DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for ornithine aminotransferase 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 moduleOrnithine aminotransferase 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 ornithine aminotransferase 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
ornithine aminotransferase (OAT) — OAT 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 3r,4edrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 10LW · 1.93 Å · ligand (3R,4E)-4-[({3-hydroxy-2-methyl-5-[(phosphonooxy)methyl]pyridin-4-yl}methyl)imino]cyclopent-1-ene-1,3-dicarboxylic acid (RMT). Experimental structure, not a prediction.
What the evidence adds up to
Ornithine aminotransferase deficiency, also called gyrate atrophy, is caused by inherited mutations in the OAT gene. A 1992 survey of 24 mutant alleles found that the majority (20/24) produced normal amounts of normally sized mRNA, but only 2/24 produced normal amounts of OAT antigen. Reproducing these mutations in Chinese hamster ovary cells confirmed that several inactivate the enzyme. A 2004 report of two unrelated neonatal cases notes that diagnosis is difficult because hyperornithinaemia is absent at that age; both cases presented with hyperammonaemia, and diagnosis required enzyme and mutation studies.
A 1994 study in mice with the sparse-fur mutation, a model of ornithine carbamoyltransferase (OCT) deficiency, tested selective inactivation of OAT using 5-fluoromethylornithine. Raising endogenous ornithine concentrations allowed the aberrant OCT to catalyse citrulline formation despite its low affinity for ornithine. Blood and tissue ammonia concentrations and orotic acid excretion were reduced near to normal values, and abnormal amino acid patterns in blood, brain and liver were normalised. The authors described selective OAT inactivation as a promising therapeutic approach in some hereditary OCT deficiencies.
A 1983 paper describes a new radioisotopic assay for OAT activity using [U-14C]ornithine, which the authors state should be useful for distinguishing vitamin B6-responsive from non-responsive types of OAT deficiency. A 2001 retrospective review of plasma ammonia and glutamine in OCT deficiency and citrullinaemia found no simple linear relationship between the two metabolites and significant differences between the disorders, but this paper concerns OCT deficiency and citrullinaemia, not OAT deficiency. A 1987 paper on OCT deficiency describes a mutation in a family with partial enzyme activity and uses denaturing gradient gel electrophoresis for diagnosis; it does not address OAT deficiency.
What is still missing: no clinical trial of 5-fluoromethylornithine or any other OAT inhibitor in human OAT deficiency has been reported. The mouse study was in OCT deficiency, not OAT deficiency. For gyrate atrophy itself, no therapy that reverses retinal degeneration has been tested in a controlled human trial. Patient stratification by residual enzyme activity and vitamin B6 responsiveness is possible with the 1983 assay but has not been systematically applied to guide treatment. Funding for a trial of OAT inhibition in gyrate atrophy or for neonatal screening protocols is absent.
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 Biological Chemistry · 1992 · 117 citations · open access
Ornithine delta-aminotransferase mutations in gyrate atrophy. Allelic heterogeneity and functional consequences.
AbstractOrnithine delta-aminotransferase is a nuclear-encoded mitochondrial matrix enzyme which catalyzes the reversible interconversion of ornithine and alpha-ketoglutarate to glutamate semialdehyde and glutamate. Inherited deficiency of ornithine delta-aminotransferase results in ornithine accumulation and a characteristic chorioretinal degeneration, gyrate atrophy of the choroid and retina. We have surveyed the ornithine delta-aminotransferase genes of gyrate atrophy patients for mutations. Using a variety of techniques, we discovered and molecularly characterized 21 newly recognized ornithine delta-aminotransferase alleles. We determined the consequences of these and three previously described mutations on ornithine delta-aminotransferase mRNA, antigen, and enzyme activity in cultured fibroblasts. The majority (20/24) of these alleles produce normal amounts of normally sized ornithine delta-aminotransferase mRNA. By contrast, only 2/24 had normal amounts of ornithine delta-aminotransferase antigen. Reproducing these mutations by site-directed mutagenesis and expressing the mutant ornithine delta-aminotransferase in Chinese hamster ovary cells confirms that several of these mutations inactivate ornithine delta-aminotransferase and cause gyrate atrophy in these patients.
