DeCure for Ornithine carbamoyltransferase deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for ornithine carbamoyltransferase deficiency — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleOrnithine carbamoyltransferase deficiency maps to a 3-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 carbamoyltransferase 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 transcarbamylase (OTC) — OTC 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 phosphonoacetyldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1OTH · 1.85 Å · ligand N-(PHOSPHONOACETYL)-L-ORNITHINE (PAO). Experimental structure, not a prediction.
What the evidence adds up to
The 1974 Bacillus subtilis study is not human data; it describes cooperative inhibition of ornithine carbamoyltransferase by excess ornithine, partial reversal by arginine and lysine, and additional inhibition by zinc ions. Arginase from the same bacterial strain increased the inhibition when arginine was present. None of this has been tested in human ornithine carbamoyltransferase deficiency.
A 1988 case series of six boys with late-onset ornithine carbamoyltransferase deficiency reported wide variation in presentation age and symptoms, which could initially mimic neurological, behavioural, or gastroenterological problems. Two patients died, and two male siblings who were probably affected also died. The authors state that with early recognition of hyperammonaemia the outlook is good, but provide no quantitative survival or response data.
A 2001 retrospective review of seven patients with ornithine carbamoyltransferase deficiency and three with citrullinaemia found that the relationship between plasma ammonia and glutamine concentrations is not a simple linear one. Patients with citrullinaemia tended to have higher plasma ammonia for a given plasma glutamine concentration compared to those with ornithine carbamoyltransferase deficiency. The authors discuss possible reasons and implications for management but report no treatment outcomes.
Two mutation-detection studies, from 2000 (65 families, 14 novel mutations) and 2012 (29 families, 25 distinct mutations including 14 novel ones), describe the genetic heterogeneity of ornithine carbamoyltransferase deficiency. The 2012 study examined 28 male and 9 female patients and identified three novel missense mutations and three novel large deletions. One manifesting heterozygote carried a hypomorphic mutation with unfavourably skewed X-inactivation in three peripheral tissues. Neither study reports therapeutic interventions or clinical outcomes.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
European Journal of Biochemistry · 1974 · 48 citations · open access
Control of Ornithine Carbamoyltransferase Activity by Arginase in <i>Bacillus subtilis</i>
AbstractPartially purified Bacillus subtilis ornithine carbamoyltransferase is cooperatively inhibited by excess of ornithine. The inhibition is decreased by lowering of pH from 9.2 to 7.6 without altering the affinity of the enzyme for the neutral species of ornithine which seems to be its true substrate. Arginine and lysine partially reverse this inhibition without affecting the catalytic activity of the enzyme. 2‐Aminobutyrate, an inhibitor of the enzyme, competitive with respect to ornithine, is not able to replace ornithine in this excess‐substrate type of inhibition. Zn 2+ is also an inhibitor of ornithine carbamoyltransferase, with competitive action towards ornithine and its inhibition is added to the excess ornithine inhibition. These data suggest that ornithine carbamoyltransferase has a regulatory site for ornithine, distinct from the catalytic one. Partially purified arginase, prepared from the same strain, increases the inhibition of ornithine carbamoyltransferase by excess of ornithine when arginine is present. An association of the two enzymes is suggested by molecular sieving. These data postulate that ornithine carbamoyltransferase is regulated by arginase under the control of arginine and ornithine. The other substrate, carbamoyl phosphate, is not involved in this regulatory mechanism. Lysine and Zn 2+ inhibit arginase competitively with respect to arginine without altering the effect of this enzyme on the inhibition of ornithine carbamoyltransferase. 2‐Aminobutyrate inhibits arginase non‐competitively with respect to arginine and prevents the inhibition of arginase towards ornithine carbamoyltransferase. These results suggest that arginase possesses a regulatory site for arginine, distinct from the catalytic one, which is also involved in the control mechanism.
Archives of Disease in Childhood · 1988 · 31 citations · open access
Late onset ornithine carbamoyl transferase deficiency in males.
AbstractSix boys with ornithine carbamoyl transferase deficiency presenting in infancy or later childhood are described. There was wide variation in both the time of presentation and the symptoms, which may initially suggest a neurological, behavioural, or gastroenterological problem. Two patients died, as did two male siblings who were probably affected, but with early recognition of the hyperammonaemia the outlook is good.
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 Inherited Metabolic Disease · 2000 · 17 citations
Mutation detection in 65 families with a possible diagnosis of ornithine carbamoyltransferase deficiency including 14 novel mutations
AbstractThe high new mutation rate and the wide spectrum of mutations found in patients with ornithine carbamoyltransferase (OCT) deficiency means that direct mutation analysis is essential for providing accurate carrier detection and prenatal diagnosis in affected families. We present our strategy for mutation detection in the OCT gene and summarize the results from 31 families with a confirmed diagnosis and 34 families with a suspected diagnosis of OCT deficiency, and describe 14 previously unreported mutations.
Ornithine carbamoyltransferase deficiency: molecular characterization of 29 families
AbstractOrnithine carbamoyltransferase deficiency is the most common inherited defect of the urea cycle. We examined 28 male and 9 female patients from 29 families and identified 25 distinct mutations in OTC, 14 of which were novel. Three novel missense mutations (p.Ala102Pro, p.Pro158Ser, p.Lys210Glu) and a novel deletion of the Leu43 are not directly involved either in the enzyme active site or in the intersubunit interactions; however, the mutations include conserved residues involved in intramolecular interaction network essential for the function of the enzyme. Three novel large deletions - a 444 kb deletion affecting RPGR, OTC and TSPAN7, a 10 kb-deletion encompassing OTC exons 5 and 6 and a 24.5 kb-deletion encompassing OTC exons 9 and 10 - have probably been initiated by double strand breaks at recombination-promoting motifs with subsequent non-homologous end joining repair. Finally, we present a manifesting heterozygote carrying a hypomorphic mutation p.Arg129His in combination with unfavorably skewed X-inactivation in three peripheral tissues.
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.
