DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for isolated sulfite oxidase 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 moduleIsolated sulfite oxidase 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
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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 isolated sulfite oxidase 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
sulfite oxidase (SUOX) — SUOX 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…
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RCSB Protein Data Bank · entry 1MJ4 · 1.2 Å · ligand PROTOPORPHYRIN IX CONTAINING FE (HEM). Experimental structure, not a prediction.
What the evidence adds up to
An infant who died with neurological abnormalities, mental retardation, and dislocated ocular lenses was found to have no detectable sulfite oxidase activity in liver, brain, and kidney. The urine contained abnormally large amounts of S-sulfo-L-cysteine, sulfite, and thiosulfate, and virtually no inorganic sulfate. This was the first demonstration of the enzymatic defect in humans. A later report described a 5-year-old girl with a mutation in the sulfite oxidase gene, a guanine to adenine transition at nucleotide 479 resulting in an Arg-160 to Gln substitution. The recombinant R160Q protein contained full molybdenum and heme but exhibited only 2% of native activity under standard assay conditions. Kinetic analysis showed a nearly 1,000-fold decrease in the apparent second-order rate constant kcat/Km, due to both an increased Km for sulfite and a decreased kcat.
Crystal structures of recombinant chicken sulfite oxidase, which has high homology to the human enzyme, were solved for the wild type and the R138Q variant (equivalent to human R160Q). The structure of the mutant revealed significant alterations in the substrate-binding pocket. The active site residue Arg-450 adopted different conformations depending on the presence or absence of bound sulfate, and the size of the binding pocket was considerably reduced. The position of the pocket relative to the cofactor shifted, increasing the distance of the sulfur atom of bound sulfate to the molybdenum. Up to eleven missense mutations in the sulfite oxidase gene have been identified from patients worldwide, and structural analysis of these mutations is now possible using the chicken enzyme model.
A 2007 report described a newborn with progressive leukoencephalopathy and lactic acidaemia diagnosed with isolated sulfite oxidase deficiency. Low plasma total homocysteine was identified as a valuable early indicator of sulfite oxidase dysfunction, providing a crucial first-line screen. Plasma cystine was not always informative in the first few days of life. A 2023 review noted that sulfite oxidase is one of five molybdenum-containing enzymes in eukaryotes and that its deficiency in humans demonstrates a unique role among all molybdenum enzymes. The review also stated that sulfite oxidase represents an important player in redox regulation, signalling, and metabolism, connecting sulfur and nitrogen metabolism in multiple ways.
What is still missing is any effective treatment for this lethal genetic disease. No therapy has been tested in clinical trials. The disease is rare, which limits funding and patient numbers for trials. Patient stratification by specific mutation type might be necessary, as the R160Q mutation and others have distinct biochemical effects, but no such stratified approach has been attempted.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Science · 1967 · 211 citations
Sulfite Oxidase Deficiency in Man: Demonstration of the Enzymatic Defect
AbstractAn infant who died with neurological abnormalities, mental retardation, and dislocated ocular lenses excreted in his urine abnormally large amounts of S-sulfo-L-cysteine, sulfite, and thiosulfate and virtulally no inorganic sutlfate. The present report establishes the occurrence of an ezymatic defect in this infant. His liver, brain, and kidney specifically lacked sulfite oxidase activity. Deficiency of sulfite oxidase, which has not apparently been described in man, provides a reasonable explanation for the abnormalities in this infant.
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.
Journal of Biological Chemistry · 2005 · 80 citations · open access
Structural Insights into Sulfite Oxidase Deficiency
AbstractSulfite oxidase deficiency is a lethal genetic disease that 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 from patients suffering from this disease worldwide. Although detailed biochemical analyses have been carried out on these mutations, no structural data could be obtained because of problems in crystallizing recombinant human and rat sulfite oxidases and the failure to clone the chicken sulfite oxidase gene. We synthesized the gene for chicken sulfite oxidase de novo, working backward from the amino acid sequence of the native chicken liver enzyme by PCR amplification of a series of 72 overlapping primers. The recombinant protein displayed the characteristic absorption spectrum of sulfite oxidase and exhibited steady state and rapid kinetic parameters comparable with those of the tissue-derived enzyme. We solved the crystal structures of the wild type and the sulfite oxidase deficiency-causing R138Q (R160Q in humans) variant of recombinant chicken sulfite oxidase in the resting and sulfate-bound forms. Significant alterations in the substrate-binding pocket were detected in the structure of the mutant, and a comparison between the wild type and mutant protein revealed that the active site residue Arg-450 adopts different conformations in the presence and absence of bound sulfate. The size of the binding pocket is thereby considerably reduced, and its position relative to the cofactor is shifted, causing an increase in the distance of the sulfur atom of the bound sulfate to the molybdenum.
