DeCure for Pyruvate carboxylase deficiency disease
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for pyruvate carboxylase deficiency disease — 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 modulePyruvate carboxylase deficiency disease 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
approvedBiotinApproved drug
Structures already discussed alongside pyruvate carboxylase deficiency disease in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
pyruvate carboxylase (PC) — PC is one of the genes in this disease's Open Targets module — part of the target space DeCure's repurposing candidates point at. The protein backbone is drawn as a cartoon. The structure has biotin bound in it, shown as sticks.
Loading structure…
helix sheet btndrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8XL9 · 2.61 Å · ligand BIOTIN (BTN). Experimental structure, not a prediction.
What the evidence adds up to
A 10-year-old girl with mental retardation, hyperalaninemia and pyruvicemia had markedly decreased pyruvate carboxylase activity in liver biopsy specimens, while pyruvate decarboxylation and glutamic pyruvic transaminase were normal. Incorporation of pyruvate-2-14C into liver glycogen was markedly diminished compared with a control. The metabolic lesion was identified as defective pyruvate carboxylase activity leading to impaired gluconeogenesis. A case of acute onset lactic acidosis due to pyruvate carboxylase deficiency showed oxaloacetate deficiency producing abnormal cytosolic and mitochondrial redox states.
Pyruvate carboxylase deficiency is a rare autosomal recessive disease with three phenotypes. Type B is characterised by lactic acidosis and hyperammonemia. In one Turkish patient with type B, ammonia values reached 860 μmol/L, the highest reported in the literature, despite anaplerotic treatment with biotin, citrate and arginine-aspartate, and continuous veno-venous hemodialysis was applied because hyperammonemia and lactic acidosis could not be controlled. A homozygous novel 12-base pair deletion on exon 8 of the PC gene was detected. The prognosis for pyruvate carboxylase deficiency is poor; most children die within the first six months of life, and survivors have neurological damage and mental disability. A 21-month-old male with abnormal movements and new-onset seizures had a novel homozygous c.2630A>G (p.Gln877Arg) variant in the PC gene, not previously described in English literature.
Whole-exome sequencing in two unrelated neonates with acute early-onset metabolic derangement and death revealed a novel homozygous variant p.G303Afs*40 and p.R156P in the PC gene. The p.G303Afs*40 was likely pathogenic; p.R156P was a variant of uncertain significance, though a known variant at the same position, p.R156Q, was also of uncertain significance. Protein secondary structure prediction showed changes in p.R156P and p.R156Q, while p.G303Afs*40 depicted significant changes at C-terminal. Simulations showed decreased affinity to ATP in all variants, and free energy calculations demonstrated destabilising effects of both p.R156P and p.R156Q. The study confirmed pathogenicity of both variants and suggested them as a cause of type B pyruvate carboxylase deficiency.
The PC gene coding region has 19 exons and 18 introns spanning approximately 16 kb of genomic DNA. Screening individuals with the simple A form of PC deficiency revealed an 1828G→A missense mutation in 11 Ojibwa and 2 Cree patients and a 2229G→T transversion in 2 brothers of Micmac origin. Carrier frequency may be as high as 1 in 10 in some groupings. The two point mutations are located in a region of homology conserved among yeast, rat, and human PC, near the carboxylation domain. What remains missing are effective treatments that control hyperammonemia and lactic acidosis in type B disease, larger patient cohorts to establish genotype-phenotype correlations, and clinical trials of any intervention.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
The Tohoku Journal of Experimental Medicine · 1969 · 37 citations · open access
Hyperalaninemia with Pyruvicemia due to Pyruvate Carboxylase Deficiency of the Liver
AbstractA 10-year-old girl with mental retardation, hyperalaninemia and pyruvicemia was described. Studies on liver biopsy specimens from this patient revealed that pyruvate carboxylase activity was markedly decreased, whereas both pyruvate decarboxylation and glutamic pyruvic transaminase were normal in activity. Furthermore, it was found that an incorporation of pyruvate-2-14C into glycogen in the liver was markedly diminished in the patient as compared with that in a control. These findings suggest that the metabolic lesion in the patient with hyper-alaninemia and pyruvicemia is a defective activity of pyruvate carboxylase of the liver, leading to an impaired gluconeogenesis.
Journal of Inherited Metabolic Disease · 1981 · 13 citations
Neonatal lactic acidosis with pyruvate carboxylase inactivity
AbstractAbstract Biochemical findings in a case of acute onset lactic acidosis due to pyruvate carboxylase deficiency are presented. Oxaloacetate deficiency arising from the inactivity of pyruvate carboxylase produces abnormal cytosolic and mitochondrial redox states. The resultant altered metabolite pattern may allow a provisional diagnosis before enzymatic studies.
