{"gene":"GK2","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":1992,"finding":"A human GK2 cDNA encoding a predicted 458-amino-acid protein was isolated by functional complementation of a galactokinase-deficient (gal1−) Saccharomyces cerevisiae strain, establishing that GK2 encodes a galactokinase (EC 2.7.1.6) capable of substituting for yeast galactokinase in vivo. The GK2 gene was mapped to chromosome 15, distinct from the previously mapped GK1 locus on chromosome 17q23-25. The encoded protein shares 29% amino acid identity with S. carlsbergensis galactokinase.","method":"Yeast complementation of gal1− mutant with human cDNA library; chromosomal mapping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional complementation in yeast is a clean genetic epistasis assay; single lab but complementation is a direct functional test","pmids":["1438294"],"is_preprint":false},{"year":1995,"finding":"When GK2 cDNA was expressed in COS cells alongside GALK1 cDNA, only GALK1 produced high levels of galactokinase activity; GK2-transfected cells showed no detectable galactokinase activity above background, despite confirmed mRNA expression by Northern blot. This demonstrates that GK2 does not function as a galactokinase in mammalian cells under these conditions, leaving its biochemical role uncertain.","method":"Transient expression in COS cells with galactokinase enzymatic activity assay; Northern blot confirmation of mRNA expression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct enzymatic activity assay with mRNA expression control, single lab; result is a clear negative finding in mammalian cells","pmids":["7542884"],"is_preprint":false}],"current_model":"GK2 encodes a predicted 458-amino-acid protein that can functionally substitute for galactokinase in yeast complementation assays, but when expressed in mammalian (COS) cells it produces no detectable galactokinase activity, leaving its enzymatic function and physiological role in mammals uncertain."},"narrative":{"mechanistic_narrative":"GK2 was identified as a candidate galactokinase through its ability to functionally complement a galactokinase-deficient (gal1−) yeast strain, restoring in vivo galactokinase activity and indicating that the encoded 458-amino-acid protein can substitute for yeast galactokinase [PMID:1438294]. However, when expressed in mammalian COS cells, GK2 produced no detectable galactokinase activity despite confirmed mRNA expression, while a control galactokinase construct was active under the same conditions [PMID:7542884]. The enzymatic function and physiological role of GK2 in mammalian cells therefore remain uncharacterized in the available corpus; beyond the yeast complementation and the negative mammalian activity assay, no substrate, interacting partner, localization, or pathway role has been established.","teleology":[{"year":1992,"claim":"Whether the GK2 gene product had any galactokinase function was unknown; isolating the cDNA by rescuing a galactokinase-deficient yeast strain established that GK2 can functionally substitute for galactokinase in vivo and is genetically distinct from GK1.","evidence":"Yeast complementation of gal1− mutant with human cDNA library plus chromosomal mapping","pmids":["1438294"],"confidence":"Medium","gaps":["Complementation in yeast does not demonstrate galactokinase activity in mammalian cells","No direct biochemical measurement of enzyme kinetics or substrate specificity","Physiological role and tissue context in humans not addressed"]},{"year":1995,"claim":"Whether GK2 acts as a galactokinase in a mammalian setting was tested directly; expression in COS cells yielded no detectable galactokinase activity despite confirmed transcription, showing GK2 does not function as a galactokinase under these conditions and leaving its biochemical role unresolved.","evidence":"Transient expression in COS cells with galactokinase enzymatic activity assay and Northern blot mRNA confirmation","pmids":["7542884"],"confidence":"Medium","gaps":["Negative result may reflect missing cofactors, post-translational modification, or improper folding in COS cells rather than absence of intrinsic activity","No alternative substrate tested","Endogenous tissue-specific expression and function not examined"]},{"year":null,"claim":"The native enzymatic activity, true substrate, subcellular localization, and physiological function of mammalian GK2 remain undefined.","evidence":"No further mechanistic studies present in the available corpus","pmids":[],"confidence":"Low","gaps":["No purified-protein biochemistry to define catalytic activity or kinetics","No identified physical partners or pathway placement","No in vivo or knockout phenotype data"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14410","full_name":"Glycerol kinase 2","aliases":["ATP:glycerol 3-phosphotransferase 2","Glycerol kinase, testis specific 2"],"length_aa":553,"mass_kda":60.6,"function":"Key enzyme in the regulation of glycerol uptake and metabolism. Essential for male fertility and sperm mitochondrial sheath formation (By similarity). Required for proper arrangement of crescent-like mitochondria to form the mitochondrial sheath during spermatogenesis (By similarity). Can induce mitochondrial clustering through interactions with PLD6 and up-regulation of phosphatidic acid synthesis in the mitochondria (PubMed:28852571)","subcellular_location":"Mitochondrion outer membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q14410/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GK2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GK2","total_profiled":1310},"omim":[{"mim_id":"600149","title":"GLYCEROL KINASE 3 PSEUDOGENE; GK3P","url":"https://www.omim.org/entry/600149"},{"mim_id":"600148","title":"GLYCEROL