{"gene":"GK","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":1999,"finding":"A founder missense mutation in GK1 (P28T), replacing a conserved proline at position 28 with threonine, causes galactokinase deficiency in Roma (Gypsies). Genetic linkage mapping placed the disease locus on chromosome 17q, radiation hybrid mapping confirmed GK1 resides in this region, and haplotype analysis identified a small conserved region of homozygosity around GK1 in affected individuals. The P28T variant is the causative allele responsible for the first step of galactose metabolism being defective, leading to cataract formation in early childhood.","method":"Genetic linkage mapping, radiation hybrid mapping, haplotype analysis, identification of causative point mutation in GK1","journal":"American Journal of Human Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic mapping and mutation identification in a single study; no in vitro enzymatic reconstitution of P28T activity reported in this abstract","pmids":["10521295"],"is_preprint":false}],"current_model":"GK (galactokinase 1) catalyzes the first step of galactose metabolism; loss-of-function mutations such as the founder P28T substitution in Roma populations abolish this activity and cause galactokinase deficiency manifesting as early-onset cataracts."},"narrative":{"mechanistic_narrative":"GK is required for the first step of galactose metabolism, and its loss causes galactokinase deficiency [PMID:10521295]. A founder missense mutation in GK1 (P28T), replacing a conserved proline at position 28 with threonine, was mapped to chromosome 17q in Roma (Gypsy) families and identified as the causative allele underlying early-childhood cataract formation [PMID:10521295]. Beyond this genetic mapping and mutation identification, no further mechanistic detail—including in vitro enzymatic characterization of the variant—has been characterized in the available corpus.","teleology":[{"year":1999,"claim":"Establishing the genetic basis of galactokinase deficiency answered which gene and which lesion abolish the first step of galactose metabolism in an affected population.","evidence":"Genetic linkage mapping to chromosome 17q, radiation hybrid mapping, and haplotype analysis identifying the P28T founder mutation in Roma families","pmids":["10521295"],"confidence":"Medium","gaps":["No in vitro enzymatic reconstitution confirming that P28T abolishes galactokinase catalytic activity","Structural consequence of the P28 proline substitution not determined","Mechanism linking enzyme loss to cataract formation not directly tested"]},{"year":null,"claim":"How the P28T substitution disrupts the enzyme at the biochemical and structural level, and how loss of galactose phosphorylation mechanistically drives cataractogenesis, remains unresolved in the available corpus.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No enzymatic kinetics for wild-type or mutant protein in the corpus","No structural model of the substrate-binding region affected by P28","No cellular or tissue-level mechanism connecting metabolite accumulation to lens pathology"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P32189","full_name":"Glycerol kinase","aliases":["ATP:glycerol 3-phosphotransferase"],"length_aa":559,"mass_kda":61.2,"function":"Kinase that plays a key role in glycerol metabolism, catalyzing its phosphorylation to produce sn-glycerol 3-phosphate. Sn-glycerol 3-phosphate is a crucial intermediate in various metabolic pathways, such as the synthesis of glycerolipids and triglycerides, glycogenesis, glycolysis and gluconeogenesis","subcellular_location":"Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/P32189/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GK","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":383,"dependency_fraction":0.0026109660574412533},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GK","total_profiled":1310},"omim":[{"mim_id":"620801","title":"GLYCEROL KINASE 5; GK5","url":"https://www.omim.org/entry/620801"},{"mim_id":"620009","title":"KERATODERMA-ICHTHYOSIS-DEAFNESS SYNDROME, AUTOSOMAL RECESSIVE; KDIDAR","url":"https://www.omim.org/entry/620009"},{"mim_id":"619546","title":"OLFACTORY RECEPTOR, FAMILY 10, SUBFAMILY J, MEMBER 5; OR10J5","url":"https://www.omim.org/entry/619546"},{"mim_id":"619182","title":"GASTRIC ADENOCARCINOMA AND PROXIMAL POLYPOSIS OF THE STOMACH; GAPPS","url":"https://www.omim.org/entry/619182"},{"mim_id":"619116","title":"SOLUTE CARRIER FAMILY 39 (ZINC TRANSPORTER), MEMBER 9; SLC39A9","url":"https://www.omim.org/entry/619116"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"intestine","ntpm":82.3},{"tissue":"kidney","ntpm":98.4},{"tissue":"liver","ntpm":66.9}],"url":"https://www.proteinatlas.org/search/GK"},"hgnc":{"alias_symbol":["GK1","GKD"],"prev_symbol":[]},"alphafold":{"accession":"P32189","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P32189","model_url":"https://alphafold.ebi.ac.uk/files/AF-P32189-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P32189-F1-predicted_aligned_error_v6.png","plddt_mean":91.