DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for galactose epimerase 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 moduleGalactose epimerase 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
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 galactose epimerase 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
UDP-galactose-4-epimerase (GALE) — GALE 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 naidrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1EK6 · 1.5 Å · ligand 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE (NAI). Experimental structure, not a prediction.
What the evidence adds up to
UDP-galactose 4-epimerase deficiency is the rarest of the three inborn errors of galactose metabolism, with classical galactosemia (GALT deficiency) affecting approximately 1 in 10,000 to 1 in 30,000 live births. In one severe case, the V94M amino acid substitution in the human epimerase impairs the enzyme predominantly at the level of V(max) rather than K(m). The structural consequence is that the hydrophobic side chain of Val94, which normally packs near the catalytic Tyr157 and limits rotation of the glycosyl portions of UDP-sugar substrates, is replaced by methionine. This opens up the Ala93 to Glu96 surface loop, allowing free rotation of the sugars into nonproductive binding modes.
In a patient with epimerase deficiency, red-cell concentrations of uridine diphosphate galactose accumulated rapidly in response to very small amounts of dietary galactose, while galactose-1-phosphate increased proportionately to galactose intake. A separate case of transient neonatal galactosaemia in a 4-week-old infant with failure to thrive showed a grossly raised plasma galactose concentration (4.48 mmol/l; reference range less than 0.24 mmol/l) but normal red cell transferase and epimerase activities; clinical and biochemical tolerance to galactose was evident by 7 months of age after dietary lactose exclusion.
Stimulation with phytohemagglutinin of leukocytes from six of the seven known individuals with epimerase deficiency consistently produced epimerase activity in cultured cells. A long-term lymphoblast culture from one proband also contained active enzyme, with comparable Km values for UDP-galactose and NAD and identical behaviour on polyacrylamide electrophoresis to control lymphoblast lines. However, a difference in the NAD requirement for heat stability at 40°C provided some evidence for a structural defect. Possible explanations include increased synthesis of a mutant enzyme or derepression of an epimerase locus during lymphocyte transformation.
The high-resolution X-ray structure of E. coli UDP-galactose 4-epimerase complexed with NADH and UDP-phenol was refined to 1.8 Å resolution with a final R-factor of 18.6%, confirming that UDP-phenol and UDP-glucose bind similarly. The carboxamide groups of the dinucleotides are displaced from the planes of the nicotinamide rings by hydrogen bonding with Ser124 and Tyr149. What remains missing is a systematic understanding of how the different mutations in human GALE correlate with clinical severity across the full range of patients, and whether the in vitro reversibility of the deficiency in stimulated lymphocytes has any therapeutic relevance. No clinical trial has tested any drug that targets epimerase deficiency, and no patient stratification by genotype or biochemical phenotype has been prospectively validated to guide management.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Protein Science · 1996 · 80 citations · open access
High‐resolution X‐ray structure of UDP‐galactose 4‐epimerase complexed with UDP‐phenol
AbstractUDP-galactose 4-epimerase from Escherichia coli catalyzes the interconversion of UDP-glucose and UDP-galactose. In recent years, the enzyme has been the subject of intensive investigation due in part to its ability to facilitate nonstereospecific hydride transfer between beta-NADH and a 4-keto hexopyranose intermediate. The first molecular model of the epimerase from E. coli was solved to 2.5 A resolution with crystals grown in the presence of a substrate analogue, UDP-phenol (Bauer AJ, Rayment I, Frey PA, Holden HM, 1992, Proteins Struct Funct Genet 12:372-381). There were concerns at the time that the inhibitor did not adequately mimic the sugar moiety of a true substrate. Here we describe the high-resolution X-ray crystal structure of the ternary complex of UDP-galactose 4-epimerase with NADH and UDP-phenol. The model was refined to 1.8 A resolution with a final overall R-factor of 18.6%. This high-resolution structural analysis demonstrates that the original concerns were unfounded and that, in fact, UDP-phenol and UDP-glucose bind similarly. The carboxamide groups of the dinucleotides, in both subunits, are displaced significantly from the planes of the nicotinamide rings by hydrogen bonding interactions with Ser 124 and Tyr 149. UDP-galactose 4-epimerase belongs to a family of enzymes known as the short-chain dehydrogenases, which contain a characteristic Tyr-Lys couple thought to be important for catalysis. The epimerase/NADH/UDP-phenol model presented here represents a well-defined ternary complex for this family of proteins and, as such, provides important information regarding the possible role of the Tyr-Lys couple in the reaction mechanism.