KINASE 2; GK2","url":"https://www.omim.org/entry/600148"},{"mim_id":"137028","title":"GALACTOKINASE 2; GALK2","url":"https://www.omim.org/entry/137028"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"testis","ntpm":83.7}],"url":"https://www.proteinatlas.org/search/GK2"},"hgnc":{"alias_symbol":["GKTA"],"prev_symbol":["GKP2"]},"alphafold":{"accession":"Q14410","domains":[{"cath_id":"3.30.420.40","chopping":"11-267_451-482","consensus_level":"medium","plddt":94.8033,"start":11,"end":482},{"cath_id":"3.30.420.40","chopping":"319-449_485-509","consensus_level":"medium","plddt":93.3081,"start":319,"end":509}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14410","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14410-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14410-F1-predicted_aligned_error_v6.png","plddt_mean":92.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GK2","jax_strain_url":"https://www.jax.org/strain/search?query=GK2"},"sequence":{"accession":"Q14410","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14410.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14410/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14410"}},"corpus_meta":[{"pmid":"1438294","id":"PMC_1438294","title":"Cloning of a human galactokinase gene (GK2) on chromosome 15 by complementation in yeast.","date":"1992","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1438294","citation_count":27,"is_preprint":false},{"pmid":"26289852","id":"PMC_26289852","title":"Identification of a panel of complex autoantigens (LGALS3, PHB2, MUC1, and GK2) in combination with CA15-3 for the diagnosis of early-stage breast cancer.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26289852","citation_count":16,"is_preprint":false},{"pmid":"24303204","id":"PMC_24303204","title":"Original Nerve Growth Factor Mimetic Dipeptide GK-2 Restores Impaired Cognitive Functions in Rat Models of Alzheimer's Disease.","date":"2013","source":"Acta naturae","url":"https://pubmed.ncbi.nlm.nih.gov/24303204","citation_count":16,"is_preprint":false},{"pmid":"24950445","id":"PMC_24950445","title":"Behavioral effect of dipeptide NGF mimetic GK-2 in an in vivo model of rat traumatic brain injury and its neuroprotective and regenerative properties in vitro.","date":"2014","source":"The International journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24950445","citation_count":12,"is_preprint":false},{"pmid":"7542884","id":"PMC_7542884","title":"Comparison of the enzymatic activities of human galactokinase GALK1 and a related human galactokinase protein GK2.","date":"1995","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/7542884","citation_count":5,"is_preprint":false},{"pmid":"31024748","id":"PMC_31024748","title":"A Novel Dipeptide NGF Mimetic GK-2 Selectively Activating the PI3K/AKT Signaling Pathway Promotes the Survival of Pancreatic β-Cells in a Rat Model of Diabetes.","date":"2019","source":"Acta naturae","url":"https://pubmed.ncbi.nlm.nih.gov/31024748","citation_count":5,"is_preprint":false},{"pmid":"26388581","id":"PMC_26388581","title":"Effectiveness of GK-2, a Nerve Growth Factor Mimetic, in Preventing Post-Resuscitation Changes in the Brain.","date":"2015","source":"Bulletin of experimental biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26388581","citation_count":4,"is_preprint":false},{"pmid":"36688733","id":"PMC_36688733","title":"Protective effect of GK2 fused BLVRA protein against oxidative stress-induced dopaminergic neuronal cell damage.","date":"2023","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/36688733","citation_count":1,"is_preprint":false},{"pmid":"41207346","id":"PMC_41207346","title":"Pharmacokinetics, tissue distribution, in vivo metabolism and liver microsomal metabolism of GK-A, GK-2 and Eucomic acid in rats were studied by liquid chromatography-tandem mass spectrometry and mass spectrometry imaging of Ginkgo semen extract.","date":"2025","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41207346","citation_count":1,"is_preprint":false},{"pmid":"35748804","id":"PMC_35748804","title":"Low molecular weight NGF mimetic GK-2 normalizes the parameters of glucose and lipid metabolism and exhibits a hepatoprotective effect on a prediabetes model in obese Wistar rats.","date":"2022","source":"Clinical and experimental pharmacology & physiology","url":"https://pubmed.ncbi.nlm.nih.gov/35748804","citation_count":1,"is_preprint":false},{"pmid":"21395008","id":"PMC_21395008","title":"[Neuroprotective effect of low-molecular peptide mimetic (GK-2) of nerve growth factor is related to activated synthesis of heat shock proteins (hsp32 and hsp70) and increased phosphorylation of TrkA receptor].","date":"2010","source":"Eksperimental'naia i klinicheskaia farmakologiia","url":"https://pubmed.ncbi.nlm.nih.gov/21395008","citation_count":1,"is_preprint":false},{"pmid":"26571801","id":"PMC_26571801","title":"[Effect of the nerve growth factor mimetic GK-2 on post-resuscitation expression of neurotrophic factors].","date":"2015","source":"Patologicheskaia fiziologiia i eksperimental'naia terapiia","url":"https://pubmed.ncbi.nlm.nih.gov/26571801","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7726,"output_tokens":948,"usd":0.018699,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6986,"output_tokens":1124,"usd":0.031515,"stage2_stop_reason":"end_turn"},"total_usd":0.050214,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the papers, I need to classify each one:\n\n- Papers [3,4,6,7,10,11,12]: These describe \"GK-2\" as a dipeptide NGF mimetic (hexamethylenediamide bis-(N-monosuccinyl-glutamyl-lysine)) — this is a small molecule drug, NOT the GK2 gene/protein.