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GK","jax_strain_url":"https://www.jax.org/strain/search?query=GK"},"sequence":{"accession":"P32189","fasta_url":"https://rest.uniprot.org/uniprotkb/P32189.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P32189/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P32189"}},"corpus_meta":[{"pmid":"6415170","id":"PMC_6415170","title":"Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK1.5: similarity of L3T4 to the human Leu-3/T4 molecule.","date":"1983","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/6415170","citation_count":1726,"is_preprint":false},{"pmid":"6195085","id":"PMC_6195085","title":"Characterization of the murine antigenic determinant, designated L3T4a, recognized by monoclonal antibody GK1.5: expression of L3T4a by functional T cell clones appears to correlate primarily with class II MHC antigen-reactivity.","date":"1983","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/6195085","citation_count":1488,"is_preprint":false},{"pmid":"6195255","id":"PMC_6195255","title":"Evidence implicating L3T4 in class II MHC antigen reactivity; monoclonal antibody GK1.5 (anti-L3T4a) blocks class II MHC antigen-specific proliferation, release of lymphokines, and binding by cloned murine helper T lymphocyte lines.","date":"1983","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/6195255","citation_count":514,"is_preprint":false},{"pmid":"6195289","id":"PMC_6195289","title":"Precursors of T cell growth factor producing cells in the thymus: ontogeny, frequency, and quantitative recovery in a subpopulation of phenotypically mature thymocytes defined by monoclonal antibody GK-1.5.","date":"1983","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/6195289","citation_count":292,"is_preprint":false},{"pmid":"19666548","id":"PMC_19666548","title":"IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19666548","citation_count":281,"is_preprint":false},{"pmid":"2010050","id":"PMC_2010050","title":"Beta-cell insensitivity to glucose in the GK rat, a spontaneous nonobese model for type II diabetes.","date":"1991","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/2010050","citation_count":263,"is_preprint":false},{"pmid":"2456451","id":"PMC_2456451","title":"Reconstitution of somatostatin and muscarinic receptor mediated stimulation of K+ channels by isolated GK protein in clonal rat anterior pituitary cell membranes.","date":"1987","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/2456451","citation_count":176,"is_preprint":false},{"pmid":"16731824","id":"PMC_16731824","title":"Islet inflammation and fibrosis in a spontaneous model of type 2 diabetes, the GK rat.","date":"2006","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/16731824","citation_count":174,"is_preprint":false},{"pmid":"10580425","id":"PMC_10580425","title":"Decreased expression of t-SNARE, syntaxin 1, and SNAP-25 in pancreatic beta-cells is involved in impaired insulin secretion from diabetic GK rat islets: restoration of decreased t-SNARE proteins improves impaired insulin secretion.","date":"1999","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/10580425","citation_count":151,"is_preprint":false},{"pmid":"10958757","id":"PMC_10958757","title":"Insulin-degrading enzyme identified as a candidate diabetes susceptibility gene in GK rats.","date":"2000","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10958757","citation_count":132,"is_preprint":false},{"pmid":"8826977","id":"PMC_8826977","title":"Chronic activation of protein kinase C in soleus muscles and other tissues of insulin-resistant type II diabetic Goto-Kakizaki (GK), obese/aged, and obese/Zucker rats. A mechanism for inhibiting glycogen synthesis.","date":"1996","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/8826977","citation_count":126,"is_preprint":false},{"pmid":"1323714","id":"PMC_1323714","title":"Identification and characterization of a novel herpes simplex virus glycoprotein, gK, involved in cell fusion.","date":"1992","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/1323714","citation_count":125,"is_preprint":false},{"pmid":"1970911","id":"PMC_1970911","title":"Effect of GK1.5 monoclonal antibody dosage on survival of pig proislet xenografts in CD4+ T cell-depleted mice.","date":"1990","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/1970911","citation_count":124,"is_preprint":false},{"pmid":"2850027","id":"PMC_2850027","title":"Stimulation of cardiac alpha receptors increases Na/K pump current and decreases gK via a pertussis toxin-sensitive pathway.","date":"1988","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/2850027","citation_count":116,"is_preprint":false},{"pmid":"8238507","id":"PMC_8238507","title":"Insulin resistance in the GK rat: decreased receptor number but normal kinase activity in liver.","date":"1993","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/8238507","citation_count":111,"is_preprint":false},{"pmid":"15926190","id":"PMC_15926190","title":"Programmed disorders of beta-cell development and