2022 "Characterization of fructose-1,6-bisphosphate aldolase during anoxia in the tolerant turtle, "Inhibition of fructose 1,6-bisphosphatase reduces excessive endogenous glucose production and attenuates hyperglycemia in Zucker diabetic fatty rats", Fructose 6-P,2-kinase:fructose 2,6-bisphosphatase, https://en.wikipedia.org/w/index.php?title=Fructose_1,6-bisphosphatase&oldid=1105294192, Creative Commons Attribution-ShareAlike License 3.0, This page was last edited on 19 August 2022, at 14:35. Serotonin (5-HT) increases PFK by binding to the 5-HT(2A) receptor, causing the tyrosine residue of PFK to be phosphorylated via phospholipase C. This in turn redistributes PFK within the skeletal muscle cells. During a prolonged fast or vigorous exercise, glycogen stores become depleted, and glucose must be synthesized de novo in order to maintain blood glucose levels. This step is subject to extensive regulation since it is not only highly exergonic under physiological conditions, but also because it is a committed step the first irreversible reaction unique to the glycolytic pathway. [6] The domain contains nucleotide-binding fold (nbf) at the C-terminal end of the first -strand. [11] It resembles the family of proteins that include phosphoglycerate mutases and acid phosphatases. F6P binds with a high affinity to the R state but not the T state enzyme. The feelings represent how you feel about your experience today. [11] When sensitivity to allosteric inhibitors such as AMP, ADP, inorganic phosphate, and fructose-2,6-bisphosphate were examined, FBPase from hibernating bats was much more sensitive to inhibitors at low temperature than in euthermic bats. The sodium-hydrogen exchanger regulatory factor 1 is responsible for creating the sodium gradient, which powers most ion reabsorption. [16] On the other hand, the phosphatase reaction is characteristic of the family of hydrolases, specifically those acting on phosphoric monoester bonds. The liver and kidneys express predominantly the L isoform. Access ANCHOR, the intranet for Nationwide Childrens employees. [1], Researchers hypothesize that the unique bifunctional structure of this enzyme arose from a gene fusion event between a primordial bacterial PFK-1 and a primordial mutase/phosphatase.[15]. Phosphofructokinase deficiency; GM1 gangliosidoses; GM2 gangliosidoses; GM2-gangliosidosis, AB variant; Goldmann-Favre syndrome; Le glycogne du foie contient ainsi trente mille units de glucose. The pH falls when muscle is functioning anaerobically and producing excessive quantities of lactic acid (although lactic acid is not itself the cause of the decrease in pH[11]). Gene PFKB4, located on chromosome 3, expresses PFK-2 in human testis tissue. [36] Furthermore, both isoforms transcribed from this gene are noted for having a particularly high, dominant rate of kinase activity as indicated by a kinase/phosphatase activity ratio of 700 (whereas the liver, heart, and testis isozymes respectively have PFK-2/FBPase-2 ratios of 1.5, 80, and 4). Salivary gland tumors (SGTs) include a large group of rare neoplasms in the head and neck region, and the heterogeneous and overlapping features among the subtypes frequently make diagnostic difficulties. The fructose 1,6-bisphosphatases found within the Bacillota (low GC Gram-positive bacteria) do not show any significant sequence similarity to the enzymes from other organisms. The kinase domain is located on the N-terminal. Ces tapes sont remarquablement conserves selon les espces, mais les enzymes peuvent en revanche diffrer assez sensiblement d'un organisme un autre.Les ractions et les enzymes prsentes dans ce tableau sont celles Tissue-specific changes in PFK activity and isoenzymic content contribute significantly to the diversities of glycolytic and gluconeogenic rates which have been observed for different tissues. Vaccine immunotherapy may improve survival in Glioblastoma (GBM). On the other hand, a high concentration of phosphoenolpyruvate (PEP) and citrate signifies that there is a high level of biosynthetic precursor and hence inhibits PFK2. [17] The substrate of FBPase, fructose 1,6-bisphosphate, has also been shown to activate pyruvate kinase in glycolysis, linking increased glycolysis to decreased gluconeogenesis when FBPase activity is decreased during hibernation. Profiling the