylalaninemia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: cytoplasm is retained as contextual support for Qdpr, but it is not the core function (IBA, GO_REF:0000033). Reason: cytoplasm records localization or complex context for Qdpr, not the defining molecular function. Supporting Evidence: UniProtKB:P11348 FUNCTION: Catalyzes the conversion of quinonoid dihydrobiopterin into tetrahydrobiopterin. file:rat/Qdpr/Qdpr-deep-research-falcon.md a cell-based study reported wild-type QDPR is mainly **cytoplasmic** (with a mutant showing altered localization) |
| GO:0004155 6,7-dihydropteridine reductase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Qdpr's quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis supports retaining 6,7-dihydropteridine reductase activity as a direct annotation (IBA, GO_REF:0000033). Reason: 6,7-dihydropteridine reductase activity directly matches Qdpr's documented role in quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis. Supporting Evidence: UniProtKB:P11348 FUNCTION: Catalyzes the conversion of quinonoid dihydrobiopterin into tetrahydrobiopterin. file:rat/Qdpr/Qdpr-deep-research-falcon.md an NAD(H)-dependent oxidoreductase that catalyzes regeneration of **tetrahydrobiopterin (BH4)** from **quinonoid dihydrobiopterin (qBH2)** |
| GO:0006729 tetrahydrobiopterin biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Qdpr's quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis supports retaining tetrahydrobiopterin biosynthetic process as a direct annotation (IBA, GO_REF:0000033). Reason: tetrahydrobiopterin biosynthetic process is a direct process-level consequence of Qdpr's documented role in quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis. Supporting Evidence: UniProtKB:P11348 FUNCTION: Catalyzes the conversion of quinonoid dihydrobiopterin into tetrahydrobiopterin. file:rat/Qdpr/Qdpr-deep-research-falcon.md Qdpr functions in **BH4 recycling**, complementing BH4 de novo synthesis and maintaining reduced cofactor supply for **PAH, TH, and TPH**. This is the primary function most relevant for annotation. |
| GO:0070402 NADPH binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: NADPH binding is retained as contextual support for Qdpr, but it is not the core function (IBA, GO_REF:0000033). Reason: NADPH binding records cofactor, substrate, or interaction context for Qdpr, but the curated core role is quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis. Supporting Evidence: UniProtKB:P11348 FUNCTION: Catalyzes the conversion of quinonoid dihydrobiopterin into tetrahydrobiopterin. file:rat/Qdpr/Qdpr-deep-research-falcon.md Older rat biochemical work indicates **NADH is more effective than NADPH in vitro**, while allowing that NADPH may contribute in vivo depending on cellular redox pools. |
| GO:0070404 NADH binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: NADH binding is retained as contextual support for Qdpr, but it is not the core function (IBA, GO_REF:0000033). Reason: NADH binding records cofactor, substrate, or interaction context for Qdpr, but the curated core role is quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis. Supporting Evidence: UniProtKB:P11348 FUNCTION: Catalyzes the conversion of quinonoid dihydrobiopterin into tetrahydrobiopterin. file:rat/Qdpr/Qdpr-deep-research-falcon.md Direct structural evidence shows **NADH bound** in the rat DHPR crystal structure and supports NADH as the physiologic electron donor. |
| GO:0004155 6,7-dihydropteridine reductase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Qdpr's quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis supports retaining 6,7-dihydropteridine reductase activity as a direct annotation (IEA, GO_REF:0000120). Reason: 6,7-dihydropteridine reductase activity directly matches Qdpr's documented role in quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis. Supporting Evidence: UniProtKB:P11348 FUNCTION: Catalyzes the conversion of quinonoid dihydrobiopterin into tetrahydrobiopterin. |
| GO:0042558 pteridine-containing compound metabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: Qdpr's quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis supports retaining pteridine-containing compound metabolic process as a direct annotation (IEA, GO_REF:0000117). Reason: pteridine-containing compound metabolic process is a direct process-level consequence of Qdpr's documented role in quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis. Supporting Evidence: UniProtKB:P11348 FUNCTION: Catalyzes the conversion of quinonoid dihydrobiopterin into tetrahydrobiopterin. file:rat/Qdpr/Qdpr-deep-research-falcon.md pterin-4Ξ±-carbinolamine dehydratase (PCD) converts a carbinolamine intermediate to **qBH2**, which is then reduced back to **BH4 by DHPR/QDPR** |
