DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for glutaryl-CoA dehydrogenase deficiency — 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 moduleGlutaryl-CoA dehydrogenase deficiency 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 glutaryl-coa dehydrogenase 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
glutaryl-CoA dehydrogenase (GCDH) — GCDH 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 faddrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2R0N · 2.3 Å · ligand FLAVIN-ADENINE DINUCLEOTIDE (FAD). Experimental structure, not a prediction.
What the evidence adds up to
Glutaryl-CoA dehydrogenase deficiency, also known as glutaric aciduria type I, is a recessive inborn error of metabolism caused by deficiency of the enzyme glutaryl-CoA dehydrogenase, which is responsible for catabolism of L-lysine, L-hydroxylysine, and L-tryptophan. Deficiency leads to abnormal accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine. Untreated individuals are at extremely high risk for encephalopathic crisis, usually triggered by intercurrent illness or other stressor, typically occurring between 3 and 36 months of age, and classically resulting in bilateral striatal injury. Treatment includes dietary lysine restriction, carnitine supplementation, and careful metabolic management during intercurrent illness.
One case report from 1984 describes a child with glutaryl-CoA dehydrogenase deficiency who presented with bilateral subdural hydromas, progressive choreoathetosis and dysarthria, and was diagnosed when investigated for hypoglycaemia at age 3.5 years. Temporary adrenocortical insufficiency was also noted. Three years after diagnosis, the adrenal insufficiency and hypoglycaemia had resolved, and treatment with riboflavin and lioresal (a GABA analogue) was reported to have prevented any further neurological deterioration in that single patient.
A 2001 biochemical study of the human glutaryl-CoA dehydrogenase enzyme examined the function of arginine-94, a cationic residue in the binding site of the acyl moiety of the substrate. Substitution of Arg-94 by glycine (a disease-causing mutation) or by glutamine reduced the catalytic rate constant to 2–3% of wild-type and increased the Michaelis constant for glutaryl-CoA 10- to 16-fold. The dissociation constants of non-oxidizable substrate analogs were not altered by the mutations, but abstraction of an alpha-proton from one analog was severely limited. The authors concluded that Arg-94 does not make a major contribution to glutaryl-CoA binding, but its electric field may stabilise dianions resulting from alpha-proton abstraction, or may orient the substrate for that abstraction.
No controlled clinical trial data exist for any drug in glutaryl-CoA dehydrogenase deficiency. The 1984 case report of riboflavin and lioresal in a single patient is not replicated. What is still missing is any randomised or even systematically collected prospective evidence for pharmacological intervention, adequate funding for a multi-centre trial, and a clear patient stratification strategy that accounts for the variable age of onset and the fact that most untreated patients suffer encephalopathic crisis before age three.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
PEDIATRICS · 2002 · 194 citations
Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency: Clinical Presentation and Follow-Up of 50 Patients
AbstractOBJECTIVES: To assess the mode of presentation, biochemical abnormalities, clinical course, and effects of therapy in patients of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. BACKGROUND: LCHAD deficiency is a rare, autosomal recessive inborn error of fatty acid oxidation. Although case reports and small series of patients have been published, these may not give a true picture of the clinical and biochemical spectrum associated with this disorder. To improve the early recognition and management of this potentially lethal disorder, we have reviewed a large cohort of LCHAD-deficient patients. METHODS: A questionnaire was sent to the referring physicians of 61 unselected patients with LCHAD deficiency diagnosed in our center. The standardized questionnaire requested information about the clinical signs and symptoms at presentation, the clinical history, family history, pregnancy, biochemical parameters at presentation, treatment, and clinical outcome. RESULTS: Questionnaires on 50 patients (82%) were returned and included in this study. The mean age of clinical presentation was 5.8 months (range: 1 day-26 months). Seven (15%) of the patients presented in the neonatal period. Thirty-nine patients (78%) presented with hypoketotic hypoglycemia, the classical features of a fatty acid oxidation disorder. Eleven patients (22%) presented with chronic problems, consisting of failure to thrive, feeding difficulties, cholestatic liver disease, and/or hypotonia. In retrospect, most (82%) of the patients presenting with an acute metabolic derangement also suffered from a combination of chronic nonspecific symptoms before the metabolic crises. Mortality in this series was high (38%), all dying before or within 3 months after diagnosis. Morbidity in the surviving patients is also high, with recurrent metabolic crises and muscle problems despite therapy. CONCLUSIONS: LCHAD deficiency often presents with a combination of chronic nonspecific symptoms. Early diagnosis is difficult in the absence of the classical metabolic derangement. Survival can be improved by prompt diagnosis, but morbidity remains alarmingly high despite current therapeutic regimes.
Journal of Inherited Metabolic Disease · 1984 · 27 citations
Glutaric aciduria type I presenting with hypoglycaemia
AbstractWe present a child with glutaryl CoA-dehydrogenase deficiency (type I glutaric aciduria) who presented with bilateral subdural hydromas, and progressive choreoathetosis and dysarthria. The diagnosis was made when she was investigated for hypoglycaemia at the age of 3.5 years. Temporary adrenocortical insufficiency was also noted. Three years after diagnosis the adrenal insufficiency and hypoglycaemia have resolved and treatment with riboflavin and 'lioresal', a GABA analogue, has prevented any further neurological deterioration.
