DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for disorder of methionine catabolism — 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 moduleDisorder of methionine catabolism 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 disorder of methionine catabolism 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
adenosylhomocysteinase (AHCY) — AHCY 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 naddrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1LI4 · 2.01 Å · ligand NICOTINAMIDE-ADENINE-DINUCLEOTIDE (NAD). Experimental structure, not a prediction.
What the evidence adds up to
A 1985 review of the literature on homocystinuria and schizophrenia found that while many patients with homocystinuria have been psychotic, few have been actually labelled schizophrenic. The authors describe a patient with homocystinuria, mental retardation, and episodic psychosis, and use this case to point to the difficulties in making a definite psychiatric diagnosis in these patients. A relationship between the two syndromes is suggested, but no controlled trial or systematic diagnostic data are provided.
A 2011 review of methionine auxotrophy in cancer reports that early clinical data on asparagine- and arginine-depleting drugs have demonstrated low toxicity and efficacy in melanoma, hepatocellular carcinoma and acute lymphoblastic leukaemia. Methionine auxotrophy is described as a novel niche under exploration. The authors state that extensive research addressing normal versus cancer cell toxicity needs to be conducted, and that further research is needed into the molecular mechanism associated with methionine depletion therapy. They also note that novel methods need to be developed to decrease the immunogenicity of methionine-depleting drugs, a current issue with protein therapeutics.
A 2021 review of methionine-based systems states that methionine-restriction therapy might be a promising approach to treat COVID-19, but provides no patient data, no trial results, and no evidence of efficacy in COVID-19. The same review summarises the use of S-adenosylmethionine for treating liver diseases, but gives no specific response rates or survival data.
A 2015 paper on the regulation of methionine biosynthesis in S. coelicolor describes the bacterial pathway only and has no relevance to human disease. No clinical data from any of these abstracts demonstrate that manipulating methionine metabolism improves outcomes in any human disorder. What is missing is any randomised controlled trial of methionine restriction or depletion in schizophrenia, cancer, or COVID-19, along with validated biomarkers to stratify patients who might benefit, and funding for such trials.
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 Journal of Nervous and Mental Disease · 1985 · 34 citations
Homocystinuria and Schizophrenia
AbstractThe autosomal recessive disorder homocystinuria involves, in all its subgroups, an abnormality of methionine metabolism. The metabolism of methionine has been a central focus of interest for those who propose the transmethylation hypothesis of schizophrenia. The "methionine effect," as described in the research literature, is thus a theoretical link between these two disorders. The authors review the literature and describe those cases where both have occurred in the same patient. They indicate that whereas many patients with homocystinuria have been psychotic, few have been actually labeled schizophrenic. A patient with homocystinuria, mental retardation, and episodic psychosis is described and this case is used to point to the difficulties in making a definite psychiatric diagnosis in these patients. A relationship between the two syndromes is suggested.
Expert Opinion on Biological Therapy · 2011 · 30 citations
Targeting methionine auxotrophy in cancer: discovery & exploration
AbstractINTRODUCTION: Amino acid auxotrophy or the metabolic defect which renders cancer incapable of surviving under amino acid depleted conditions is being exploited and explored as a therapeutic against cancer. Early clinical data on asparagine- and arginine-depleting drugs have demonstrated low toxicity and efficacy in melanoma, hepatocellular carcinoma and acute lymphoblastic leukemia. Methionine auxotrophy is a novel niche currently under exploration for targeting certain cancers. AREAS COVERED: In this review we explore the discovery of methionine auxotrophy followed by in vitro, in vivo and patient data on targeting cancer with methionine depletion. We end with a small discussion on bioengineering, pegylation and red blood cell encapsulation as mechanisms for decreasing immunogenicity of methionine-depleting drugs. We hope to provide a platform for future pharmacology, toxicology and cytotoxicity studies with methionine depletion therapy and drugs. EXPERT OPINION: Although methionine auxotrophy seems as a viable target, extensive research addressing normal versus cancer cell toxicity needs to be conducted. Further research also needs to be conducted into the molecular mechanism associated with methionine depletion therapy. Finally, novel methods need to be developed to decrease the immunogenicity of methionine-depleting drugs, a current issue with protein therapeutics.
New England Journal of Medicine · 1965 · 23 citations
Aminoaciduria
AbstractDisorders of Methionine MetabolismThe normal pathway of methionine metabolism is shown in Figure 3. Methionine has at least two major roles in addition to that in protein synthesis: it is the major methyl donor of the body and supplies methyl groups for synthesis of many compounds; and it is a precursor of cysteine and cystine. When there is a block in the metabolic pathway from methionine to cysteine, the plasma and urine cystine and taurine may be abnormally low.At least two inborn errors of methionine metabolism have been described thus far. They are named after the accumulated amino acid . . .
Biomedical applications of methionine-based systems
AbstractMethionine (Met), an essential amino acid in the human body, possesses versatile features based on its chemical modification, cell metabolism and metabolic derivatives. Benefitting from its multifunctional properties, Met holds immense potential for biomedical applications. In this review, we systematically summarize the recent progress in Met-based strategies for biomedical applications. First, given the unique structural characteristics of Met, two chemical modification methods are briefly introduced. Subsequently, due to the disordered metabolic state of tumor cells, applications of Met in cancer treatment and diagnosis are summarized in detail. Furthermore, the efficacy of S-adenosylmethionine (SAM), as the most important metabolic derivative of Met, for treating liver diseases is mentioned. Finally, we analyze the current challenges and development trends of Met in the biomedical field, and suggest that Met-restriction therapy might be a promising approach to treat COVID-19.
Model of the regulation of the methionine biosynthesis in <i>S</i>. <i>coelicolor</i>.
Abstract<p>Methionine is synthesised from homoserin (HS) via homocystein. Two methionine synthases, MetH and MetE, catalyse the final step. MetH which uses adenosylcobalamin as methyl donor catalyses the reaction with high turnover rate when coenzyme B12 is present. In the absence of B12, a B12-dependent riboswitch allows transcription of <i>metE</i> mRNA leading to increased methionine production by MetE. High methionine concentration results in feed back regulation of both MetH and MetE. MetH is controlled by the transcriptional regulator NdgR [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120147#pone.0120147.ref018" target="_blank">18</a>]. In addition, high methionin concentration also induces the expression of scr5239, which in turn represses <i>metE</i> translation. A possible link between nitrogen and methionine metabolism via the sRNA is speculative.</p>
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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