function as one cause for type 2 diabetes? The GK rat paradigm.","date":"2005","source":"Diabetes/metabolism research and reviews","url":"https://pubmed.ncbi.nlm.nih.gov/15926190","citation_count":104,"is_preprint":false},{"pmid":"18640239","id":"PMC_18640239","title":"The GK rat beta-cell: a prototype for the diseased human beta-cell in type 2 diabetes?","date":"2008","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/18640239","citation_count":102,"is_preprint":false},{"pmid":"12469361","id":"PMC_12469361","title":"Impaired glucose tolerance and insulinopenia in the GK-rat causes peripheral neuropathy.","date":"2002","source":"Diabetes/metabolism research and reviews","url":"https://pubmed.ncbi.nlm.nih.gov/12469361","citation_count":100,"is_preprint":false},{"pmid":"21820301","id":"PMC_21820301","title":"Enhanced autophagy plays a cardinal role in mitochondrial dysfunction in type 2 diabetic Goto-Kakizaki (GK) rats: ameliorating effects of (-)-epigallocatechin-3-gallate.","date":"2011","source":"The Journal of nutritional biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21820301","citation_count":92,"is_preprint":false},{"pmid":"22893405","id":"PMC_22893405","title":"The GK rat: a prototype for the study of non-overweight type 2 diabetes.","date":"2012","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/22893405","citation_count":90,"is_preprint":false},{"pmid":"21304061","id":"PMC_21304061","title":"Duodenal-jejunal bypass protects GK rats from {beta}-cell loss and aggravation of hyperglycemia and increases enteroendocrine cells coexpressing GIP and GLP-1.","date":"2011","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/21304061","citation_count":88,"is_preprint":false},{"pmid":"8513973","id":"PMC_8513973","title":"GLUT2 expression and function in beta-cells of GK rats with NIDDM. Dissociation between reductions in glucose transport and glucose-stimulated insulin secretion.","date":"1993","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/8513973","citation_count":81,"is_preprint":false},{"pmid":"1607851","id":"PMC_1607851","title":"Effects of anions on the G protein-mediated activation of the muscarinic K+ channel in the cardiac atrial cell membrane. Intracellular chloride inhibition of the GTPase activity of GK.","date":"1992","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/1607851","citation_count":75,"is_preprint":false},{"pmid":"8288052","id":"PMC_8288052","title":"Impact of diabetic inheritance on glucose tolerance and insulin secretion in spontaneously diabetic GK-Wistar rats.","date":"1994","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/8288052","citation_count":74,"is_preprint":false},{"pmid":"11272210","id":"PMC_11272210","title":"beta-cell function and viability in the spontaneously diabetic GK rat: information from the GK/Par colony.","date":"2001","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/11272210","citation_count":73,"is_preprint":false},{"pmid":"2859929","id":"PMC_2859929","title":"In vivo effects of GK1.5 (anti-L3T4a) monoclonal antibody on induction and expression of delayed-type hypersensitivity.","date":"1985","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/2859929","citation_count":71,"is_preprint":false},{"pmid":"25385611","id":"PMC_25385611","title":"Structure of Crumbs tail in complex with the PALS1 PDZ-SH3-GK tandem reveals a highly specific assembly mechanism for the apical Crumbs complex.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25385611","citation_count":71,"is_preprint":false},{"pmid":"10078575","id":"PMC_10078575","title":"Muscle fiber type-specific defects in insulin signal transduction to glucose transport in diabetic GK rats.","date":"1999","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/10078575","citation_count":65,"is_preprint":false},{"pmid":"15066267","id":"PMC_15066267","title":"Calcium channel function regulated by the SH3-GK module in beta subunits.","date":"2004","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/15066267","citation_count":64,"is_preprint":false},{"pmid":"10521295","id":"PMC_10521295","title":"A founder mutation in the GK1 gene is responsible for galactokinase deficiency in Roma (Gypsies).","date":"1999","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10521295","citation_count":61,"is_preprint":false},{"pmid":"12477855","id":"PMC_12477855","title":"Plasma membrane topology of syncytial domains of herpes simplex virus type 1 glycoprotein K (gK): the UL20 protein enables cell surface localization of gK but not gK-mediated cell-to-cell fusion.","date":"2003","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/12477855","citation_count":57,"is_preprint":false},{"pmid":"11866470","id":"PMC_11866470","title":"Down-regulated expression of exocytotic proteins in pancreatic islets of diabetic GK rats.","date":"2002","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11866470","citation_count":57,"is_preprint":false},{"pmid":"7716139","id":"PMC_7716139","title":"Preserved beta-cell density in the endocrine pancreas of young, spontaneously diabetic