DeCure for Pterin-4 alpha-carbinolamine dehydratase 1 deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for pterin-4 alpha-carbinolamine dehydratase 1 deficiency — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease modulePterin-4 alpha-carbinolamine dehydratase 1 deficiency maps to a 2-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
approvedTetrahydrobiopterinApproved drug
Structures already discussed alongside pterin-4 alpha-carbinolamine dehydratase 1 deficiency in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN — Tetrahydrobiopterin has a real, experimentally solved structure in complex with this target (PDB 1D1V, 1.93 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet h4bdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1D1V · 1.93 Å · ligand Tetrahydrobiopterin (H4B). Experimental structure, not a prediction.
What the evidence adds up to
Pterin-4a-carbinolamine dehydratase (PCD) deficiency is one of four tetrahydrobiopterin (BH4) deficiencies surveyed in an international database of 626 patients, of whom 23 had PCD deficiency. Up to 57% of neonates with any BH4 deficiency were already clinically symptomatic at diagnosis. During infancy and childhood the predominant symptoms were muscular hypotonia, mental retardation, and age-dependent movement disorders including dystonia. The laboratory diagnosis relies on newborn screening for phenylketonuria, characteristic pterin profiles in urine or dried blood spots, and measurement of DHPR activity in blood. The survey authors concluded that outcomes are highly variable but that early diagnosis and treatment result in improved outcomes; they did not report separate outcome data for the PCD subgroup.
PCD catalyses the regeneration of the essential cofactor 6(R)-BH4 in the phenylalanine hydroxylase system. Mutations in PCD or its deactivation by hydrogen peroxide generate 7(R,S)BH4, a potent inhibitor of phenylalanine hydroxylase implicated in primapterinuria, a variant form of phenylketonuria. A 2006 study synthesised and separated the 7(R) and 7(S) diastereomers and found that both function as poor cofactors for phenylalanine hydroxylase, but only 7(S)BH4 acts as a potent competitive inhibitor against 6(R)BH4, with a Ki of 2.3–4.9 µM. 7(S)BH4 was not an inhibitor of tyrosine hydroxylase in the physiological range, presumably because serine-251 is replaced by alanine-297 in that enzyme.
A 1995 study characterised the human wild-type PCD protein and two mutants, Cys81Ser and Cys81Arg. The Cys81Arg mutant had been proposed as causative in a hyperphenylalaninaemic patient. Wild-type and Cys81Ser enhanced the rate of the phenylalanine hydroxylase assay approximately 10-fold, similar to native rat liver dehydratase. The Cys81Arg mutant had significantly lower activity. All three proteins enhanced the spontaneous dehydration of a synthetic substrate approximately 50–70-fold at 4°C and pH 8.5.
What is still missing is any controlled trial of treatment for PCD deficiency specifically, any data on whether the 23 patients in the survey received uniform therapy or had consistent outcomes, and any stratification by genotype or age at diagnosis. The biochemical mechanism of 7(S)BH4 inhibition is understood in vitro, but no clinical study has tested whether blocking that inhibition improves outcomes in patients.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Inherited Metabolic Disease · 2012 · 137 citations
An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia
AbstractOBJECTIVES: The present study summarizes clinical and biochemical findings, current treatment strategies and follow-up in patients with tetrahydrobiopterin (BH(4)) deficiencies. METHODS: We analyzed the clinical, biochemical and treatment data of 626 patients with BH(4) deficiencies [355 with 6-pyruvoyl-tetrahydropterin synthase (PTPS), 217 with dihydropteridine reductase (DHPR), 31 with autosomal recessive GTP cyclohydrolase I (GTPCH), and 23 with pterin-4a-carbinolamine dehydratase (PCD) deficiencies] from the BIODEF Database. Patients with autosomal dominant GTPCH and SR deficiencies will not be discussed in detail. RESULTS: Up to 57 % of neonates with BH(4) deficiencies are already clinically symptomatic. During infancy and childhood, the predominant symptoms are muscular hypotonia, mental retardation and age-dependent movement disorders, including dystonia. The laboratory diagnosis of BH(4) deficiency is based on a positive newborn screening (NBS) for phenylketonuria (PKU), characteristic profiles of urinary or dried blood spot pterins (biopterin, neopterin, and primapterin), and the measurement of DHPR activity in blood. Some patients with autosomal recessive GTPCH deficiency and all with sepiapterin reductase deficiency may be diagnosed late due to normal blood phenylalanine in NBS. L-dopa, 5-hydroxytryptophan, and BH(4) are supplemented in PTPS and GTPCH-deficient patients, whereas L-dopa, 5-hydroxytryptophan, folinic acid and diet are used in DHPR-deficient patients. Medication doses vary widely among patients, and our understanding of the effects of dopamine agonists and monoamine catabolism inhibitors are limited. CONCLUSIONS: BH(4) deficiencies are a group of treatable pediatric neurotransmitter disorders that are characterized by motor dysfunction, mental retardation, impaired muscle tone, movement disorders and epileptic seizures. Although the outcomes of BH(4) deficiencies are highly variable, early diagnosis and treatment result in improved outcomes.