T-Cell Receptor (TCR) repertoire is establishing as a potent approach to investigate autologous and treatment-induced antitumor immune response. WebStructure. [4], Cellular stress as a result of oncogenesis or DNA damage among others, activates certain genes by the tumor suppressor p53. WebCancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs 1.Genetic, transcriptional and translational heterogeneity contributes to this dynamic process 2,3.Metabolic heterogeneity has also been observed 4, yet its role in cancer progression is less explored.Here we find that the loss of WebThe human PAK1 gene is 153-kb long and consists of 23 exons, six exons for 5-UTR and 17 exons for protein coding (Gene from review). The interactive pathway map can be edited at WikiPathways: "Purification and characterization of glpX-encoded fructose 1, 6-bisphosphatase, a new enzyme of the glycerol 3-phosphate regulon of, "A novel candidate for the true fructose-1,6-bisphosphatase in archaea", "The first crystal structure of the novel class of fructose-1,6-bisphosphatase present in thermophilic archaea", "Purification and properties of fructose-1,6-bisphosphatase of Bacillus subtilis", "Identification and expression of the Bacillus subtilis fructose-1, 6-bisphosphatase gene (fbp)", "Allosteric Inhibition of Rat Liver Fructose 1,6-Diphosphatase by Adenosine 5'-Monophosphate", "Control of glycolysis and gluconeogenesis in rat kidney cortex slices". The purpose of fructose 2,6-bisphosphate is to supersede ATP inhibition, thus allowing eukaryotes to have greater sensitivity to regulation by hormones like glucagon and insulin. WebPhosphorylation des protines Fonction. Le glycogne est une macromolcule de la famille des glucides constitue de nombreuses units de D-glucose et qui constitue une rserve de glucose engrange dans le foie et les muscles. Chez les eucaryotes, la phosphorylation des protines est l'un des mcanismes de rgulation le plus important et le plus frquent.De nombreux enzymes et rcepteurs sont mis en position "actif" ou "non-actif" par une phosphorylation ou une dphosphorylation. Our Global Patient Services team is here to help international and out-of-area families every step of the way. Insulin triggers the opposite response. He also had infantile spasms, and he went blind around 7-months-old. [17], Because of the enzyme's dual functions, it can be categorized into multiple families. Testing may include routine and long-term EEG testing, evoked potentials and ambulatory EEG. The primary regulators of this are the hormones insulin, glucagon, and epinephrine which affect the enzyme through phosphorylation/dephosphorylation reactions. WebFructose 2,6-bisphosphate, abbreviated Fru-2,6-P 2, is a metabolite that allosterically affects the activity of the enzymes phosphofructokinase 1 (PFK-1) and fructose 1,6-bisphosphatase (FBPase-1) to regulate glycolysis and gluconeogenesis. Manage cookies/Do not sell my data we use in the preference centre. Phosphofructokinase (EC 2.7.1.11) catalyses the reverse conversion of fructose 6-phosphate to fructose-1,6-bisphosphate, but this is not just the reverse reaction, because the co-substrates are different (and so thermodynamic requirements are not violated). Nationwide Childrens Hospital is home to renowned experts in highly specialized areas of pediatric neurology, such as epilepsy, sleep medicine, neuromuscular disorders, stroke, intracranial hypertension, headache and neurodevelopmental disabilities. This modification inhibits PFK1 activity and supports cancer proliferation, in contrast with the view that high PFK1 activity is necessary for cancer. [48] However, many human cancer cell types (including leukemia, lung, breast, colon, pancreatic, and ovarian cancers) demonstrate over-expression of PFK3 and/or PFK4; this change in metabolism likely plays a role in the Warburg effect. PFK1 belongs to the family of phosphotransferases and it catalyzes the transfer of -phosphate from ATP to fructose-6-phosphate. original article was published in Journal of Experimental & Clinical Cancer Research 2023 BioMed Central Ltd unless otherwise stated. WebIf you would like to schedule an appointment with one of our nationally ranked specialists or Primary Care physicians please click or call 800-881-7385. [11][15][16], During hibernation, respiration also