DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for orotic aciduria — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleOrotic aciduria maps to a 1-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 orotic aciduria 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
uridine monophosphate synthetase (UMPS) — UMPS 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 5fudrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3G3D · 1.7 Å · ligand 5-FLUORO-URIDINE-5'-MONOPHOSPHATE (5FU). Experimental structure, not a prediction.
What the evidence adds up to
Orotic aciduria is a rare hereditary disease of pyrimidine synthesis in which the activity of the enzymes orotidyl pyrophosphorylase and orotidyl decarboxylase is reduced. These enzymes normally convert orotic acid into orotidine monophosphate, a nucleotide required for nucleic acid synthesis. The condition is characterised by increased urinary excretion of orotic acid, T-lymphocyte deficiency, megaloblastic anaemia, and delayed mental and physical development. A 1962 study described the disease as resistant to the usual haematinic agents and noted that studies of surviving siblings and parents of the first reported patient showed decreased erythrocyte activities of both enzymes, consistent with an autosomal recessive inheritance pattern.
A 2016 report described a patient with orotic aciduria and deficiency of uridine monophosphate synthetase who was studied over ten years and had no megaloblastic anaemia. In that patient, excretion of orotic acid was 8.24 mmol/mol of creatinine and orotidine was 0.52 mmol/mol of creatinine, giving a ratio of 15.85. The authors concluded that patients with orotic aciduria with and without megaloblastic anaemia cannot be distinguished by the ratio of orotic acid to orotidine.
A 2010 study developed a fast assay using hydrophilic interaction liquid chromatography-tandem mass spectrometry to measure orotic acid in dried blood spots, plasma, and urine. In 20 healthy children, orotic acid concentrations were less than 0.69 micromolar in plasma, less than 0.82 micromolar in dried blood spots, and ranged from 0.2 to 1.4 mmol/mol of creatinine in urine. A patient with citrullinemia showed plasma orotic acid of 133 micromolar and dried blood spot levels of 39 micromolar. A patient with hyperammonemia-hyperornithinemia-homocitrullinemia syndrome had a urinary orotic acid level of 9.1 mmol/mol of creatinine. The authors stated the method could potentially discriminate affected patients from reference subjects but that clinical validation should be expanded on a higher number of patients.
No treatment trials, no drug repurposing data, and no survival or response rate numbers appear in these abstracts. What is missing is any clinical trial testing a therapy in orotic aciduria patients, any patient stratification beyond the presence or absence of megaloblastic anaemia, and any funding for a systematic drug screen or repurposing study in this ultrarare disease.
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 Separation Science · 2010 · 21 citations
Orotic acid quantification in dried blood spots and biological fluids by hydrophilic interaction liquid chromatography tandem mass spectrometry
AbstractOrotic acid (ORA) is an intermediate metabolite in the pathway of pyrimidine nucleotides; its urinary excretion is useful to diagnose the hereditary orotic aciduria and some hyperammonemic inherited defects of urea cycle enzymes and amino acid transporters. ORA analysis is based on stable isotope dilution by GC-MS or LC-MS/MS methods. We developed a fast assay that measures the ORA in dried blood spots (DBS), plasma and urine using hydrophilic interaction LC-MS/MS. Within- and between-day analytical imprecision (CV%) of three quality control levels, in plasma, DBS and urine, ranged from 0.8 to 14.1%, while the inaccuracy ranged from -13.5 to 9.4%. In healthy children (n=20), ORA concentrations were less than 0.69 microM in plasma, less than 0.82 microM in DBS and from 0.2 to 1.4 mmol/mol of creatinine in urine. A patient with citrullinemia showed ORA levels of 133 microM in plasma and 39 microM in DBS. A patient with hyperammonemia-hyperornithinemia-homocitrullinemia (HHH) syndrome presented a urinary ORA level of 9.1 mmol/mol of creatinine. The method is potentially able to discriminate affected patients from reference subjects; the clinical validation should be expanded on a higher number of patients.