Specific interaction of the diastereomers 7(R)‐ and 7(S)‐tetrahydrobiopterin with phenylalanine hydroxylase: implications for understanding primapterinuria and vitiligo
AbstractPterin‐4a‐carbinolamine dehydratase (PCD) is an essential component of the phenylalanine hydroxylase (PAH) system, catalyzing the regeneration of the essential cofactor 6(R)‐L‐erythro‐5,6,7,8‐tetrahydrobiopterin [6(R)BH 4 ]. Mutations in PCD or its deactivation by hydrogen peroxide result in the generation of 7(R,S)BH 4 , which is a potent inhibitor of PAH that has been implicated in primapterinuria, a variant form of phenylketonuria, and in the skin depigmentation disorder vitiligo. We have synthesized and separated the 7(R) and 7(S) diastereomers confirming their structure by NMR. Both 7(R)‐ and 7(S)BH 4 function as poor cofactors for PAH, whereas only 7(S)BH 4 acts as a potent competitive inhibitor vs. 6(R)BH 4 ( K i 2.3–4.9 µM). Kinetic and binding studies, as well as characterization of the pterin‐enzyme complexes by fluorescence spectroscopy, revealed that the inhibitory effects of 7(R,S)BH 4 on PAH are in fact specifically based on 7(S)BH 4 binding. The molecular dynamics simulated structures of the pterin‐PAH complexes indicate that 7(S)BH 4 inhibition is due to its interaction with the polar region at the pterin binding site close to Ser‐251, whereas its low efficiency as cofactor is related to a suboptimal positioning toward the catalytic iron. 7(S)BH 4 is not an inhibitor for tyrosine hydroxylase (TH) in the physiological range, presumably due to the replacement of Ser‐251 by the corresponding Ala297. Taken together, our results identified structural determinants for the specific regulation of PAH and TH by 7(S)BH 4 , which in turn aid in the understanding of primapterinuria and acute vitiligo. —Pey, A. L., Martinez, A., Charubala, R., Maitland, D. J., Teigen, K., Calvo, A., Pfleiderer, W., Wood, J. M., Schallreuter, K. U. Specific interaction of the diastereomers 7(R)‐ and 7(S)‐tetrahydrobiopterin with phenylalanine hydroxylase: implications for understanding primapterinuria and vitiligo FASEB J. 20, E1451–E1464 (2006)
European Journal of Biochemistry · 1995 · 20 citations
Human Pterin-4alpha-Carbinolamine Dehydratase/Dimerization Cofactor of Hepatocyte Nuclear Factor-1alpha. Characterization and Kinetic Analysis of Wild-Type and Mutant Enzymes
AbstractPterin-4a-carbinolamine dehydratase/dimerization cofactor for hepatocyte nuclear factor-1 alpha is a protein with two different functions. We have overexpressed and purified the human wild-type protein, and its Cys81Ser and Cys81Arg mutants. The Cys81Arg mutant has been proposed to be causative in a hyperphenylalaninaemic patient [Citron, B. A., Kaufman, S., Milstien, S., Naylor, E. W., Greene, C. L. & Davis, M. D. (1993) Am. J. Hum. Genet. 53, 768-774]. The dehydratase behaves as a tetramer on gel filtration, while cross-linking experiments showed mono-, di-, tri-, and tetrameric forms, irrespective of the presence of the single Cys81. Sulfhydryl-modifying reagents did not affect the activity, but rather showed that Cys81 is exposed. Various pterins bind and quench the tryptophan fluorescence suggesting the presence of a specific binding site. The fluorescence is destroyed upon light irradiation. Wild-type and the Cys81Ser protein enhance the rate of the phenylalanine hydroxylase assay approximately 10-fold, a value similar to that of native dehydratase from rat liver; the Cys81Arg mutant, in contrast, has significantly lower activity. This is compatible with the hypothesis that the dehydratase is a rate-limiting factor for the in vivo phenylalanine hydroxylase reaction. The three proteins enhance the spontaneous dehydration of the synthetic substrate 6,6-dimethyl-7,8-dihydropterin-4a-carbinolamine approximately 50-70-fold at 4 degrees C and pH 8.5. The results are discussed in view of the recently solved three-dimensional structure of the enzyme [Ficner, R., Sauer, U. W., Stier, G. & Suck, D. (1995) EMBO J. 14, 2032-2042].
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