\n- Paper [9]: \"GK-2\" here is N-[2-(1-β-D-Glucopyranosyl-1H-indol-3-yl)acetyl]-L-glutamic acid from Ginkgo Semen — a plant compound, not the gene.\n- Paper [2]: Uses GK2 as an autoantigen biomarker — no mechanistic data about the protein itself.\n- Paper [8]: Uses \"GK2\" as a protein transduction domain derived from adenosine A2A receptor — this appears to be a different protein/domain, not the galactokinase GK2 gene.\n- Papers [1,5]: These are directly about GK2 (galactokinase 2, also known as GKTA/GKP2), the canonical gene in question.\n\nOnly papers [1] and [5] describe the canonical GK2 gene protein mechanistically.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"A human GK2 cDNA encoding a predicted 458-amino-acid protein was isolated by functional complementation of a galactokinase-deficient (gal1−) Saccharomyces cerevisiae strain, establishing that GK2 encodes a galactokinase (EC 2.7.1.6) capable of substituting for yeast galactokinase in vivo. The GK2 gene was mapped to chromosome 15, distinct from the previously mapped GK1 locus on chromosome 17q23-25. The encoded protein shares 29% amino acid identity with S. carlsbergensis galactokinase.\",\n      \"method\": \"Yeast complementation of gal1− mutant with human cDNA library; chromosomal mapping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional complementation in yeast is a clean genetic epistasis assay; single lab but complementation is a direct functional test\",\n      \"pmids\": [\"1438294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"When GK2 cDNA was expressed in COS cells alongside GALK1 cDNA, only GALK1 produced high levels of galactokinase activity; GK2-transfected cells showed no detectable galactokinase activity above background, despite confirmed mRNA expression by Northern blot. This demonstrates that GK2 does not function as a galactokinase in mammalian cells under these conditions, leaving its biochemical role uncertain.\",\n      \"method\": \"Transient expression in COS cells with galactokinase enzymatic activity assay; Northern blot confirmation of mRNA expression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct enzymatic activity assay with mRNA expression control, single lab; result is a clear negative finding in mammalian cells\",\n      \"pmids\": [\"7542884\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GK2 encodes a predicted 458-amino-acid protein that can functionally substitute for galactokinase in yeast complementation assays, but when expressed in mammalian (COS) cells it produces no detectable galactokinase activity, leaving its enzymatic function and physiological role in mammals uncertain.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GK2 was identified as a candidate galactokinase through its ability to functionally complement a galactokinase-deficient (gal1\\u2212) yeast strain, restoring in vivo galactokinase activity and indicating that the encoded 458-amino-acid protein can substitute for yeast galactokinase [#0]. However, when expressed in mammalian COS cells, GK2 produced no detectable galactokinase activity despite confirmed mRNA expression, while a control galactokinase construct was active under the same conditions [#1]. The enzymatic function and physiological role of GK2 in mammalian cells therefore remain uncharacterized in the available corpus; beyond the yeast complementation and the negative mammalian activity assay, no substrate, interacting partner, localization, or pathway role has been established.\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Whether the GK2 gene product had any galactokinase function was unknown; isolating the cDNA by rescuing a galactokinase-deficient yeast strain established that GK2 can functionally substitute for galactokinase in vivo and is genetically distinct from GK1.\",\n      \"evidence\": \"Yeast complementation of gal1\\u2212 mutant with human cDNA library plus chromosomal mapping\",\n      \"pmids\": [\n        \"1438294\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Complementation in yeast does not demonstrate galactokinase activity in mammalian cells\",\n        \"No direct biochemical measurement of enzyme kinetics or substrate specificity\",\n        \"Physiological role and tissue context in humans not addressed\"\n      ]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Whether GK2 acts as a galactokinase in a mammalian setting was tested directly; expression in COS cells yielded no detectable galactokinase activity despite confirmed transcription, showing GK2 does not function as a galactokinase under these conditions and leaving its biochemical role unresolved.\",\n      \"evidence\": \"Transient expression in COS cells with galactokinase enzymatic activity assay and Northern blot mRNA confirmation\",\n      \"pmids\": [\n        \"7542884\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Negative result may reflect missing cofactors, post-translational modification, or improper folding in COS cells rather than absence of intrinsic activity\",\n        \"No alternative substrate tested\",\n        \"Endogenous tissue-specific expression and function not examined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The native enzymatic activity, true substrate, subcellular localization, and physiological function of mammalian GK2 remain undefined.\",\n      \"evidence\": \"No further mechanistic studies present in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No purified-protein biochemistry to define catalytic activity or kinetics\",\n        \"No identified physical partners or pathway placement\",\n        \"No in vivo or knockout phenotype data\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":2,"faith_total":2,"faith_pct":100.0}}