Australian and New Zealand Journal of Medicine · 1973 · 7 citations
Orotic Acid
AbstractSummary: Excess urinary excretion of orotic acid, the first pyrimidine compound formed by de novo biosynthesis, is observed in hereditary orotic aciduria, ornithine transcarbamylase deficiency, following the administration of allopurinol and 6-azauridine, and in pregnancy. Only in the case of the hereditary disease does the interference with pyrimidine synthesis represent a lethal threat to the patient. However, continued administration of 6-azauridine can lead to a mild anaemia and the effects of allopurinol, particularly when administered with other drugs, requires further investigation. Orotic acid has been investigated as a therapeutic agent in neonatal jaundice, myocardial infarction, pernicious anaemia and hyperuricaemia. It would appear to be worth consideration as prophylactic therapy for neonatal jaundice. The possibility that orotic acid could be useful in the treatment of heart disease is also worth exploration. No toxic effects arising from the administration of orotic acid have been observed.
Hereditary Orotic Aciduria and the Excretion of Orotidine
Abstract<b>Objective</b> Orotic aciduria and deficiency of uridine monophosphate synthetase have been observed in a patient, studied over 10 years, who had no megaloblastic anemia. Excretion of orotic acid and orotidine were 8.24 and 0.52 mmol/mol of creatinine. The ratio of 15.85 differed appreciably from that of 6 patients reported with no megaloblastic anemia. <b>Methods</b> The analysis of orotidine by gas chromotography mass spectrometry was conducted. <b>Conclusion</b> Patients with orotic aciduria with and without megaloblastic anemia cannot be distinguished by ratio of orotic acid to orotidine.
Studies on the Enzymatic Defect of Orotic Aciduria.
Abstracts1 April 1962Studies on the Enzymatic Defect of Orotic Aciduria.L. H. Smith Jr., M.D.L. H. Smith Jr., M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-56-4-678_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptOrotic aciduria is a rare metabolic disease characterized by megaloblastic anemia, resistant to the usual hematinic agents, and the presence of large amounts of urinary orotic acid, a pyrimidine nucleotide precusor. Studies on the surviving siblings and the parents of the propositus of orotic aciduria have demonstrated decreased erythrocyte activities of orotidylic pyrophosphorylase and orotidylic decarboxylase, enzymes which convert orotic acid into uridylic acid. The pattern of inheritance is consistent with that of an autosomal recessive trait. TwoEntamoeba colimutants and a neurospora crassa mutant with somewhat analogous enzyme defects have been studied as examples of "microbiological orotic aciduria."... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Boston, Mass. (BS) PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 April 1962Volume 56, Issue 4Page: 678-678KeywordsEnzymesMegaloblastic anemiaMetabolic disorders Issue Published: 1 April 1962 PDF DownloadLoading ...
Zenodo (CERN European Organization for Nuclear Research) · 2024 · 0 citations · open access
WHAT IS OROTACIDURIA
AbstractOrotic aciduria is a hereditary disease of pyrimidine synthesis, which is manifested by increased urinary excretion of orotic acid (orotate), T-lymphocyte deficiency, megaloblastic anemia, and delayed mental and physical development. With this disease, the activity of the enzymes orotidyl pyrophosphorylase and orotidyl decarboxylase, which convert orotic acid into the nucleotide orotidine monophosphate necessary for the synthesis of nucleic acids, is reduced.
Zenodo (CERN European Organization for Nuclear Research) · 2024 · 0 citations · open access
WHAT IS OROTACIDURIA
AbstractOrotic aciduria is a hereditary disease of pyrimidine synthesis, which is manifested by increased urinary excretion of orotic acid (orotate), T-lymphocyte deficiency, megaloblastic anemia, and delayed mental and physical development. With this disease, the activity of the enzymes orotidyl pyrophosphorylase and orotidyl decarboxylase, which convert orotic acid into the nucleotide orotidine monophosphate necessary for the synthesis of nucleic acids, is reduced.
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.
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