DeCure for Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for sulfite oxidase deficiency due to molybdenum cofactor deficiency type B — 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 moduleSulfite oxidase deficiency due to molybdenum cofactor deficiency type B 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
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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 sulfite oxidase deficiency due to molybdenum cofactor deficiency type b 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
integrin subunit alpha 2 (ITGA2) — ITGA2 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 2sdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9RIE · 1.305 Å · ligand (2S)-2-hydroxybutanedioic acid (LMR). Experimental structure, not a prediction.
What the evidence adds up to
A 1998 study identified a specific mutation in the sulfite oxidase gene in a five-year-old girl with isolated sulfite oxidase deficiency: a guanine-to-adenine transition at nucleotide 479, causing an arginine-to-glutamine substitution at position 160 (R160Q). The recombinant mutant protein retained its full complement of molybdenum and heme but exhibited only 2% of native enzyme activity under standard assay conditions. Kinetic analysis showed a nearly 1,000-fold decrease in the apparent second-order rate constant kcat/Km, driven by both an increased Km for sulfite and a decreased kcat. The same paper proposed that arginine 160 normally attracts the anionic substrate sulfite to the molybdenum binding site.
Molybdenum cofactor deficiency (MoCD) and isolated sulfite oxidase deficiency are autosomal recessive disorders that produce severe neurological symptoms because sulfite oxidase activity is absent. A 2002 paper confirmed that prenatal diagnosis is possible by measuring sulfite oxidase activity in chorionic villus sampling tissue, or by mutation analysis of the relevant genes — MOCS1, MOCS2, or GEPH for MoCD, and SUOX for isolated sulfite oxidase deficiency. A 1998 family report described a late-onset MoCD variant: the index case presented at one year of age with lethargy, inconsolable crying, and a seizure; by 17 months she had mild motor delay, language regression, and feeding difficulties, followed by progressive global deterioration with dystonia and further seizures, then a plateau. A sibling had only isolated lens dislocation with an identical biochemical profile. Both children had strikingly abnormal MRIs.
A 2019 review summarised that molybdenum cofactor is required for sulfite oxidase, xanthine dehydrogenase, aldehyde oxidase, and nitrite reductase, and that its deficiency is linked to mental retardation, brain immaturity, nervous shocks, and neurodegenerative diseases. The review noted that substitution- and gene-therapies have been introduced for MoCD types A and B in recent years, but stated that definitive treatment remains ill-defined and that more investigations are needed. A 2004 chapter on sulfite oxidase explained that the enzyme is a homodimer located in the mitochondrial intermembrane space, with each subunit containing a molybdenum cofactor domain and a heme domain; oxidation of sulfite to sulfate occurs at the molybdenum centre, and electrons are transferred singly to cytochrome c via the b5 heme.
What is still missing is a definitive treatment for either MoCD or isolated sulfite oxidase deficiency. No large controlled trial has been reported for any therapy in these conditions. Patient numbers are extremely small, and the phenotypic variability — including late-onset forms with milder presentations — complicates any attempt to stratify patients for future studies. Funding for natural history registries and for trials of substrate reduction or cofactor replacement remains scarce.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Proceedings of the National Academy of Sciences · 1998 · 132 citations · open access
Human sulfite oxidase R160Q: Identification of the mutation in a sulfite oxidase-deficient patient and expression and characterization of the mutant enzyme
AbstractSulfite oxidase catalyzes the terminal reaction in the degradation of sulfur amino acids. Genetic deficiency of sulfite oxidase results in neurological abnormalities and often leads to death at an early age. The mutation in the sulfite oxidase gene responsible for sulfite oxidase deficiency in a 5-year-old girl was identified by sequence analysis of cDNA obtained from fibroblast mRNA to be a guanine to adenine transition at nucleotide 479 resulting in the amino acid substitution of Arg-160 to Gln. Recombinant protein containing the R160Q mutation was expressed in Escherichia coli, purified, and characterized. The mutant protein contained its full complement of molybdenum and heme, but exhibited 2% of native activity under standard assay conditions. Absorption spectroscopy of the isolated molybdenum domains of native sulfite oxidase and of the R160Q mutant showed significant differences in the 480- and 350-nm absorption bands, suggestive of altered geometry at the molybdenum center. Kinetic analysis of the R160Q protein showed an increase in Km for sulfite combined with a decrease in kcat resulting in a decrease of nearly 1,000-fold in the apparent second-order rate constant kcat/Km. Kinetic parameters for the in vitro generated R160K mutant were found to be intermediate in value between those of the native protein and the R160Q mutant. Native sulfite oxidase was rapidly inactivated by phenylglyoxal, yielding a modified protein with kinetic parameters mimicking those of the R160Q mutant. It is proposed that Arg-160 attracts the anionic substrate sulfite to the binding site near the molybdenum.