Journal of Inherited Metabolic Disease · 1982 · 47 citations
Further observations in a case of uridine diphosphate galactose‐4‐epimerase deficiency with a severe clinical presentation
AbstractThe red-cell concentrations of galactose-1-phosphate and uridine diphosphate galactose have been studied in relation to dietary galactose in a case of uridine diphosphate galactose-4-epimerase deficiency (McKusick 23035). Uridine diphosphate galactose accumulates rapidly in response to very small amounts of galactose but the concentration of galactose-1-phosphate increases proportionately to galactose intake. The significance of the observation is discussed with respect to the pathogenesis and treatment of the disease.
Journal of Biological Chemistry · 2001 · 45 citations · open access
Molecular Basis for Severe Epimerase Deficiency Galactosemia
AbstractGalactosemia is an inherited disorder characterized by an inability to metabolize galactose. Although classical galactosemia results from impairment of the second enzyme of the Leloir pathway, namely galactose-1-phosphate uridylyltransferase, alternate forms of the disorder can occur due to either galactokinase or UDP-galactose 4-epimerase deficiencies. One of the more severe cases of epimerase deficiency galactosemia arises from an amino acid substitution at position 94. It has been previously demonstrated that the V94M protein is impaired relative to the wild-type enzyme predominantly at the level of V(max) rather than K(m). To address the molecular consequences the mutation imparts on the three-dimensional architecture of the enzyme, we have solved the structures of the V94M-substituted human epimerase complexed with NADH and UDP-glucose, UDP-galactose, UDP-GlcNAc, or UDP-GalNAc. In the wild-type enzyme, the hydrophobic side chain of Val(94) packs near the aromatic group of the catalytic Tyr(157) and serves as a molecular "fence" to limit the rotation of the glycosyl portions of the UDP-sugar substrates within the active site. The net effect of the V94M substitution is an opening up of the Ala(93) to Glu(96) surface loop, which allows free rotation of the sugars into nonproductive binding modes.
Proceedings of the National Academy of Sciences · 1975 · 25 citations · open access
Reversal of UDP-galactose 4-epimerase deficiency of human leukocytes in culture.
AbstractStimulation with phytohemagglutinin of the leukocytes from six of the seven known individuals with UDP-galactose 4-epimerase (= UDP-glucose 4-epimerase; EC 5.1.3.2) deficiency consistently resulted in the appearance of epimerase activity in the cultured cells. A long-term lymphoblast culture derived from one proband also contained an active epimerase enzyme. A comparison of the properties of this enzyme with those of epimerase produced by control lymphoblast lines revealed comparable Km values for UDP-galactose and NAD and identical behavior on polyacrylamide electrophoresis. However, a difference in the NAD requirement for heat stability at 40 degree provided some evidence for a structural defect in this enzyme. Possible explanations for the appearance of UDP-galactose 4-epimerase activity in stimulated lymphocytes include an increased rate of synthesis of a mutant enzyme and a derepression of an epimerase locus during lymphocyte transformation.
Current Protocols in Human Genetics · 2008 · 21 citations
Diagnosis of Inherited Disorders of Galactose Metabolism
AbstractGalactose metabolism occurs through an evolutionarily conserved pathway in which galactose and uridine diphosphoglucose are converted to glucose-1-phosphate and uridine diphosphogalactose through the action of three sequential enzymes: galactokinase (GALK, EC 2.7.1.6), galactose-1-phosphate uridyltransferase (GALT, EC 2.7.7.12), and uridine phosphogalactose 4'-epimerase (GALE, EC 5.1.3.2). Inborn errors of galactose metabolism occur with impaired activity for each of the enzymes. Classical galactosemia is the most common and the most severe of these diseases and is caused by deficiency of the GALT enzyme, affecting from approximately 1 in 10,000 to 1 in 30,000 live births. Deficiency of GALE is the rarest of the three diseases. Assays for galactitol and galactose-1-phosphate and methods for assaying enzyme activities of GALT, GALK, and GALE are provided here. Interpretation of diagnostic results for screen-positive newborns or symptomatic patients, as well as therapeutic interventions based on biochemical phenotype and molecular genotype, are also included as decision trees.
Archives of Disease in Childhood · 1988 · 7 citations · open access
Transient neonatal galactosaemia.
AbstractA 4 week old infant who failed to thrive was found to have galactose in his urine. Plasma galactose concentration was grossly raised (4.48 mmol/l; reference range less than 0.24 mmol/l) but red cell transferase and epimerase activities were normal. He improved when dietary lactose was excluded. Clinical and biochemical tolerance to galactose was evident by 7 months of age.
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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