| GO:0004155 6,7-dihydropteridine reductase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Qdpr's quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis supports retaining 6,7-dihydropteridine reductase activity as a direct annotation (ISO, GO_REF:0000121). Reason: 6,7-dihydropteridine reductase activity directly matches Qdpr's documented role in quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis. Supporting Evidence: UniProtKB:P11348 FUNCTION: Catalyzes the conversion of quinonoid dihydrobiopterin into tetrahydrobiopterin. |
| GO:0001889 liver development | IEP PMID:710385 Dihydropteridine reductase activity of adult, fetal and neop... | MARK AS OVER ANNOTATED | Summary: liver development is treated as over-annotation because it is contextual or downstream of Qdpr's direct role (IEP, PMID:710385). Reason: The IEP rests on the observation that hepatic dihydropteridine reductase activity rises during development (the "developmental upsurge" begins earlier than that of phenylalanine hydroxylase). That is an expression/activity pattern of a cofactor-regenerating enzyme in maturing liver; nothing in the study shows Qdpr contributing to the morphogenesis or differentiation that constitute liver development, so the process term overshoots the evidence. Supporting Evidence: PMID:710385 Optimal conditions for the assay of dihydropteridine reductase in crude tissue extracts have been developed. Among adult rat tissues, liver and kidney had the highest activity followed by thymus, lung, cerebellum and cerebrum. PMID:710385 In both liver and kidney the developmental upsurge of dihydropteridine reductase, which produces the cofactor necessary for the hydroxylation of aromatic amino acids, begins earlier than does that of phenylalanine hydroxylase. |
| GO:0010044 response to aluminum ion | IEP PMID:3477172 The effect of lead and aluminium on rat dihydropteridine red... | UNDECIDED | Summary: response to aluminum ion (IEP, PMID:3477172) cannot be adjudicated; the cached record for this short proceedings paper has a title but no abstract. Reason: The title ("The effect of lead and aluminium on rat dihydropteridine reductase") indicates that aluminium exposure altered Qdpr activity, but the cached record has no abstract or full text, so it is not possible to see whether the observation was enzyme inhibition by the metal in vitro or a regulated change in expression in vivo. An earlier version marked this row over-annotated; that verdict rested on a study that could not be read, so the row is left for a curator with access to the paper. If the observation was direct enzyme inhibition, the term would overshoot (the enzyme is the target of the metal rather than a participant in a cellular response). Supporting Evidence: PMID:3477172 The effect of lead and aluminium on rat dihydropteridine reductase |
| GO:0010288 response to lead ion | IEP PMID:3815851 The effect of lead on tetrahydrobiopterin metabolism. A poss... | MARK AS OVER ANNOTATED | Summary: response to lead ion is treated as over-annotation because it is contextual or downstream of Qdpr's direct role (IEP, PMID:3815851). Reason: The study shows that low-level lead in vivo inhibits dihydropteridine reductase, with a secondary rise in tetrahydrobiopterin synthesis. Inhibition of the enzyme by the metal makes Qdpr a target of lead toxicity; it does not show Qdpr carrying out a cellular response to lead, so the response-process term overshoots what was observed. Retained as a documented sensitivity rather than removed. Supporting Evidence: PMID:3815851 The use of low levels of lead in vivo in rats has been found to inhibit dihydropteridine reductase and cause an apparent increase in tetrahydrobiopterin biosynthesis. |
| GO:0033762 response to glucagon | IEP PMID:4155291 Effect of glucagon on phenylalanine metabolism and phenylala... | MARK AS OVER ANNOTATED | Summary: response to glucagon is treated as over-annotation because it is contextual or downstream of Qdpr's direct role (IEP, PMID:4155291). Reason: Glucagon treatment for 10 days induced hepatic dihydropteridine reductase more than twofold. That is a genuine expression-pattern observation, but the enzyme is a downstream induced output; there is no evidence that Qdpr activity mediates any part of the glucagon response (signalling or metabolic outcome), so the process term overshoots the induction data. Supporting Evidence: PMID:4155291 Glucagon administered subcutaneously to rats for 10 days had no significant effect on liver phenylalanine hydroxylase activity, but induced liver dihydropteridine reductase more than twofold. |