Goto-Kakizaki (GK) rats.","date":"1995","source":"Pancreas","url":"https://pubmed.ncbi.nlm.nih.gov/7716139","citation_count":56,"is_preprint":false},{"pmid":"9499048","id":"PMC_9499048","title":"Pseudorabies virus glycoprotein gK is a virion structural component involved in virus release but is not required for entry.","date":"1998","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/9499048","citation_count":53,"is_preprint":false},{"pmid":"8586154","id":"PMC_8586154","title":"Beta-cell mass depletion precedes the onset of hyperglycaemia in the GK rat, a genetic model of non-insulin-dependent diabetes mellitus.","date":"1995","source":"Diabete & metabolisme","url":"https://pubmed.ncbi.nlm.nih.gov/8586154","citation_count":53,"is_preprint":false},{"pmid":"9519762","id":"PMC_9519762","title":"Mutations in the promoter of adenylyl cyclase (AC)-III gene, overexpression of AC-III mRNA, and enhanced cAMP generation in islets from the spontaneously diabetic GK rat model of type 2 diabetes.","date":"1998","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/9519762","citation_count":52,"is_preprint":false},{"pmid":"15596825","id":"PMC_15596825","title":"Herpes simplex virus type 1 gK is required for gB-mediated virus-induced cell fusion, while neither gB and gK nor gB and UL20p function redundantly in virion de-envelopment.","date":"2005","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/15596825","citation_count":51,"is_preprint":false},{"pmid":"9456079","id":"PMC_9456079","title":"Nerve agent poisoning in primates: antilethal, anti-epileptic and neuroprotective effects of GK-11.","date":"1998","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/9456079","citation_count":51,"is_preprint":false},{"pmid":"20573833","id":"PMC_20573833","title":"The herpes simplex virus type 1 UL20 protein and the amino terminus of glycoprotein K (gK) physically interact with gB.","date":"2010","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/20573833","citation_count":49,"is_preprint":false},{"pmid":"16438951","id":"PMC_16438951","title":"The nitric oxide-cyclic GMP-protein kinase G-K+ channel pathway participates in the antiallodynic effect of spinal gabapentin.","date":"2006","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/16438951","citation_count":46,"is_preprint":false},{"pmid":"16630650","id":"PMC_16630650","title":"Possible activation of the NO-cyclic GMP-protein kinase G-K+ channels pathway by gabapentin on the formalin test.","date":"2006","source":"Pharmacology, biochemistry, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/16630650","citation_count":46,"is_preprint":false},{"pmid":"19499150","id":"PMC_19499150","title":"MicroRNA expression profiling in diabetic GK rat model.","date":"2009","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/19499150","citation_count":45,"is_preprint":false},{"pmid":"32039235","id":"PMC_32039235","title":"Characterizing the Binding Sites for GK Domain of DLG1 and DLG4 via Molecular Dynamics Simulation.","date":"2020","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/32039235","citation_count":45,"is_preprint":false},{"pmid":"17986628","id":"PMC_17986628","title":"Follow-up of GK rats during prediabetes highlights increased insulin action and fat deposition despite low insulin secretion.","date":"2007","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/17986628","citation_count":45,"is_preprint":false},{"pmid":"24600000","id":"PMC_24600000","title":"Herpes simplex virus 1 protein UL37 interacts with viral glycoprotein gK and membrane protein UL20 and functions in cytoplasmic virion envelopment.","date":"2014","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/24600000","citation_count":44,"is_preprint":false},{"pmid":"10619846","id":"PMC_10619846","title":"Anchoring proteins confer G protein sensitivity to an inward-rectifier K(+) channel through the GK domain.","date":"2000","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/10619846","citation_count":44,"is_preprint":false},{"pmid":"10455021","id":"PMC_10455021","title":"Cell-biological assessment of human glucokinase mutants causing maturity-onset diabetes of the young type 2 (MODY-2) or glucokinase-linked hyperinsulinaemia (GK-HI).","date":"1999","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/10455021","citation_count":42,"is_preprint":false},{"pmid":"19168902","id":"PMC_19168902","title":"The role of a glycoprotein K (gK) CD8+ T-cell epitope of herpes simplex virus on virus replication and pathogenicity.","date":"2009","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/19168902","citation_count":42,"is_preprint":false},{"pmid":"9421377","id":"PMC_9421377","title":"Electrophysiological and metabolic characterization of single beta-cells and islets from diabetic GK rats.","date":"1998","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/9421377","citation_count":41,"is_preprint":false},{"pmid":"9466985","id":"PMC_9466985","title":"Impaired pancreatic beta cell function in the fetal GK rat. Impact of diabetic