DeCure for Adenine phosphoribosyltransferase deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for adenine phosphoribosyltransferase 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 moduleAdenine phosphoribosyltransferase 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
No approved-drug candidate for adenine phosphoribosyltransferase deficiency is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
adenine phosphoribosyltransferase (APRT) — APRT is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet ampdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4X45 · 1.75 Å · ligand ADENOSINE MONOPHOSPHATE (AMP). Experimental structure, not a prediction.
What the evidence adds up to
A 1977 study using human lymphoblast mutants found that cells lacking adenine phosphoribosyltransferase (APRT) remained sensitive to growth inhibition by adenine, and cells lacking adenosine kinase remained sensitive to adenosine when adenosine deaminase was inhibited. The authors concluded that the toxicity of adenine and adenosine to these cells is not mediated by the nucleotides they are converted into. This work did not involve patients.
By 1982, immunochemical and protein blot analysis of haemolysates from 30 patients in six families with APRT deficiency showed that four homozygotes had less than 1% of normal enzyme activity and immunoreactive protein. In 26 heterozygotes, enzyme activity was uniformly about 25% of normal, but the level of immunoreactive protein varied between 22% and 112% of control, and was consistent within each kindred. One heterozygote had both a normal and a more acidic enzyme subunit. The authors concluded that different mutations in the APRT structural gene exist, that the variant enzymes are more labile in vivo or catalytically nonfunctional, and that heterozygotes express only 25% of normal activity because normal and variant subunits form a hybrid dimer that is either more labile or less active.
A 1986 report of a single case of 2,8-dihydroxyadenine urolithiasis found reduced APRT activity. The patient’s enzyme had normal affinity for adenine but reduced affinity for the substrate phosphoribosyl-pyrophosphate, and was much more stable at 60°C than the control enzyme. The authors described it as a variant enzyme. A 1987 study identified the specific mutations in a patient with complete APRT deficiency: a trinucleotide deletion (corresponding to phenylalanine) on one allele, and a single nucleotide insertion adjacent to a splice site on the other allele that caused aberrant splicing and absence of exon 4 in the cDNA.
A 1988 survey of 948 Japanese urological departments identified 76 families with 2,8-dihydroxyadenine lithiasis. Of 51 families where APRT activity was assayed, 76% were partially deficient. The distribution of affected families was roughly similar to the Japanese population, and the rate of the partial-deficiency type did not differ significantly across regions. The authors proposed that a unique mutant gene, APRT*J, created many years ago in a Japanese ancestor, explains the large number of cases in Japan. What remains missing is any clinical trial of a treatment, any data on long-term outcomes beyond stone formation, and any systematic effort to stratify patients by the specific mutation they carry.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Science · 1977 · 113 citations
Adenine and Adenosine Are Toxic to Human Lymphoblast Mutants Defective in Purine Salvage Enzymes
AbstractMutants deficient in adenosine kinase or adenine phosphoribosyltransferase activities were selected from the WI-L2 line of human lymphoblasts. The adenosine kinase-deficient mutant was still as sensitive as its parent to growth inhibition caused by adenosine deaminase was inhibited. Similarly, the adenine phosphoribosyltransferase mutant remained sensitive to growth inhibition caused by adenine. Thus, the toxicity of adenine and adenosine to human lymphoblasts is not mediated by nucleotides to which they may be converted.
Journal of Clinical Investigation · 1987 · 93 citations · open access
Human adenine phosphoribosyltransferase. Identification of allelic mutations at the nucleotide level as a cause of complete deficiency of the enzyme.
AbstractThis study reports the first demonstration of specific mutations leading to human adenine phosphoribosyltransferase (APRT) deficiency. The molecular basis of the deficiency was investigated by determining the sequence of both alleles of a patient with a complete deficiency in APRT activity. A trinucleotide deletion, corresponding to phenylalanine on the deduced amino acid sequence, was confirmed on one allele. A single nucleotide insertion, immediately adjacent to the splice site at the 5' end of the fourth intervening sequence, was confirmed on the other allele. This insertion lead to aberrant splicing, as was demonstrated by the absence of exon 4 in the complementary DNA sequence and by altered RNase mapping analysis of the abnormal messenger RNA.
