DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for methylcobalamin deficiency type cblG — 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 moduleMethylcobalamin deficiency type cblG 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
approvedHydroxocobalaminApproved drugapprovedCyanocobalaminApproved drug
Structures already discussed alongside methylcobalamin deficiency type cblg in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
The surface-exposed lipo-protein of BtuG2 — Hydroxocobalamin has a real, experimentally solved structure in complex with this target (PDB 8BB0, 1.5 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet i2adrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8BB0 · 1.5 Å · ligand Hydroxocobalamin (I2A). Experimental structure, not a prediction.
What the evidence adds up to
In 23 older adults with serum cobalamin below 221 pmol/L and methylmalonic acid above 271 nmol/L, daily oral cobalamin at 25 µg and 100 µg lowered but did not normalise methylmalonic acid in most subjects. Only 1000 µg/day normalised methylmalonic acid in most of this group. Homocysteine was normalised in six of eleven subjects who had elevated pretreatment levels. The authors concluded that most cobalamin-deficient older people require more than 100 µg of oral cobalamin, a dose above what standard multivitamins contain.
The cblG disorder is caused by mutations in methionine synthase (MTR) that decrease conversion of hydroxocobalamin to methylcobalamin. In four extremely rare cases classified as cblG-variant, methionine synthase activity was undetectable. These cells expressed only a truncated 124 kDa form of the enzyme, whereas cblG, cblC and control fibroblasts also expressed a full-size methionine synthase. The truncated protein interacted with MMACHC, the protein defective in cblC, and this interaction was reduced 2.2-fold and 1.5-fold in cblC cells carrying the p.R161Q and p.R206W mutations respectively, and 5.0-fold in HEK cells with methionine synthase knocked down by siRNA. The authors proposed that the interaction between methionine synthase and MMACHC may regulate cellular cobalamin processing.
In a separate study using MMACHC-mutant cells as a model of functional cobalamin deficiency, supplementation with hydroxocobalamin failed to restore the protein changes seen in these cells to a normal phenotype. The authors described major protein changes involving the cytoskeleton, neurological system, and signalling and detoxification pathways, and concluded that a defective cobalamin processing pathway produces irreversible changes at the protein level.
What remains missing is any clinical trial of cobalamin supplementation specifically in patients with confirmed cblG or cblG-variant mutations. The dose-response data come from older adults with acquired deficiency, not from people with inherited enzyme defects. The molecular studies show that even in cell models, hydroxocobalamin does not reverse all protein-level abnormalities. No trial has tested whether any form or dose of cobalamin improves clinical outcomes such as anaemia, neurological function, or survival in cblG patients, and no study has stratified patients by the specific MTR mutation or by the presence or absence of the truncated enzyme.
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 the American Geriatrics Society · 2002 · 89 citations
Response of Elevated Methylmalonic Acid to Three Dose Levels of Oral Cobalamin in Older Adults
AbstractOBJECTIVES: Because the effects of lower-dose oral cobalamin (Cbl) supplements on older people with cobalamin deficiency are not known, we determined whether oral Cbl supplements at three different dose levels would normalize elevated serum methylmalonic acid (MMA) and total homocysteine (tHcy) concentrations. DESIGN: Sequential nonrandomized intervention study of three dose levels. SETTINGS: Two university-based senior care clinics. PARTICIPANTS: Twenty-three older adults (aged >/=65) with serum Cbl levels of 221 pmol/L (300 pg/mL) or lower and serum MMA greater than 271 nmol/L who had been enrolled in a previous screening study for Cbl deficiency (mean age 79 +/- 9; 17 male, 6 female; 17 white, 6 other). INTERVENTION: Sequential daily treatment with 25 microg oral cobalamin, followed by 100 microg and 1,000 microg cobalamin each for a 6-week period. MEASUREMENTS: Serum MMA, tHcy, and other metabolites at baseline and after each 6-week dosing interval. RESULTS: Treatment with 25 microg and 100 microg lowered but did not normalize MMA levels in most subjects. A dose of 1,000 microg/day proved to be the most effective in lowering MMA levels to within normal limits. Serum tHcy was normalized in six of 11 subjects who had elevated tHcy pretreatment with oral Cbl alone and in one subject in combination with a multivitamin. CONCLUSIONS: Most Cbl-deficient older people require more than 100 microg of oral Cbl to normalize serum MMA, which is a larger dose than is available in most standard multivitamins and Cbl supplements.