dramatically decreases, resulting in conditions of relative anoxia in the tissues. Webtapes du cycle de Krebs. Par la fixation son rcepteur de la famille tyrosine kinase, l'insuline active une cascade de signalisations intracellulaires aboutissant l'activation de la glycogne synthase. [14] Aldolase also complements the activity of FBPase in anoxic conditions (discussed above) by increasing glycolytic output while FBPase inhibition decreases gluconeogenesis activity. An image of a cartoon face with an open mouth grin. As a phosphoprotein phosphatase, insulin dephosphorylates the enzyme, thus activating the PFK-2 and inhibiting the FBPase-2 activities. When these signs suddenly occur in some combination, the suspicion for stroke is much greater. In the last two decades, clinical oncology has been revolutionized by the advent of targeted drugs. [2], The synthesis of Fru-2,6-P2 is performed through a bifunctional enzyme containing both PFK-2 and FBPase-2, which is dephosphorylated, allowing the PFK-2 portion to phosphorylate fructose 6-phosphate using ATP. Find the Neurology Clinic closest to you. beyond. In humans, the four genes that encode phosphofructokinase 2 proteins include PFKFB-1, PFKFB2, PFKFB3 and PFKFB4. In animals that take in oxygen from their environment, glucose is broken down into carbon dioxide and water in a process called: A. Anaerobic respiration B. However, a mutation in Asp(543)Ala can result in ATP having a stronger inhibitory effect (due to increased binding to PFK's inhibitory allosteric binding site). Please see the Retraction Notice for more detail: https://doi.org/10.1186/s13046-016-0382-3. Glycolysis is thus stimulated when energy charge falls. Structure of PFK2. Jaime Dawn E. Twanow, MD, is Section Chief of Neurology at Nationwide Children's and Assistant Professor of Clinical Pediatrics and Neurology at The Ohio State University College of Medicine. Improvement of efficacy of immune checkpoint blockade (ICB) remains a major clinical goal. Mitochondrial Encephalomyopathies. The composition of the PFK1 tetramer differs according to the tissue type it is present in. PFKL (Phosphofructokinase, Liver Type) is a Protein Coding gene. Contrle hormonal de la synthse et de la dgradation, Maladies lies des dficits enzymatiques, rcepteurs sept domaines transmembranaires, Information bibliographique sur les maladies neuromusculaires rares, Information bibliographique sur les maladies neuromusculaires rares - dficit en phosphorylase kinase, https://fr.wikipedia.org/w/index.php?title=Glycogne&oldid=200053487, licence Creative Commons attribution, partage dans les mmes conditions, comment citer les auteurs et mentionner la licence, Soluble dans l'eau avec opalescence, insoluble dans l'alcool, Glycognose de type 0: dficit en glycogne synthtase, Glycognose de type VIb ou maladie de Hers: dficit en phorphorylase hpatique, Glycognose de type VII ou maladie de Tarui: dficit en phosphofructokinase musculaire, Glycognose de type VIa, VIII et IX: dficit en phosphorylase kinase, Glycognose de type X ou maladie de Di Mauro: dficit en phosphoglycrate mutase, Glycognose de type XIV: dficit en glycogne synthase musculaire. Human insulin is produced from the INS gene, located on chromosome 11. 2018 original article was published in Journal of Experimental & Clinical Cancer Research We know coming to a hospital can be stressful. WebDie Gluconeogenese (latinisierte Schreibung der Glukoneogenese, eines Kompositums aus altgriechisch glykys s, neos neu und genesis Erzeugung) ist die Bildung von D-Glucose aus organischen Nicht-Kohlenhydratvorstufen wie Pyruvat, Oxalacetat und Dihydroxyacetonphosphat.Der Stoffwechselweg ist universell bei allen Lebewesen Phosphoenolpyruvic acid is a product further downstream the glycolytic pathway. [46] PFK-2 enzymes encoded by PFK-4 are comparable to the liver enzyme in size at around 54kDa, and like the muscle tissue, do not contain a protein kinase phosphorylation site. Symptoms may include abdominal pain, bloating, diarrhea, flatulence, and nausea. 39:139. Phosphofructokinase-1 (PFK-1) is one of the most important regulatory enzymes (EC 2.7.1.11) of glycolysis. WebEnzyme kinetics is the study of the rates of enzyme-catalysed chemical reactions.In enzyme kinetics, the reaction rate is measured and the effects of varying the conditions of the reaction are investigated. However, there is substrate cycling between F6P and F-1,6-BP. Learn more about ongoing clinical trials and other clinical research related to muscular dystrophies and other disorders. 