Isolated Sulfite Oxidase Deficiency in the Newborn: Lactic Acidaemia and Leukoencephalopathy
AbstractWe report a newborn with progressive leukoencephalopathy and lactic acidaemia, diagnosed with isolated sulfite oxidase deficiency. We show that low plasma total homocysteine (PTHcy) is a valuable early indicator of sulfite oxidase dysfunction, providing a crucial first-line screen, whereas plasma cystine is not always informative in the first few days of life.
The History of Animal and Plant Sulfite Oxidase—A Personal View
AbstractSulfite oxidase is one of five molybdenum-containing enzymes known in eukaryotes where it catalyzes the oxidation of sulfite to sulfate. This review covers the history of sulfite oxidase research starting out with the early years of its discovery as a hepatic mitochondrial enzyme in vertebrates, leading to basic biochemical and structural properties that have inspired research for decades. A personal view on sulfite oxidase in plants, that sulfates are assimilated for their de novo synthesis of cysteine, is presented by Ralf Mendel with numerous unexpected findings and unique properties of this single-cofactor sulfite oxidase localized to peroxisomes. Guenter Schwarz connects his research to sulfite oxidase via its deficiency in humans, demonstrating its unique role amongst all molybdenum enzymes in humans. In essence, in both the plant and animal kingdoms, sulfite oxidase represents an important player in redox regulation, signaling and metabolism, thereby connecting sulfur and nitrogen metabolism in multiple ways.
Structural analysis of missense mutations causing isolated sulfite oxidase deficiency
AbstractThe physiologically essential oxidation of sulfite to sulfate is catalyzed by the molybdoheme enzyme, sulfite oxidase. Deficiencies of this enzyme in human patients lead to severe neurological symptoms, which usually result in death in early childhood. Up to date eleven missense mutations in the gene encoding sulfite oxidase have been identified from sulfite oxidase deficient patients. The structural characterization of these mutants is now possible after the chicken sulfite oxidase gene has been synthesized chemically and due to the high homology to the human enzyme it provides a good model of human sulfite oxidase. This review focuses on the possible effects of the sulfite oxidase deficiency causing mutations based on our new structures of recombinant chicken sulfite oxidase.
Stable clinical course in three siblings with late-onset isolated sulfite oxidase deficiency: a case series and literature review
AbstractAbstract Background Isolated sulfite oxidase deficiency (ISOD) is an autosomal recessive disorder caused by a deficiency of sulfite oxidase, which is encoded by the sulfite oxidase gene (SUOX). Clinically, the disorder is classified as one of two forms: the late-onset mild form or the classic early-onset form. The latter is life-threatening and always leads to death during early childhood. Mild ISOD cases are rare and may benefit from dietary therapy. To date, no cases of ISOD have been reported to recover spontaneously. Here, we present three mild ISOD cases in one family, each with a stable clinical course and spontaneous recovery. Case presentation All three siblings had two novel compound heterozygous mutations in the SUOX gene (NM_000456; c.1096C > T [p.R366C] and c.1376G > A [p.R459Q]). The siblings included two males and one female with late ages of onset (12–16 months) and presented with specific neuroimaging abnormalities limited to the bilateral globus pallidus and substantia nigra. The three patients had decreased plasma homocysteine levels. They exhibited a monophasic clinical course continuing up to 8.5 years even without dietary therapy. Conclusion This is the first report of mild ISOD cases with a stable clinical course and spontaneous recovery without dietary therapy. Our study provides an expansion for the clinical spectrum of ISOD. Furthermore, we highlight the importance of including ISOD in the differential diagnosis for patients presenting with late-onset symptoms, bilaterally symmetric regions of abnormal intensities in the basal ganglia, and decreased plasma homocysteine levels.
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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