AbstractPyruvate carboxylase (PC) converts pyruvate to oxaloacetate, which is an important step in gluconeogenesis. Pyruvate carboxylase deficiency (PCD) is a rare inherited metabolic disorder characterized by movement disorders, neurologic disturbances, hypoglycemia, lactic acidosis, hyperammonemia, and elevated levels of pyruvate and alanine in plasma. The prognosis for PCD is poor. Most children die within the first six months of life, and those who survive longer have neurological damage and mental disability. This is due to the accumulation of lactic acid and toxic components in the blood. Here we describe the case of a 21-month-old male presenting with abnormal movements and new-onset seizures. His family history is relevant because of parental consanguinity. A genetic analysis showed a novel mutation, homozygous c. 2630A>G (p. Gln877Arg) variant, in the PC gene, a mutation not previously described in the English literature.
Journal of Pediatric Endocrinology and Metabolism · 2020 · 5 citations
Challenges in the management of an ignored cause of hyperammonemic encephalopathy: pyruvate carboxylase deficiency
AbstractPyruvate carboxylase (PC) deficiency is a rare autosomal recessive disease and provides clinics in three essential phenotypes. Type B PC deficiency is characterized by lactic acidosis and hyperammonemia. We report a Turkish patient who was diagnosed with type B PC deficiency. Despite the application of anaplerotic treatment with biotin, citrate and arginine-aspartate, continuous veno-venous hemodialysis (CVVHD) treatments were applied due to the failure to keep hyperammonemia and lactic acidosis under control. Ammonia values increasing to 860 μmol/L were observed. A homozygous novel variant was detected in PC gene analyses containing a 12-base pair deletion on exon 8. Although the mutation found was not reported previously, it was accepted as a pathogenic variant due to its presence in a functional region of the protein. In type B PC deficiency, although a high level of ammonia is expected, it rarely exceeds 200 μmol/L. As far as we know, the present case has the highest ammonia values in the literature. This paper has been shared to highlight to keep PC deficiency in mind regarding the differential diagnosis of hyperammonemia, particularly in the presence of lactic acidosis, and to serve as a model for the use of different modalities in the management process of PC deficiency.
̒Ulūm va funūn-i bastah/bandī · 2023 · 1 citations · open access
In silico Analysis of Two Novel Variants in the Pyruvate Carboxylase (PC) Gene Associated with the Severe Form of PC Deficiency
AbstractBackground: Inborne errors of metabolism are a common cause of neonatal death. This study evaluated the acute early-onset metabolic derangement and death in two unrelated neonates. Methods: Whole-exome sequencing (WES), Sanger sequencing, homology modeling, and in silico bioinformatics analysis were employed to assess the effects of variants on protein structure and function. Results: WES revealed a novel homozygous variant, p.G303Afs*40 and p.R156P, in the pyruvate carboxylase (PC) gene of each neonate, which both were confirmed by Sanger sequencing. Based on the American College of Medical Genetics and Genomics guidelines, the p.G303Afs*40 was likely pathogenic, and the p.R156P was a variant of uncertain significance (VUS). Nevertheless, a known variant at position 156, the p.R156Q, was also a VUS. Protein secondary structure prediction showed changes in p.R156P and p.R156Q variants compared to the wild-type protein. However, p.G303Afs*40 depicted significant changes at C-terminal. Furthermore, comparing the interaction of wild-type and variant proteins with the ATP ligand during simulations, revealed a decreased affinity to the ATP in all the variants. Moreover, analysis of Single nucleotide polymorphism impacts on PC protein using Polyphen-2, SNAP2, FATHMM, and SNPs&GO servers predicted both R156P and R156Q as damaging variants. Likewise, free energy calculations demonstrated the destabilizing effect of both variants on PC. Conclusion: This study confirmed the pathogenicity of both variants and suggested them as a cause of type B Pyruvate carboxylase deficiency. The results of this study would provide the family with prenatal diagnosis and expand the variant spectrum in the PC gene,which is beneficial for geneticists and endocrinologists.
AbstractWe characterized the pyruvate carboxylase (PC) gene by PCR amplification, subcloning, and sequencing. The coding region has 19 exons and 18 introns spanning approximately 16 kb of genomic DNA. Screening both the cDNA and the gene of individuals with the simple A form of PC deficiency revealed an 1828G-->A missense mutation in 11 Ojibwa and 2 Cree patients and a 2229G-->T transversion mutation in 2 brothers of Micmac origin. Carrier frequency may be as high as 1/10 in some groupings. The two point mutations are located in a region of homology conserved among yeast, rat, and human PC, in the vicinity of the carboxylation domain of the enzyme. These data provide the first characterization of the human PC gene structure, the identification of common pathogenic mutations, and the demonstration of a founder effect in the Ojibwa and Cree patients.
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.