Journal of Biological Chemistry · 2001 · 24 citations · open access
The Function of Arg-94 in the Oxidation and Decarboxylation of Glutaryl-CoA by Human Glutaryl-CoA Dehydrogenase
AbstractGlutaryl-CoA dehydrogenase catalyzes the oxidation and decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2). Inherited defects in the protein cause glutaric acidemia type I, a fatal neurologic disease. Glutaryl-CoA dehydrogenase is the only member of the acyl-CoA dehydrogenase family with a cationic residue, Arg-94, situated in the binding site of the acyl moiety of the substrate. Crystallographic investigations suggest that Arg-94 is within hydrogen bonding distance of the gamma-carboxylate of glutaryl-CoA. Substitution of Arg-94 by glycine, a disease-causing mutation, and by glutamine, which is sterically more closely related to arginine, reduced k(cat) of the mutant dehydrogenases to 2-3% of k(cat) of the wild type enzyme. K(m) of these mutant dehydrogenases for glutaryl-CoA increases 10- to 16-fold. The steady-state kinetic constants of alternative substrates, hexanoyl-CoA and glutaramyl-CoA, which are not decarboxylated, are modestly affected by the mutations. The latter changes are probably due to steric and polar effects. The dissociation constants of the non-oxidizable substrate analogs, 3-thiaglutaryl-CoA and acetoacetyl-CoA, are not altered by the mutations. However, abstraction of a alpha-proton from 3-thiaglutaryl-CoA, to yield a charge transfer complex with the oxidized flavin, is severely limited. In contrast, abstraction of the alpha-proton of acetoacetyl-CoA by Arg-94 --> Gln mutant dehydrogenase is unaffected, and the resulting enolate forms a charge transfer complex with the oxidized flavin. These experiments indicate that Arg-94 does not make a major contribution to glutaryl-CoA binding. However, the electric field of Arg-94 may stabilize the dianions resulting from abstraction of the alpha-proton of glutaryl-CoA and 3-thiaglutaryl-CoA, both of which contain gamma-carboxylates. It is also possible that Arg-94 may orient glutaryl-CoA and 3-thiaglutaryl-CoA for abstraction of an alpha-proton.
The effect of long-term oral L-carnitine administration on insulin sensitivity, glucose disposal, plasma concentrations of leptin and acylcarnitines, and urinary acylcarnitine excretion in warmblood horses
AbstractBACKGROUND: Insulin resistance in horses is an emerging field of interest as it is thought to be a contributing factor in the pathogenesis of many equine conditions. OBJECTIVES: The objectives of the present study were to determine the effects of long-term oral administration of L-carnitine on insulin sensitivity, glucose disposal, plasma leptin concentrations and acylcarnitine spectrum both in plasma and urine. ANIMALS AND METHODS: Six 3-year-old healthy warmblood geldings were used. In a double blind 2 × 2 Latin square design at a dosage of 100 mg/kg body weight (BW)/day for 28 days the effects of oral supplementation of L-carnitine (as fumarate) were assessed. Glucose disposal and insulin sensitivity were measured by means of the euglycemic-hyperinsulinemic clamp technique. Radioimmunoassays were used to determine plasma leptin and insulin concentrations. Electrospray tandem mass spectrometry was used to assess acylcarnitines both in plasma and urine. Statistical analysis was performed using a linear mixed-effects model and P values <0.05 were considered significant. RESULTS: Long-term L-carnitine administration did not affect insulin sensitivity. Plasma leptin and free carnitine concentrations in plasma and urine increased significantly (P = 0.047 and 0.000, respectively) following L-carnitine administration as well as short-chain acylcarnitines in plasma and urinary excretion of short- and medium-chain acylcarnitines. CONCLUSION AND CLINICAL RELEVANCE: Given the effects of oral administration of L-carnitine further clinical study is necessary in order to assess the potential beneficial effects in equine patients suffering from metabolic myopathies such as acquired multiple acyl-CoA dehydrogenase deficiency. IMPACT FOR HUMAN MEDICINE: The current study supports the treatment rationale of short-chain acyl-CoA dehydrogenase deficiency in humans with L-carnitine at an oral dosage of 100 mg/kg BW/day.
Oxford University Press eBooks · 2017 · 0 citations
Glutaric Aciduria Type I
AbstractGlutaric Aciduria type I is a recessive inborn error of metabolism caused by deficiency of glutaryl-CoA dehydrogenase. This enzyme is responsible for catabolism of L-lysine, L-hydroxylysine, and L-tryptophan. Deficiency of this enzyme leads to abnormal accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine. Untreated individuals are at extremely high risk for encephalopathic crisis, usually triggered by an intercurrent illness or other stressor, and typically occurring between 3 and 36 months of age. This crisis classically results in bilateral striatal injury. Treatment, which can help to prevent encephalopathic crises, includes dietary lysine restriction, carnitine supplementation, and careful metabolic management during intercurrent illness.
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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