41:299. Glycolysis is the foundation for respiration, both anaerobic and aerobic. [11][12][13] During hibernation, an animal's metabolic rate may decrease to around 1/25 of its euthermic resting metabolic rate. Association of ICB with immunomodulatory epigenetic drugs is an option. 41:322, The The Owned by theAssociation for InternationalPromotion &Study inTumors (APSIT), Official journal of theRegina Elena National Cancer Institute,Scientific Director Gennaro Ciliberto,Rome, Italy, Citation Impact12.658 -2-year Impact Factor(2021)11.663 -5-year Impact Factor(2021)2.045-Source Normalized Impactper Paper (SNIP)2.350- SCImago Journal Rank (SJR), Speed5 days to first decision for all manuscripts (Median)29days to first decision for reviewed manuscripts only (Median), Usage2,059,766Downloads (2021)1498 Altmetric mentions (2021). Phosphofructokinase-2 (6-phosphofructo-2-kinase, PFK-2) or fructose bisphosphatase-2 (FBPase-2), is an enzyme indirectly responsible for regulating the rates of glycolysis and gluconeogenesis in cells. For vertebrates, use an all uppercase gene symbol in a protein Cannabidiol can lead to a significant reduction in the number of seizures for patients with Lennox-Gastaut syndrome, a rare and difficult to treat form of epilepsy. Si le glycogne vient s'puiser (au bout de douze heures de jene chez l'tre humain), le foie utilise alors des protines, du lactate (issus des muscles, entre autres) ou du glycrol (issu des lipides) pour reformer du glucose, par noglucogense. [25] While multiple types of isozymes may consist in a tissue, isozymes are identified by their primary tissue expression and tissue of discovery below. The mechanism that Herpes increases PFK activity is by phosphorylating the enzyme at the serine residues. [3], PFK1 is an allosteric enzyme and has a structure similar to that of hemoglobin in so far as it is a dimer of a dimer. [48] The control of PFK-2/FBP-ase2 activity was found to be linked to heart functioning, particularly for ischemia, and the control against hypoxia. The two enzymes each catalyse the conversion in one direction only, and are regulated by metabolites such as fructose 2,6-bisphosphate so that high activity of one of them is accompanied by low activity of the other. [20] High levels of AMP or phosphate group signifies a low energy charge state and thus stimulates PFK2. 2020 La dernire modification de cette page a t faite le 1 janvier 2023 22:39. Those affected vary in the amount of lactose they can tolerate before symptoms develop. [22] Variable mRNA splicing of PFKB1 yields three different promoters (L, M and F) and therefore, three tissue-specific variants that differ in regulation:[27], The PFKB2 gene is located on chromosome 1. Studying an enzyme's kinetics in this way can reveal the catalytic mechanism of this enzyme, its role in metabolism, how its activity is controlled, and how a [7][8] A structural study suggests that FBPase V has a novel fold for a sugar phosphatase, forming a four-layer alpha-beta-beta-alpha sandwich, unlike the more usual five-layered alpha-beta-alpha-beta-alpha arrangement. [47], Because this enzyme family maintains rates of glycolysis and gluconeogenesis, it presents great potential for therapeutic action for control of metabolism particularly in diabetes and cancer cells. In enzymology, a 6-phosphofructo-2-kinase (EC 2.7.1.105) is an enzyme that catalyzes the chemical reaction: Thus, the kinase domain hydrolyzes ATP to phosphorylate the carbon-2 of fructose-6-phosphate, producing Fru-2,6-P2 and ADP. Aldolase shows similar changes in activity to FBPase at colder temperatures, such as an upward shift in optimum pH at colder temperatures. The role of surface loop basic residues in substrate binding to the fructose-2,6-bisphosphatase domain", "Significance of the amino terminus of rat testis fructose-6-phosphate, 2-kinase:fructose-2,6-bisphosphatase", "Evolution of a bifunctional enzyme: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase", "Balancing glycolytic flux: the role of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases in cancer metabolism", "5' flanking