DeCure for Gamma-glutamyl transpeptidase deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for gamma-glutamyl transpeptidase 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 moduleGamma-glutamyl transpeptidase 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 gamma-glutamyl transpeptidase 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
gamma-glutamyltransferase 1 (GGT1) — GGT1 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 gludrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4GDX · 1.67 Å · ligand GLUTAMIC ACID (GLU). Experimental structure, not a prediction.
What the evidence adds up to
A 1979 report describes a mentally retarded young woman with severe behavioural problems who excreted large amounts of glutathione due to a generalised gamma-glutamyl transpeptidase deficiency. This was the second detailed case. Plasma levels and renal reabsorption of amino acids were normal. Enzyme activity in the parents’ urine, plasma and leukocytes was normal, but in their cultured fibroblasts it fell below the minimum of the control range. An autosomal recessive mode of inheritance was suggested.
Biochemical work from 1974 on purified rat kidney enzyme showed that many gamma-glutamyl amino acids act as gamma-glutamyl donors, with L-gamma-glutamyl-L-glutamine and L-gamma-glutamyl-L-methionine the most active. Glutathione disulfide was about 5% as active as glutathione. Of 32 amino acids tested, L-glutamine and L-methionine were the best acceptors of the gamma-glutamyl group. Several dipeptides, including glycylglycine, were more active acceptors than L-glutamine. The enzyme was substantially inhibited by the gamma-glutamyl hydrazones of a number of alpha-keto acids, with the derivative of alpha-ketoglutarate inhibiting most strongly; inhibition was competitive with respect to the gamma-glutamyl donor.
A 1990 study identified a highly reactive threonine residue at the active site of gamma-glutamyl transpeptidase. Treating the enzyme with a selective reagent led to stoichiometric binding, with more than 90% of the label bound to the light subunit. The labelled peptide corresponded to amino acid residues 517-527, and the radioactivity was released with threonine-523 during sequencing. The light subunit contains 14 other threonine residues and 19 serine residues that were not labelled.
No clinical trial of any drug for gamma-glutamyl transpeptidase deficiency has been reported. The biochemical understanding of the enzyme’s active site and its inhibition by gamma-glutamyl hydrazones has not been translated into a tested therapeutic strategy. What is missing is any clinical study, any attempt at enzyme replacement or substrate reduction, and any patient stratification beyond the two described cases.
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 Biological Chemistry · 1974 · 541 citations · open access
Interaction of γ-Glutamyl Transpeptidase with Amino Acids, Dipeptides, and Derivatives and Analogs of Glutathione
AbstractAbstract A highly purified and apparently homogeneous preparation of rat kidney γ-glutamyl transpeptidase was examined with respect to its γ-glutamyl donor and acceptor specificities. Many γ-glutamyl amino acids were active as γ-glutamyl donors, the most active being l-γ-glutamyl-l-glutamine and l-γglutamyl-l-methionine. Glutathione disulfide was about 5% as active as glutathione, while substantial activity was found with S-methylglutathione and ophthalmic acid. In the course of this work convenient spectrophotometric methods for the determination of γ-glutamyl transpeptidase activity were developed in which S-substituted derivatives of glutathione were used, e.g. the S-propanone and S-acetophenone derivatives; these procedures are based on the high ultraviolet absorbance of the corresponding S-substituted products. Several of the S-substituted glutathiones were more active in transpeptidation than glutathione itself. Kinetic studies were carried out which indicate a ping-pong mechanism consistent with intermediate formation of a γglutamyl enzyme. Of the 32 amino acids tested, l-glutamine and l-methionine were the best acceptors of the γ-glutamyl group. A number of dipeptides were active as acceptors, and several of these were more active than l-glutamine, e.g. glycylglycine, glycyl-l-alanine, l-methionyl-l-serine, lglutaminyl-l-glutamine, and l-α-aminobutyrylglycine. Aminoacylglycine derivatives were (in the five instances studied) more active than the corresponding free NH2-terminal amino acids; the corresponding aminoacyl-l-alanine derivatives were less active than the aminoacylglycines. The high reactivity of certain dipeptides may reflect their affinity for the cysteinylglycine site of the enzyme, but the findings are also consistent with a function of γ-glutamyl transpeptidase in peptide transport as well as in amino acid transport. γGlutamyl transpeptidase is inhibited substantially by the γglutamyl hydrazones of a number of α-keto acids. Inhibition is competitive with respect to the γ-glutamyl donor; of seven α-keto acid γ-glutamyl hydrazones, the derivative of α-ketoglutarate inhibited the most.
Proceedings of the National Academy of Sciences · 1977 · 102 citations · open access
Affinity labeling of gamma-glutamyl transpeptidase and location of the gamma-glutamyl binding site on the light subunit.
AbstractGamma-Glutamyl transpeptidase, which consists of two nonidentical subunits, is rapidly inactivated with respect to its transpeptidase and hydrolase activities by the gamma-glutamyl analogs 6-diazo-5-oxo-L-norleucine and L-azaserine. Inactivation, which is prevented by gamma-glutamyl substrates (but not by acceptor substrates), is accelerated by maleate, which was previously shown to enhance utilization of glutamine by transpeptidase. 6-Diazo-5-oxo--norleucine reacts specifically, covalently, and stoichiometrically at the gamma-glutamyl site of the enzyme, which was localized through studies with 6-diazo-5-OXO-[14C]norleucine to the light subunits of both the transpeptidase of rat kidney (which has subunits of molecular weights 22,000 and 46,000) and the transpeptidase of human kidney (which has subunits of molecular weights 22,000 and 62,000). The findings, which indicate that these enzymes have similar gamma-glutamyl binding subunits, are relevant to the structure-function relationships of this membrane-bound enzyme and its physiological role.
AbstractA mentally retarded young woman with severe behaviour problems was found to excrete large amounts of glutathione due to a generalized gamma-glutamyl transpeptidase deficiency. As in the only other case described in detail, plasma levels and renal reabsorption of the amino acids were normal. In the parents' urine, plasma and leukocytes, enzyme activity was normal but in their cultured fibroblasts it was below the minimum for the control range. An autosomal recessive mode of inheritance is suggested. The implications of these findings for possible role of the gamma-glutamyl cycle in amino acid transport are briefly discussed.
Proceedings of the National Academy of Sciences · 1990 · 31 citations · open access
Identification of a highly reactive threonine residue at the active site of gamma-glutamyl transpeptidase.
Abstractgamma-Glutamyl transpeptidase [(5-glutamyl)-peptide:amino-acid 5-glutamyltransferase, EC 2.3.2.2], an enzyme of major importance in glutathione metabolism, was inactivated by treating it with L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-[3-14C]isoxazoleacetic acid. This selective reagent binds stoichiometrically to the enzyme; more than 90% of the label was bound to its light subunit. Enzymatic digestion of the light subunit gave a 14C-labeled peptide that corresponds to amino acid residues 517-527 of the enzyme and two incomplete digestion products that contain this labeled peptide moiety. The radioactivity associated with this peptide was released with threonine-523 during sequencing by the automated gas-phase Edman method. The light subunit contains 14 other threonine residues and a total of 19 serine residues; these were not labeled. Threonine-523 is situated in the enzyme in an environment that greatly increases its reactivity, indicating that other amino acid residues of the enzyme must also participate in the active-site chemistry of the enzyme.
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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