| GO:0071466 cellular response to xenobiotic stimulus | IEP PMID:2484967 Regulation of GTP cyclohydrolase I and dihydropteridine redu... | MARK AS OVER ANNOTATED | Summary: cellular response to xenobiotic stimulus is treated as over-annotation because it is contextual or downstream of Qdpr's direct role (IEP, PMID:2484967). Reason: In PC12 cells, cAMP-raising agents and forskolin left dihydropteridine reductase activity unchanged; only theophylline lowered it, and only at 96 h. A single late decrease with one compound (while GTP cyclohydrolase I was the responsive enzyme) does not establish that Qdpr participates in a cellular response to xenobiotics, so the term overshoots the data. Supporting Evidence: PMID:2484967 The addition of 8-bromo cyclic AMP, forskolin, theophylline, and 3-isobutyl-1-methylxanthine to the medium of PC 12 cells resulted in an increase in GTP cyclohydrolase I activity, but had no effect on dihydropteridine reductase activity, except theophylline which caused a decrease in dihydropteridine reductase activity at 96 h. |
| GO:0004155 6,7-dihydropteridine reductase activity | IMP PMID:8262916 The crystallographic structure of a human dihydropteridine r... | ACCEPT | Summary: Qdpr's quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis supports retaining 6,7-dihydropteridine reductase activity as a direct annotation (IMP, PMID:8262916). Reason: 6,7-dihydropteridine reductase activity directly matches Qdpr's documented role in quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis. Supporting Evidence: PMID:8262916 A human dihydropteridine reductase (EC 1.6.99.10) has been created from a rat cDNA clone by a single five-oligonucleotide mutagenesis reaction and expressed in good yield in Escherichia coli. |
| GO:0070402 NADPH binding | IMP PMID:1639779 Characterization and nucleotide binding properties of a muta... | KEEP AS NON CORE | Summary: NADPH binding is retained as contextual support for Qdpr, but it is not the core function (IMP, PMID:1639779). Reason: NADPH binding records cofactor, substrate, or interaction context for Qdpr, but the curated core role is quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis. Supporting Evidence: PMID:1639779 Kinetic constants for the interaction of NADH and NADPH with native rat dihydropteridine reductase (DHPR) and an Escherichia coli expressed mutant (D-37-I) have been determined. PMID:1639779 indicate that the native enzyme has a considerable preference for NADH with an optimum kcat/Km of 12 microM-1 s-1 |
| GO:0006729 tetrahydrobiopterin biosynthetic process | IMP PMID:9235988 The comparative interaction of quinonoid (6R)-dihydrobiopter... | ACCEPT | Summary: Qdpr's quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis supports retaining tetrahydrobiopterin biosynthetic process as a direct annotation (IMP, PMID:9235988). Reason: tetrahydrobiopterin biosynthetic process is a direct process-level consequence of Qdpr's documented role in quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis. Supporting Evidence: PMID:9235988 Kinetic parameters and primary deuterium isotope effects have been determined for wild-type dihydropteridine reductase (EC 1.6.99.7) and the Ala133Ser, Lys150Gln, Tyr146His, Tyr146Phe single, and Tyr146Phe/Ala133Ser and Tyr146Phe/Lys150Gln double mutant enzyme forms using the natural substrate, quinonoid (6R)-l-erythro-dihydrobiopterin (qBH2) and an alternate substrate, quinonoid 6,7-dimethyldihydropteridine. PMID:9235988 For qBH2, where Dkcat < Dkcat/KPt was consistently observed, the rate determining step is ascribed to release of the tetrahydropterin product. |
| GO:0042802 identical protein binding | IPI PMID:1631094 Crystal structure of rat liver dihydropteridine reductase | KEEP AS NON CORE | Summary: identical protein binding is retained as contextual support for Qdpr, but it is not the core function (IPI, PMID:1631094). Reason: identical protein binding records the physiological homodimerization of Qdpr (UniProt annotates the subunit structure as a homodimer); it is a real, evidenced interaction but not the defining catalytic function, which is quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis. Supporting Evidence: PMID:1631094 DHPR is an alpha/beta protein with a Rossmann-type dinucleotide fold for NADH binding. Insertion of an extra threonine residue in the human enzyme is associated with severe symptoms of a variant form of phenylketonuria and maps to a tightly linked sequence of secondary-structural elements near the dimer interface. file:rat/Qdpr/Qdpr-deep-research-falcon.md The protein exists as a **dimer in solution**; dimerization is mediated by a **four-helix bundle** formed by helices contributed from each protomer. |
| GO:0070404 NADH binding | IPI PMID:8631945 Altered structural and mechanistic properties of mutant dihy... | KEEP AS NON CORE | Summary: NADH binding is retained as contextual support for Qdpr, but it is not the core function (IPI, PMID:8631945). Reason: NADH binding records cofactor, substrate, or interaction context for Qdpr, but the curated core role is quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis. Supporting Evidence: PMID:8631945 Nine single genetic mutants of rat dihydropteridine reductase (EC 1.6.99.7), D37I, W86I, Y146F, Y146H, K150Q, K150I, K150M, N186A, and A133S and one double mutant, Y146F/K150Q, have been engineered, overexpressed in Escherichia coli and their proteins purified. PMID:8631945 It is readily apparent that specific interactions of the apoenzyme with the cofactor, NADH, are vital to the integrity of the total protein tertiary structure and that the generation of the active site requires bound cofactor in addition to a suitably placed W86. |