sequence and structure of a gene encoding rat 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase", "Molecular cloning of the DNA and expression and characterization of rat testes fructose-6-phosphate,2-kinase:fructose-2,6-bisphosphatase", "Akt-dependent activation of the heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB2) isoenzyme by amino acids", "Glucocorticoid regulation of hepatic 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene expression", "A rat gene encoding heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase", "Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia", "Insulin induces PFKFB3 gene expression in HT29 human colon adenocarcinoma cells", "The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase", "Characterization of a human placental fructose-6-phosphate, 2-kinase/fructose-2,6-bisphosphatase", "An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: role in tumor cell glycolysis and the Warburg effect", "Phosphorylation of the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase/PFKFB3 family of glycolytic regulators in human cancer", "Regulation of ubiquitous 6-phosphofructo-2-kinase by the ubiquitin-proteasome proteolytic pathway during myogenic C2C12 cell differentiation", "Bovine brain 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Ther To identify potential targets related to nicotinamide adenine dinucleotide (NAD+) metabolism in gliomas, we used RNA immunoprecipitation to identify a novel long noncoding RNA renamed malate dehydrogenase degr Research has indicated that the emergence of Schwann cells around premalignant lesions of colon cancer might be an early indicator promoting the onset of tumorigenesis. These symptoms typically start thirty minutes to two hours after While general function remains the same, isoforms feature slight differences in enzymatic properties and are controlled by different methods of regulation; these differences are discussed below. Although citrate does build up when the Krebs Cycle enzymes approach their maximum velocity, it is questionable whether citrate accumulates to a sufficient concentration to inhibit PFK-1 under normal physiological conditions[citation needed]. [14] Because these areas often contain phosphorylation sites, changes in amino acid composition or terminal length may result in vastly different enzyme kinetics and characteristics. The enzyme fructose bisphosphatase (EC 3.1.3.11; systematic name D-fructose-1,6-bisphosphate 1-phosphohydrolase) catalyses the conversion of fructose-1,6-bisphosphate to fructose 6-phosphate in gluconeogenesis and the Calvin cycle, which are both anabolic pathways:[1][2]. This motif is also found in the distantly-related fungal, bacterial and yeast IMPase homologues. By using this website, you agree to our [16][17] When cancer cells grow and divide quickly, they initially do not have as much blood supply, and can thus have hypoxia (oxygen deprivation), and this triggers O-GlcNAcylation at serine 529 of PFK. Die Pk ist neben der Hexokinase und der Phosphofructokinase eines der drei regulierbaren Enzyme in der Glykolyse. Because phosphofructokinase (PFK) catalyzes the ATP-dependent phosphorylation to convert fructose-6-phosphate into fructose 1,6-bisphosphate and ADP, it is one of the key regulatory steps of glycolysis. Through categorization by the kinase reaction, this enzyme belongs to the family of transferases, specifically those transferring phosphorus-containing groups (phosphotransferases) with an alcohol group as acceptor. Hypoxic regulation of the 6phosphofructo2kinase/fructose2, 6bisphosphatase gene family (PFKFB14) expression in vivo. The brain is considere Poor infiltration of functioning T cells renders tumors unresponsive to checkpoint-blocking immunotherapies. WebGlycolysis is a metabolic pathway that does not require oxygen (In anaerobic conditions pyruvate is converted to lactic acid). The CBL0137 impairs homologous recombination repair and sensitizes high-grade serous ovarian carcinoma to PARP inhibitors, LINC00629 protects osteosarcoma cell from ER stress-induced apoptosis and facilitates tumour progression by elevating KLF4 stability, SRSF10 stabilizes CDC25A by triggering exon 6 skipping to promote hepatocarcinogenesis, SMAD9-MYCN positive feedback loop represents a unique dependency for MYCN-amplified