Identification of two mutant alleles of transcobalamin II in an affected family
AbstractTranscobalamin II (TC II) deficiency is a rare autosomal recessive disease leading to cobalamin (Cbl; Vitamin B12) deficiency characterized by failure to thrive, megaloblastic anemia, impaired immunodefence and neurological manifestations. By means of Southern blotting and sequence analysis of TC II cDNA amplified from fibroblasts of an affected child and his parents, we have identified two mutant TC II alleles, one with a gross deletion and the other with a 4 nucleotide deletion. Both the mutations caused TC II mRNA and protein deficiency and hence defective plasma transport of Cbl and the development of Cbl deficiency in the affected child. The present study has identified molecular defects that cause TC II deficiency and lead to intracellular Cbl deficiency in humans.
Interaction between methionine synthase isoforms and MMACHC: characterization in cblG-variant, cblG and cblC inherited causes of megaloblastic anaemia
AbstractThe cblG and cblC disorders of cobalamin (Cbl) metabolism are two inherited causes of megaloblastic anaemia. In cblG, mutations in methionine synthase (MTR) decrease conversion of hydroxocobalamin (HOCbl) to methylcobalamin, while in cblC, mutations in MMACHC disrupt formation of cob(II)alamin (detected as HOCbl). Cases with undetectable methionine synthase (MS) activity are extremely rare and classified as 'cblG-variant'. In four 'cblG-variant' cases, we observed a decreased conversion of cyanocobalamin to HOCbl that is also seen in cblC cases. To explore this observation, we studied the gene defects, splicing products and expression of MS, as well as MS/MMACHC protein interactions in cblG-variant, cblG, cblC and control fibroblasts. We observed a full-size MS encoded by MTR-001 and a 124 kDa truncated MS encoded by MTR-201 in cblG, cblC, control fibroblasts and HEK cells, but only the MTR-201 transcript and inactive truncated MS in cblG-variant cells. Co-immunoprecipitation and proximity ligation assay showed interaction between truncated MS and MMACHC in cblG-variant cells. This interaction decreased 2.2, 1.5 and 5.0-fold in the proximity ligation assay of cblC cells with p.R161Q and p.R206W mutations, and HEK cells with knock down expression of MS by siRNA, respectively, when compared with control cells. In 3D modelling and docking analysis, both truncated and full-size MS provide a loop anchored to MMACHC, which makes contacts with R-161 and R-206 residues. Our data suggest that the interaction of MS with MMACHC may play a role in the regulation of the cellular processing of Cbls that is required for Cbl cofactor synthesis.
Journal of Inherited Metabolic Disease · 2021 · 30 citations
Methionine synthase deficiency: Variable clinical presentation and benefit of early diagnosis and treatment
AbstractMethionine synthase deficiency (cblG complementation group) is a rare inborn error of metabolism affecting the homocysteine re-methylation pathway. It leads to a biochemical phenotype of hyperhomocysteinemia and hypomethioninemia. The clinical presentation of cblG is variable, ranging from seizures, encephalopathy, macrocytic anemia, hypotonia, and feeding difficulties in the neonatal period to onset of psychiatric symptoms or acute neurologic changes in adolescence or adulthood. Given the variable and nonspecific symptoms seen in cblG, the diagnosis of affected patients is often delayed. Medical management of cblG includes the use of hydroxocobalamin, betaine, folinic acid, and in some cases methionine supplementation. Treatment has been shown to lead to improvement in the biochemical profile of affected patients, with lowering of total homocysteine levels and increasing methionine levels. However, the published literature contains differing conclusions on whether treatment is effective in changing the natural history of the disease. Herein, we present five patients with cblG who have shown substantial clinical benefit from treatment with objective improvement in their neurologic outcomes. We demonstrate more favorable outcomes in our patients who were treated early in life, especially those who were treated before neurologic symptoms manifested. Given improved outcomes from treatment of presymptomatic patients, cblG warrants inclusion in newborn screening.
Clinical Chemistry and Laboratory Medicine (CCLM) · 2012 · 28 citations · open access
Proteomics of vitamin B12 processing
AbstractThe causes of cobalamin (B12, Cbl) deficiency are multifactorial. Whether nutritional due to poor dietary intake, or functional due to impairments in absorption or intracellular processing and trafficking events, the major symptoms of Cbl deficiency include megaloblastic anemia, neurological deterioration and in extreme cases, failure to thrive and death. The common biomarkers of Cbl deficiency (hyperhomocysteinemia and methylmalonic acidemia) are extremely valuable diagnostic indicators of the condition, but little is known about the changes that occur at the protein level. A mechanistic explanation bridging the physiological changes associated with functional B12 deficiency with its intracellular processers and carriers is lacking. In this article, we will cover the effects of B12 deficiency in a cblC-disrupted background (also referred to as MMACHC) as a model of functional Cbl deficiency. As will be shown, major protein changes involve the cytoskeleton, the neurological system as well as signaling and detoxification pathways. Supplementation of cultured MMACHC-mutant cells with hydroxocobalamin (HOCbl) failed to restore these variants to the normal phenotype, suggesting that a defective Cbl processing pathway produces irreversible changes at the protein level.
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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