| GO:0004155 6,7-dihydropteridine reductase activity | IDA PMID:660556 Regional and subcellular distribution and some factors in th... | ACCEPT | Summary: Qdpr's quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis supports retaining 6,7-dihydropteridine reductase activity as a direct annotation (IDA, PMID:660556). Reason: 6,7-dihydropteridine reductase activity directly matches Qdpr's documented role in quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis. Supporting Evidence: PMID:660556 We have studied the regional and subcellular distribution, functional role, and pharmacology of quinoid dihydropterin reductase (QDPR) and endogenous reduced pterins (PH4) subserving tyrosin hydroxylase (TOH) and tryptophan hydroxylase in the rat brain. |
| GO:0006729 tetrahydrobiopterin biosynthetic process | IDA PMID:660556 Regional and subcellular distribution and some factors in th... | ACCEPT | Summary: Qdpr's quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis supports retaining tetrahydrobiopterin biosynthetic process as a direct annotation (IDA, PMID:660556). Reason: tetrahydrobiopterin biosynthetic process is a direct process-level consequence of Qdpr's documented role in quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis. Supporting Evidence: PMID:660556 We have studied the regional and subcellular distribution, functional role, and pharmacology of quinoid dihydropterin reductase (QDPR) and endogenous reduced pterins (PH4) subserving tyrosin hydroxylase (TOH) and tryptophan hydroxylase in the rat brain. |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: cytoplasm is retained as contextual support for Qdpr, but it is not the core function (ISO, GO_REF:0000121). Reason: cytoplasm records localization or complex context for Qdpr, not the defining molecular function. Supporting Evidence: UniProtKB:P11348 FUNCTION: Catalyzes the conversion of quinonoid dihydrobiopterin into tetrahydrobiopterin. file:rat/Qdpr/Qdpr-deep-research-falcon.md The biochemical role of DHPR in BH4 recycling is most consistent with a **soluble cytosolic enzyme** that interacts with cytosolic BH4-dependent hydroxylation systems |
| GO:0004155 6,7-dihydropteridine reductase activity | IMP PMID:1898002 Role of aspartate-37 in determining cofactor specificity and... | ACCEPT | Summary: Qdpr's quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis supports retaining 6,7-dihydropteridine reductase activity as a direct annotation (IMP, PMID:1898002). Reason: 6,7-dihydropteridine reductase activity directly matches Qdpr's documented role in quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis. Supporting Evidence: PMID:1898002 Full-length rat dihydropteridine reductase (DHPR) cDNAs have been combined with a prokaryotic expression vector and introduced into Escherichia coli. PMID:1898002 Transformed bacteria express dihydropteridine reductase immunoreactive proteins and demonstrate conversion of quinonoid dihydropteridines to their tetrahydro forms. |
| GO:0006729 tetrahydrobiopterin biosynthetic process | IMP PMID:1898002 Role of aspartate-37 in determining cofactor specificity and... | ACCEPT | Summary: Qdpr's quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis supports retaining tetrahydrobiopterin biosynthetic process as a direct annotation (IMP, PMID:1898002). Reason: tetrahydrobiopterin biosynthetic process is a direct process-level consequence of Qdpr's documented role in quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis. Supporting Evidence: PMID:1898002 Full-length rat dihydropteridine reductase (DHPR) cDNAs have been combined with a prokaryotic expression vector and introduced into Escherichia coli. PMID:1898002 Transformed bacteria express dihydropteridine reductase immunoreactive proteins and demonstrate conversion of quinonoid dihydropteridines to their tetrahydro forms. |
| GO:0006729 tetrahydrobiopterin biosynthetic process | TAS PMID:3680258 Structural studies and isolation of cDNA clones providing th... | ACCEPT | Summary: Qdpr's quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis supports retaining tetrahydrobiopterin biosynthetic process as a direct annotation (TAS, PMID:3680258). Reason: tetrahydrobiopterin biosynthetic process is a direct process-level consequence of Qdpr's documented role in quinonoid dihydrobiopterin reduction during tetrahydrobiopterin recycling/biosynthesis. Supporting Evidence: PMID:3680258 The cleavage of reductively alkylated rat liver dihydropteridine reductase with cyanogen bromide afforded a mixture of peptides, six of which (CB-1 to CB-6) were isolated and purified by C8 reverse-phase high performance liquid chromatography. |
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