Prenatal diagnosis of molybdenum cofactor deficiency and isolated sulfite oxidase deficiency
AbstractMolybdenum cofactor deficiency and isolated sulfite oxidase deficiency are autosomal recessive inborn errors of metabolism with severe neurological symptoms resulting from a lack of sulfite oxidase activity. The deficiencies can be diagnosed prenatally by monitoring sulfite oxidase activity in chorionic villus sampling (CVS) tissue. In those families in which the specific defects have been identified, diagnosis can be achieved by mutation analysis or linkage studies directed at affected genes. These include MOCS1, MOCS2 or GEPH, in cases of molybdenum cofactor deficiency, or SUOX in patients with isolated sulfite oxidase deficiency.
Developmental Medicine & Child Neurology · 1998 · 44 citations · open access
Molybdenum cofactor deficiency – phenotypic variability in a family with a late‐onset variant
AbstractIn a family with molybdenum cofactor deficiency, the onset in the index case was delayed until 1 year of age, when the patient presented with an episode of lethargy and inconsolable crying culminating in a seizure. By 17 months she showed mild motor delay, regression in language skills, and feeding difficulties. Progressive global deterioration followed, associated with sustained irritability, dystonic posturing, and further seizures, before her condition subsequently plateaued. Low plasma uric acid, raised urinary xanthine and hypoxanthine, and positive urinary sulphite were found, which, coupled with assay of sulphite oxidase activity in cultured fibroblasts, confirmed the diagnosis. A sibling had isolated lens dislocation and an identical biochemical profile. MRI in both children was strikingly abnormal. Molybdenum cofactor deficiency may present as a late-onset variant with considerable phenotypic variability.
Journal of Nutrition and Food Security · 2019 · 6 citations · open access
Molybdenum Cofactor Biology and Disorders Related to Its Deficiency; A Review Study
AbstractBackground: Molybden, as a vital and essential micronutrient is directly involved in the metabolism of other elements including carbon, sulfur, and nitrogen. Molybdenum alone is not biologically active unless it binds to specific cofactors. Except for the bacterial nitrogenase, which contains molybdenum-Iron complex, molybdenum cofactor (Moco) is considered as the bioactive component placed in active site regions of molybdenum-containing enzymes. This review aimed to discuss the biological mechanisms involved in molybdenum metabolism highlighting Molybdenum cofactor deficiencies. Methods: Articles indexed in Pubmed, Google Scholar, and Scopus databases were used to extract the required information. Results: Moco, as the cofactor of sulfite oxidase, xanthine dehydrogenase, aldehyde oxidase, and nitrite reductase plays a substantial role in maintaining normal body homeostasis and reactive oxygen species (ROS) production. Lack of Moco is found to be associated with many inborn genetic disorders, such as mental retardation, brain immaturity, nervous shocks, and neurodegenerative diseases. Conclusion: Moco insufficiency compromises normal human body metabolism since it is reported to regulate the metabolic pathways of other elements. Although in recent years, substitution- and gene-therapies have been introduced to restore the metabolic pathways of patients with MoCD type A and B, the definitive treatment for this type of inborn disease has still remained ill-defined. More investigations are needed to completely understand the underlying pathophysiology of molybdenum-related diseases.
Encyclopedia of Inorganic and Bioinorganic Chemistry · 2004 · 0 citations
Sulfite Oxidase
AbstractAbstract Sulfite oxidase catalyzes the physiologically vital oxidation of sulfite to sulfate, the terminal reaction in the oxidative degradation of the sulfur‐containing amino acids, cysteine and methionine. It belongs to the molybdenum cofactor (Moco)‐containing family of enzymes that are characterized by the presence of a mononuclear Mo atom coordinated to the sulfur atoms of a pterin derivative, named molybdopterin. The homodimeric sulfite oxidase is located in the mitochondrial intermembrane space and each subunit contains a larger Moco‐containing domain and a smaller heme‐containing domain. Oxidation of sulfite to sulfate occurs at the molybdenum center with concomitant reduction of Mo(VI) to Mo(IV). Two electrons are singly transferred to the b 5 heme of the enzyme and from there to cytochrome c . Sulfite oxidase deficiency results from defects either in the genes encoding proteins involved in molybdenum cofactor biosynthesis or in the sulfite oxidase gene itself. Several point mutations in the sulfite oxidase gene have been identified in patients with this disease worldwide. The crystal structure of wild‐type chicken sulfite oxidase provides the first atomic model for this enzyme and suggests possible reasons for how these substitutions interfere with catalysis or substrate binding.
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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