Distribution of Patients with 2,8-Dihydroxyadenine Urolithiasis and Adenine Phosphoribosyltransferase Deficiency in Japan
Abstract2,8-Dihydroxyadenine urolithiasis is caused by genetic deficiencies of adenine phosphoribosyl-transferase. This disease has occurred in a large number of Japanese patients and more than half of all families with this disease are only partially deficient in enzyme activities (Japanese type adenine phosphoribosyltransferase deficiency). To clarify the reasons for the preponderance of Japanese cases we sent questionnaires to 948 Japanese urological departments. The data thus obtained indicated that 76 families had 2,8-dihydroxyadenine lithiasis and of 51 families in which adenine phosphoribosyltransferase activities were assayed 76 per cent were only partially deficient in adenine phosphoribosyltransferase activities. The distribution of the 2,8-dihydroxyadenine families was roughly similar to that of the population in Japan and the rates of the Japanese type adenine phosphoribosyltransferase deficiency families were not significantly different among the various parts of Japan. These data indicate that the wide distribution of the unique mutant gene, APRT*J, that was created many years ago in a Japanese ancestor, explains at least in part the large number of 2,8-dihydroxyadenine lithiasis and adenine phosphoribosyltransferase deficiency families among the Japanese.
Journal of Biological Chemistry · 1982 · 24 citations · open access
Human adenine phosphoribosyltransferase. Immunochemical quantitation and protein blot analysis of mutant forms of the enzyme.
AbstractWe have studied the catalytic, immunochemical, and electrophoretic properties of adenine phosphoribosyltransferase in hemolysates from 30 patients with a deficiency of this enzyme in six unrelated families. We have found that: 1) the level of adenine phosphoribosyltransferase enzyme activity and immunoreactive protein in the four homozygous deficient patients was less than 1% of control values; 2) adenine phosphoribosyltransferase enzyme activity was uniformly decreased to approximately 25% of normal in all 26 heterozygotes studied while the level of adenine phosphoribosyltransferase immunoreactive protein was consistent within each kindred but ranged in value from 22% to 112% of control; and 3) protein blot analysis revealed a single isoelectric form of the adenine phosphoribosyltransferase subunit in hemolysate from normal controls and from every heterozygote except for patient M.R. who exhibited both a normal and a more acidic adenine phosphoribosyltransferase subunit species. These studies provide the first evidence for the existence of a variety of different mutations in the structural gene for adenine phosphoribosyltransferase in patients exhibiting a deficiency of enzyme activity. We further conclude from our data that: 1) the variant enzymes are more labile in vivo and/or catalytically nonfunctional, and 2) heterozygotes express only 25% of normal enzyme activity because the normal and variant enzyme subunits form a hybrid dimer which is either more labile or less catalytically active than the normal adenine phosphoribosyltransferase dimer.
Archives of Internal Medicine · 1986 · 1 citations
A Mutant Adenine Phosphoribosyltransferase in 2,8-Dihydroxyadenine Urolithiasis
AbstractIn one case of 2,8-dihydroxyadenine urolithiasis, reduced adenine phosphoribosyltransferase activity was found. The patient's enzyme had normal affinity for adenine but reduced affinity for substrate phosphoribosyl-pyrophosphate. It was much more stable at 60 degrees C than control. It seems that erythrocyte adenine phosphoribosyltransferase obtained from the patient may be a variant enzyme.
Archives of Internal Medicine · 1986 · 0 citations
A mutant adenine phosphoribosyltransferase in 2,8-dihydroxyadenine urolithiasis
Abstract• In one case of 2,8-dihydroxyadenine urolithiasis, reduced adenine phosphoribosyltransferase activity was found. The patient's enzyme had normal affinity for adenine but reduced affinity for substrate phosphoribosyl-pyrophosphate. It was much more stable at 60°C than control. It seems that erythrocyte adenine phosphoribosyltransferase obtained from the patient may be a variant enzyme. (<i>Arch Intern Med</i>1986;146:2068-2070)
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.