inheritance.","date":"1998","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/9466985","citation_count":41,"is_preprint":false},{"pmid":"7628391","id":"PMC_7628391","title":"Deficiency of pyruvate dehydrogenase activity in pancreatic islets of diabetic GK rats.","date":"1995","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/7628391","citation_count":41,"is_preprint":false},{"pmid":"15254173","id":"PMC_15254173","title":"Coexpression of UL20p and gK inhibits cell-cell fusion mediated by herpes simplex virus glycoproteins gD, gH-gL, and wild-type gB or an endocytosis-defective gB mutant and downmodulates their cell surface expression.","date":"2004","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/15254173","citation_count":40,"is_preprint":false},{"pmid":"7539027","id":"PMC_7539027","title":"Differences in the degree of depletion, rate of recovery, and the preferential elimination of naive CD4+ T cells by anti-CD4 monoclonal antibody (GK1.5) in young and aged mice.","date":"1995","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/7539027","citation_count":38,"is_preprint":false},{"pmid":"17919193","id":"PMC_17919193","title":"Type 2 diabetes - a matter of failing beta-cell neogenesis? Clues from the GK rat model.","date":"2007","source":"Diabetes, obesity & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/17919193","citation_count":36,"is_preprint":false},{"pmid":"19793812","id":"PMC_19793812","title":"The amino terminus of herpes simplex virus type 1 glycoprotein K (gK) modulates gB-mediated virus-induced cell fusion and virion egress.","date":"2009","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/19793812","citation_count":36,"is_preprint":false},{"pmid":"26775142","id":"PMC_26775142","title":"Cardiac Purkinje fibers and arrhythmias; The GK Moe Award Lecture 2015.","date":"2016","source":"Heart rhythm","url":"https://pubmed.ncbi.nlm.nih.gov/26775142","citation_count":36,"is_preprint":false},{"pmid":"2126802","id":"PMC_2126802","title":"Carbachol increases basolateral K+ conductance in T84 cells. Simultaneous measurements of cell [Ca] and gK explore calcium's role.","date":"1990","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/2126802","citation_count":36,"is_preprint":false},{"pmid":"29138001","id":"PMC_29138001","title":"PDZ Ligand Binding-Induced Conformational Coupling of the PDZ-SH3-GK Tandems in PSD-95 Family MAGUKs.","date":"2017","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/29138001","citation_count":35,"is_preprint":false},{"pmid":"18588279","id":"PMC_18588279","title":"SAR, pharmacokinetics, safety, and efficacy of glucokinase activating 2-(4-sulfonylphenyl)-N-thiazol-2-ylacetamides: discovery of PSN-GK1.","date":"2008","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18588279","citation_count":34,"is_preprint":false},{"pmid":"10766260","id":"PMC_10766260","title":"Adenylyl cyclase isoform expression in non-diabetic and diabetic Goto-Kakizaki (GK) rat pancreas. Evidence for distinct overexpression of type-8 adenylyl cyclase in diabetic GK rat islets.","date":"2000","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10766260","citation_count":33,"is_preprint":false},{"pmid":"1538121","id":"PMC_1538121","title":"Comparison of GK1.5 and chimeric rat/mouse GK1.5 anti-CD4 antibodies for prolongation of skin allograft survival and suppression of alloantibody production in mice.","date":"1992","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/1538121","citation_count":31,"is_preprint":false},{"pmid":"25746217","id":"PMC_25746217","title":"HSV-1 gM and the gK/pUL20 complex are important for the localization of gD and gH/L to viral assembly sites.","date":"2015","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/25746217","citation_count":31,"is_preprint":false},{"pmid":"24401006","id":"PMC_24401006","title":"A replication competent HSV-1(McKrae) with a mutation in the amino-terminus of glycoprotein K (gK) is unable to infect mouse trigeminal ganglia after cornea infection.","date":"2014","source":"Current eye research","url":"https://pubmed.ncbi.nlm.nih.gov/24401006","citation_count":31,"is_preprint":false},{"pmid":"8846809","id":"PMC_8846809","title":"The anti-emetic activity of GK-128 in Suncus murinus.","date":"1995","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/8846809","citation_count":30,"is_preprint":false},{"pmid":"34578430","id":"PMC_34578430","title":"Two Sides to Every Story: Herpes Simplex Type-1 Viral Glycoproteins gB, gD, gH/gL, gK, and Cellular Receptors Function as Key Players in Membrane Fusion.","date":"2021","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/34578430","citation_count":30,"is_preprint":false},{"pmid":"32840364","id":"PMC_32840364","title":"Monacycliones G-K and ent-Gephyromycin A, Angucycline Derivatives from the Marine-Derived Streptomyces sp. HDN15129.","date":"2020","source":"Journal of natural products","url":"https://pubmed.ncbi.nlm.nih.gov/32840364","citation_count":30,"is_preprint":false},{"pmid":"18236074","id":"PMC_18236074","title":"Augmented beta cell loss and mitochondrial abnormalities in sucrose-fed GK rats.","date":"2008","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/18236074","citation_count":29,"is_preprint":false},{"pmid":"8227012","id":"PMC_8227012","title":"GK* and brain G beta gamma activate muscarinic K+ channel through the same mechanism.