Journal of Inherited Metabolic Disease · 2004 · 42 citations
Ornithine aminotransferase deficiency: Diagnostic difficulties in neonatal presentation
AbstractWe describe two unrelated cases of ornithine aminotransferase (OAT) deficiency with rare neonatal presentation of hyperammonaemia. The diagnosis in the neonatal presentation of OAT deficiency is hampered as hyperornithinaemia is absent. Enzyme and mutation studies confirmed the diagnosis. OAT deficiency should be included in differential diagnosis of neonatal hyperammonaemia.
Journal of Inherited Metabolic Disease · 2001 · 17 citations
Plasma glutamine and ammonia concentrations in ornithine carbamoyltransferase deficiency and citrullinaemia
AbstractA retrospective review of the plasma ammonia and glutamine concentrations during the long-term management of 7 patients with ornithine carbamoyltransferase (OCT) deficiency and three with citrullinaemia is presented. The relationship between the plasma concentrations of ammonia and glutamine is not a simple linear one and there are significant differences between the two disorders. Patients with citrullinaemia tend to have higher plasma ammonia concentrations for a given plasma glutamine concentration compared to those with OCT deficiency. The possible reasons for these differences and the implications for management are discussed.
Journal of Nutritional Science and Vitaminology · 1983 · 8 citations · open access
A new sensitive and convenient assay of ornithine aminotransferase.
AbstractA new radioisotopic assay for ornithine aminotransferase with [U-14C]ornithine as a substrate was developed. The dihydroquinazolinium compound formed was extracted from the reaction mixture with n-butanol and an addition of high concentration of sodium sulfate. This assay is sensitive and convenient and more than 50 assays can be done in one day without any special apparatus. The activities of ornithine aminotransferase in rat liver and human lymphoblastoid cells could be measured at nanomole levels by this method. Thus, the assay should be useful for measurement of OAT activity in cultured cells and for studies on the metabolic bases of the different types of ornithine aminotransferase deficiency: vitamin B6-responsive and -nonresponsive types.
Journal of Inherited Metabolic Disease · 1994 · 7 citations
Decreased hyperammonaemia and orotic aciduria due to inactivation of ornithine aminotransferase in mice with a hereditary abnormal ornithine carbamoyltransferase
AbstractMice with the X-chromosomal sparse-fur (spf) mutation are an animal model of some hereditary deficiencies of ornithine carbamoyltransferase (OCT) in man. Orotic aciduria and hyperammonaemia are the most conspicuous metabolic changes in these diseases. Selective inactivation of ornithine aminotransferase (OAT) by 5-fluoromethylornithine raises endogenous ornithine concentrations so that citrulline formation is effectively catalysed by the aberrant OCT, in spite of its low affinity for ornithine. As a consequence, blood and tissue ammonia concentrations and orotic acid excretion are reduced near to normal values, and the abnormal amino acid patterns in blood, brain and liver are normalized. Selective inactivation of OAT seems a promising therapeutic approach in some hereditary OCT deficiencies, and a total that may allow us to clarify the role of ammonia and orotic acid in the development of nanism and abnormal behaviour in spf mutant mice.
Acid hydrolysis and pretreatment of lignocellulosic substrates: Final subcontract report
AbstractOrnithine transcarbamylase (ornithine carbamoyltransferase, EC 2.1.3.3) deficiency is an X-linked inborn error of metabolism with considerable phenotypic variability in affected males. Using a combination of the polymerase chain reaction and denaturing gradient gel electrophoresis (DGGE), we defined a mutation in a family in whom affected males have significant residual enzyme activity. A C----T change in the first nucleotide of codon 277 resulted in the substitution of a tryptophan for an arginine at amino acid 245 of the mature protein. This change appears to represent a deleterious mutation rather than a polymorphism on the basis of several factors: the change occurs at a highly conserved arginine residue, significant size and change differences exist between arginine and tryptophan, and this change was not seen on DGGE screening of 26 unrelated individuals representing 43 chromosomes. Diagnosis of an at-risk male newborn in this family was performed using direct mutational analysis. In families with partial enzyme deficiencies in whom biochemical data may be difficult to evaluate, direct detection of mutations at the OTC locus permits definitive diagnosis. This represents the first description of a mutation in late onset OTC deficiency and demonstrates direct mutational analysis by DGGE for prospective diagnosis in a genetic disorder.
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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