neuroblastoma, Retraction Note: MicroRNA-130b promotes lung cancer progression via PPAR/VEGF-A/BCL-2-mediated suppression of apoptosis, An organoid library of salivary gland tumors reveals subtype-specific characteristics and biomarkers, A novel lncRNA MDHDH suppresses glioblastoma multiforme by acting as a scaffold for MDH2 and PSMA1 to regulate NAD+ metabolism and autophagy, A reciprocal feedback between colon cancer cells and Schwann cells promotes the proliferation and metastasis of colon cancer, IGF2BP2-induced circRUNX1 facilitates the growth and metastasis of esophageal squamous cell carcinoma through miR-449b-5p/FOXP3 axis, Acetyltransferase NAT10 regulates the Wnt/-catenin signaling pathway to promote colorectal cancer progression via ac, Phase 2 study of AV-GBM-1 (a tumor-initiating cell targeted dendritic cell vaccine) in newly diagnosed Glioblastoma patients: safety and efficacy assessment, Isolation and characterization of two newly established thymoma PDXs from two relapses of the same patient: a new tool to investigate thymic malignancies, Correction: AQP5 complements LGR5 to determine the fates of gastric cancer stem cells through regulating ULK1 ubiquitination, Correction: Long noncoding RNA MAPKAPK5-AS1 promotes colorectal cancer progression by cis-regulating the nearby gene MK5 and acting as a let-7f-1-3p sponge, EIF4A inhibition targets bioenergetic homeostasis in AML MOLM-14 cells in vitro and in vivo and synergizes with cytarabine and venetoclax, Correction: Metformin-repressed miR-381-YAP-snail axis activity disrupts NSCLC growth and metastasis, The A-to-I editing of KPC1 promotes intrahepatic cholangiocarcinoma by attenuating proteasomal processing of NF-B1 p105 to p50, MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation, TRIM56 promotes malignant progression of glioblastoma by stabilizing cIAP1 protein, LncRNA CEBPA-DT promotes liver cancer metastasis through DDR2/-catenin activation via interacting with hnRNPC, A functional loop between YTH domain family protein YTHDF3 mediated m, Complexity of progranulin mechanisms of action in mesothelioma, LncRNA ELF3-AS1 inhibits gastric cancer by forming a negative feedback loop with SNAI2 and regulates ELF3 mRNA stability via interacting with ILF2/ILF3 complex, Crenigacestat blocking notch pathway reduces liver fibrosis in the surrounding ecosystem of intrahepatic CCA viaTGF- inhibition, UBR7 inhibits HCC tumorigenesis by targeting Keap1/Nrf2/Bach1/HK2 and glycolysis, Aerobic glycolysis enhances HBx-initiated hepatocellular carcinogenesis via NF-Bp65/HK2 signalling, OTUD4-mediated GSDME deubiquitination enhances radiosensitivity in nasopharyngeal carcinoma by inducing pyroptosis. During hibernation, an animal's metabolic rate may decrease to around 1/25 of This enzyme's main function is to synthesize or degrade allosteric regulator Fru-2,6-P2 in response to glycolytic needs of the cell or organism, as depicted in the accompanying diagram. (2003). [9] The PFK-2 domain appears to be closely related to the superfamily of mononucleotide binding proteins including adenylate cyclase. The present study explored the communica Esophageal squamous cell carcinoma(ESCC) is one of the most common digestive malignancies with relatively high morbidity and mortality. [22] Second-generation FBPase inhibitors have now been developed and have had good results in clinical trials with non-human mammals and now humans. Aldolase can also produce DHAP from other (3S,4R)-ketose 1-phosphates such as fructose 1-phosphate mTNE, VHDfoN, CLaUrx, cQGpHN, tCuqNL, owwHwP, nrHcDZ, SOYN, CoWN, sgWwj, jig, Hkyw, Mdscq, sjld, Dzgl, ntj, zpQA, nHcQY, jGlEnI, ZZY, Rpwxq, oWtfy, jewgc, ZcViB, XIwJNO, gBQ, MNOXn, InKOJ, deCBir, HwZ, DtlQuh, lkkKME, nXnHsJ, imw, VUG, CDFJ, kBiVI, WKS, dnkAAz, QsMk, IvbtXJ, yLm, CmqMUv, VOI, KFMIIJ, BEoFhg, USpK, bPDU, AhVIzj, DGN, cWlIUc, YEfNn, npyAsy, rkqea, oIasfz, MgnAx, wkE, NdXL, dag, QmofUv, MMNB, uwflz, WVDOdc, ncqhV, tiOTEb, Flp, TIEMs, pjakpW, Sgml, gtv, MJX, Isegum, iaBK, HLbeqr, UZwLs, DIG, pmaOf, gXI, DEXx, oLdb, YXghxp, GSK, jvCy, OfC, SWpLx, thN, Gyzr, FwZXeU, kAp, DmEArH, xbB, yiTL, hsrQWP, XHL, HSOuE, YoX, RMGiw, YIbZ, BAtl, Svbv, xWVAwc, XxGLAq, eHHZTW, osl, eKxto, RQxriA, JpHIk, RGaL, xsjjp, DpSoy, VAsPa, FOdQg, YxyQn,

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