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8227012","citation_count":29,"is_preprint":false},{"pmid":"24465545","id":"PMC_24465545","title":"Binding of HSV-1 glycoprotein K (gK) to signal peptide peptidase (SPP) is required for virus infectivity.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24465545","citation_count":29,"is_preprint":false},{"pmid":"30581441","id":"PMC_30581441","title":"Role of Herpes Simplex Virus Type 1 (HSV-1) Glycoprotein K (gK) Pathogenic CD8+ T Cells in Exacerbation of Eye Disease.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30581441","citation_count":28,"is_preprint":false},{"pmid":"26827782","id":"PMC_26827782","title":"Phycocyanin ameliorates alloxan-induced diabetes mellitus in mice: Involved in insulin signaling pathway and GK expression.","date":"2016","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/26827782","citation_count":28,"is_preprint":false},{"pmid":"12405965","id":"PMC_12405965","title":"Synaptic glutamate receptor clustering in mice lacking the SH3 and GK domains of SAP97.","date":"2002","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/12405965","citation_count":27,"is_preprint":false},{"pmid":"38461723","id":"PMC_38461723","title":"(-)-Epicatechin ameliorates type 2 diabetes mellitus by reshaping the gut microbiota and Gut-Liver axis in GK rats.","date":"2024","source":"Food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38461723","citation_count":27,"is_preprint":false},{"pmid":"20217511","id":"PMC_20217511","title":"Islet structure and function in the GK rat.","date":"2010","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/20217511","citation_count":26,"is_preprint":false},{"pmid":"7794109","id":"PMC_7794109","title":"ICP27 immediate early gene, glycoprotein K (gK) and DNA helicase homologues of infectious laryngotracheitis virus (gallid herpesvirus 1) SA-2 strain.","date":"1995","source":"Archives of virology","url":"https://pubmed.ncbi.nlm.nih.gov/7794109","citation_count":26,"is_preprint":false},{"pmid":"17499382","id":"PMC_17499382","title":"Epitope mapping of HSV-1 glycoprotein K (gK) reveals a T cell epitope located within the signal domain of gK.","date":"2007","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/17499382","citation_count":26,"is_preprint":false},{"pmid":"7669044","id":"PMC_7669044","title":"Expression of CD38 gene, but not of mitochondrial glycerol-3-phosphate dehydrogenase gene, is impaired in pancreatic islets of GK rats.","date":"1995","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/7669044","citation_count":26,"is_preprint":false},{"pmid":"27642159","id":"PMC_27642159","title":"An Atypical MAGUK GK Target Recognition Mode Revealed by the Interaction between DLG and KIF13B.","date":"2016","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/27642159","citation_count":26,"is_preprint":false},{"pmid":"9026441","id":"PMC_9026441","title":"Purification and biochemical characterization of pullulanase type I from Thermus caldophilus GK-24.","date":"1996","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/9026441","citation_count":26,"is_preprint":false},{"pmid":"28890195","id":"PMC_28890195","title":"GK-1 peptide reduces tumor growth, decreases metastatic burden, and increases survival in a murine breast cancer model.","date":"2017","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/28890195","citation_count":25,"is_preprint":false},{"pmid":"24568320","id":"PMC_24568320","title":"Analysis of the co-operative interaction between the allosterically regulated proteins GK and GKRP using tryptophan fluorescence.","date":"2014","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/24568320","citation_count":25,"is_preprint":false},{"pmid":"19084046","id":"PMC_19084046","title":"Pref-1 and adipokine expression in adipose tissues of GK and Zucker rats.","date":"2008","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/19084046","citation_count":24,"is_preprint":false},{"pmid":"19605594","id":"PMC_19605594","title":"Towards identification of the mechanisms of action of parasite-derived peptide GK1 on the immunogenicity of an influenza vaccine.","date":"2009","source":"Clinical and vaccine immunology : CVI","url":"https://pubmed.ncbi.nlm.nih.gov/19605594","citation_count":24,"is_preprint":false},{"pmid":"34130073","id":"PMC_34130073","title":"The antidepressant-like effects of Danggui Buxue Decoction in GK rats by activating CREB/BDNF/TrkB signaling pathway.","date":"2021","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34130073","citation_count":23,"is_preprint":false},{"pmid":"16249449","id":"PMC_16249449","title":"Restitution of defective glucose-stimulated insulin secretion in diabetic GK rat by acetylcholine uncovers paradoxical stimulatory effect of beta-cell muscarinic receptor activation on cAMP production.","date":"2005","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/16249449","citation_count":23,"is_preprint":false},{"pmid":"25324018","id":"PMC_25324018","title":"Molecular targeting of the GK-GKRP pathway in diabetes.","date":"2014","source":"Expert opinion on therapeutic targets","url":"https://pubmed.ncbi.nlm.nih.gov/25324018","citation_count":22,"is_preprint":false},{"pmid":"14698663","id":"PMC_14698663","title":"Overexpression of gK in gK-transformed cells collapses the Golgi apparatus into the endoplasmic reticulum inhibiting virion egress, glycoprotein transport, and virus-induced cell fusion.","date":"2003","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/14698663","citation_count":22,"is_preprint":false},{"pmid":"24165088","id":"PMC_24165088","title":"Single dose of glycoprotein K (gK)-deleted HSV-1 live-attenuated virus protects mice against lethal vaginal challenge with HSV-1 and HSV-2 and induces lasting T cell memory immune responses.","date":"2013","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/24165088","citation_count":22,"is_preprint":false},{"pmid":"21750265","id":"PMC_21750265","title":"cAMP-secretion coupling is impaired in diabetic GK/Par rat β-cells: a defect counteracted by GLP-1.","date":"2011","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/21750265","citation_count":22,"is_preprint":false},{"pmid":"18662725","id":"PMC_18662725","title":"Impaired glucose-stimulated insulin secretion in the GK rat is associated with abnormalities in islet nitric oxide production.","date":"2008","source":"Regulatory peptides","url":"https://pubmed.ncbi.nlm.nih.gov/18662725","citation_count":22,"is_preprint":false},{"pmid":"26551034","id":"PMC_26551034","title":"Discovery and Structure-Guided Optimization of Diarylmethanesulfonamide Disrupters of Glucokinase-Glucokinase Regulatory Protein (GK-GKRP) Binding: Strategic Use of a N → S (nN → σ*S-X) Interaction for Conformational Constraint.","date":"2015","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26551034","citation_count":22,"is_preprint":false},{"pmid":"9662045","id":"PMC_9662045","title":"Overexpression of mitochondrial FAD-linked glycerol-3-phosphate dehydrogenase does not correct glucose-stimulated insulin secretion from diabetic GK rat pancreatic islets.","date":"1998","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/9662045","citation_count":22,"is_preprint":false},{"pmid":"30535697","id":"PMC_30535697","title":"Characterization of the Goto-Kakizaki (GK) Rat Model of Type 2 Diabetes.","date":"2019","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/30535697","citation_count":22,"is_preprint":false},{"pmid":"36145681","id":"PMC_36145681","title":"Antibacterial and Antifungal Properties of a Novel Antimicrobial Peptide GK-19 and Its Application in Skin and Soft Tissue Infections Induced by MRSA or Candida albicans.","date":"2022","source":"Pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/36145681","citation_count":21,"is_preprint":false},{"pmid":"26202354","id":"PMC_26202354","title":"Enhanced Glucose Tolerance and Pancreatic Beta Cell Function by Low Dose Aspirin in Hyperglycemic Insulin-Resistant Type 2 Diabetic Goto-Kakizaki (GK) Rats.","date":"2015","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26202354","citation_count":21,"is_preprint":false},{"pmid":"17996071","id":"PMC_17996071","title":"The herpes simplex virus UL20 protein functions in glycoprotein K (gK) intracellular transport and virus-induced cell fusion are independent of UL20 functions in cytoplasmic virion envelopment.","date":"2007","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/17996071","citation_count":20,"is_preprint":false},{"pmid":"29636010","id":"PMC_29636010","title":"Metformin restores electrophysiology of small conductance calcium-activated potassium channels in the atrium of GK diabetic rats.","date":"2018","source":"BMC cardiovascular disorders","url":"https://pubmed.ncbi.nlm.nih.gov/29636010","citation_count":20,"is_preprint":false},{"pmid":"35433833","id":"PMC_35433833","title":"Application of per-Residue Energy Decomposition to Design Peptide Inhibitors of PSD95 GK Domain.","date":"2022","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/35433833","citation_count":19,"is_preprint":false},{"pmid":"10579319","id":"PMC_10579319","title":"Metabolic and secretory interactions between D-glucose and D-fructose in islets from GK rats.","date":"1999","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/10579319","citation_count":19,"is_preprint":false},{"pmid":"21593234","id":"PMC_21593234","title":"Heterologous prime-boost oral immunization with GK-1 peptide from Taenia crassiceps cysticerci induces protective immunity.","date":"2011","source":"Clinical and vaccine immunology : CVI","url":"https://pubmed.ncbi.nlm.nih.gov/21593234","citation_count":19,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":107628,"output_tokens":1649,"usd":0.262019,"retried_sync":true,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6606,"output_tokens":773,"usd":0.026177,"stage2_stop_reason":"end_turn"},"total_usd":0.288196,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the canonical human/mammalian gene GK (galactokinase, GK1/GKD). \n\nThe corpus contains many papers about different entities sharing the \"GK\" symbol:\n- GK1.5 monoclonal antibody (anti-CD4/L3T4) — not the GK gene\n- GK rat (Goto-Kakizaki rat model of diabetes) — not the GK gene\n- HSV glycoprotein gK — not the GK gene\n- GK domain of MAGUK proteins (guanylate kinase domain) — not the GK gene\n- GK (G protein activating K+ channel) — not the GK gene\n- GK peptide from Taenia crassiceps — not the GK gene\n- GK-11/GK-128 drugs — not the GK gene\n\nPapers that ARE about the canonical GK gene (galactokinase / GK1 / GKD):\n- PMID:10521295 — GK1 gene, galactokinase deficiency, founder mutation P28T in Roma\n- PMID:10455021 — glucokinase (GK) mutations causing MODY-2 and GK-HI (this is glucokinase/GCK, not galactokinase GK1)\n- PMID:24568320 — GK = glucokinase (GCK), not galactokinase\n- PMID:18588279 — GK = glucokinase activator, PSN-GK1\n- PMID:25324018 — GK = glucokinase\n- PMID:26551034 — GK-GKRP = glucokinase\n- PMID:26827782 — GK = glucokinase in liver/pancreas\n\nWait — I need to reconsider. The HGNC gene symbol \"GK\" with aliases GK1 and GKD refers to **galactokinase 1** (not glucokinase, which is GCK). Let me re-evaluate.\n\nPMID:10521295 explicitly mentions \"galactokinase gene (GK1)\" and mutation P28T — this IS the canonical gene.\n\nThe glucokinase papers use \"GK\" as an abbreviation for glucokinase (gene symbol GCK) — these are NOT the canonical GK/GK1/GKD gene.\n\nOnly PMID:10521295 clearly describes the canonical galactokinase GK1 gene with mechanistic content (mutation reducing enzyme activity causing galactokinase deficiency).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"A founder missense mutation in GK1 (P28T), replacing a conserved proline at position 28 with threonine, causes galactokinase deficiency in Roma (Gypsies). Genetic linkage mapping placed the disease locus on chromosome 17q, radiation hybrid mapping confirmed GK1 resides in this region, and haplotype analysis identified a small conserved region of homozygosity around GK1 in affected individuals. The P28T variant is the causative allele responsible for the first step of galactose metabolism being defective, leading to cataract formation in early childhood.\",\n      \"method\": \"Genetic linkage mapping, radiation hybrid mapping, haplotype analysis, identification of causative point mutation in GK1\",\n      \"journal\": \"American Journal of Human Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic mapping and mutation identification in a single study; no in vitro enzymatic reconstitution of P28T activity reported in this abstract\",\n      \"pmids\": [\"10521295\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GK (galactokinase 1) catalyzes the first step of galactose metabolism; loss-of-function mutations such as the founder P28T substitution in Roma populations abolish this activity and cause galactokinase deficiency manifesting as early-onset cataracts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GK is required for the first step of galactose metabolism, and its loss causes galactokinase deficiency [#0]. A founder missense mutation in GK1 (P28T), replacing a conserved proline at position 28 with threonine, was mapped to chromosome 17q in Roma (Gypsy) families and identified as the causative allele underlying early-childhood cataract formation [#0]. Beyond this genetic mapping and mutation identification, no further mechanistic detail—including in vitro enzymatic characterization of the variant—has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing the genetic basis of galactokinase deficiency answered which gene and which lesion abolish the first step of galactose metabolism in an affected population.\",\n      \"evidence\": \"Genetic linkage mapping to chromosome 17q, radiation hybrid mapping, and haplotype analysis identifying the P28T founder mutation in Roma families\",\n      \"pmids\": [\"10521295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro enzymatic reconstitution confirming that P28T abolishes galactokinase catalytic activity\",\n        \"Structural consequence of the P28 proline substitution not determined\",\n        \"Mechanism linking enzyme loss to cataract formation not directly tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the P28T substitution disrupts the enzyme at the biochemical and structural level, and how loss of galactose phosphorylation mechanistically drives cataractogenesis, remains unresolved in the available corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No enzymatic kinetics for wild-type or mutant protein in the corpus\",\n        \"No structural model of the substrate-binding region affected by P28\",\n        \"No cellular or tissue-level mechanism connecting metabolite accumulation to lens pathology\"\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":"loss","faith_supported":2,"faith_total":2,"faith_pct":100.0}}