Hexokinase is active even at low glucose levels. In addition, glucokinase plays a critical role in the hepatic conversion of glucose into glycogen, which is a major contributor to the removal of glucose from the portal vein in . Hall J Cohen D GK regulatory protein (GKRP) is a polypeptide (molecular weight: 68 kDa) that only exists in mammalian liver. In the liver, glucokinase helps determine when excess glucose should be taken in and converted to glycogen, which is a major source of stored energy in the body. Matschinsky et al. Both the three-dimensional model created on the basis of the crystal structure of yeast hexokinase B (35) and the recently described crystal structures of the complex (active) and free (inactive) glucokinase conformations (36) proved to be helpful for the localization of the putative GRP-binding motifs. Discover a faster, simpler path to publishing in a high-quality journal. Recently, different small chemical compounds have been described that are able to activate glucokinase (36,4850). Why does glucokinase have low affinity for glucose? de Bakker PI Conversely, in the fasting state, the combined decrease in glucose and insulin concentrations and increase in glucagon concentrations, halt GCK activity. 50 Baltrusch S, Francini F, Lenzen S & Tiedge M (2005) Interaction of glucokinase with the liver regulatory protein is conferred by leucine-asparagine motifs of the enzyme. 1 A). 2B). The gene order near the GCKR gene in the other fish genomes examined differed from that of zebrafish, and they shared an order that was consistent with that shown for the takifugu (Figure 1). van Schaftingen E, Vandercammen A, Detheux M, Davies DR. Adv Enzyme Regul. Bronchial airway [] Genomic alignments were used to refine the predicted potential coding regions of the genes. Glucokinase functions only in emergencies, when the concentration of glucose in the blood rises to abnormally high levels. In addition to regulation at the transcriptional level, GCK is also regulated in the liver at the post-transcriptional level by glucokinase regulatory protein (GCKR) [11], [12]. A single mutational event cannot explain the origin of the inactivated mammalian GCKR genes. Glucokinase, then, has a low affinity (high Km), so . : Structure/function studies of human beta-cell glucokinase: enzymatic properties of a sequence polymorphism, mutations associated with diabetes, and other site-directed mutants. Knigsrainer I Hirsch J, Peter A Hexokinase is in pretty much of all of our tissues except for the liver and beta cells of the pancreas. | Explore the latest full-text research PDFs . Diabetes 54, 2829. Glucokinase (GCK) adjusts hepatic glucose phosphorylation to blood glucose levels, acting as a glucose sensor. By phosphorylating glucose to glucose-6-phosphate, glucokinase functions as the pancreatic beta-cell glucose sensor, regulating glucose-stimulated insulin secretion . Data are expressed as means SE. Liver Glucokinase. The nuclear-to-cytoplasmic glucokinase ratio of the wild-type protein at both glucose concentrations was comparable with glucokinase distribution data obtained from liver samples of starved and 2-hrefed rats, as well as with data upon primary hepatocytes at high and low glucose (4244). Many activating and inactivating glucokinase mutants have been characterized in patients with diabetes and hyperinsulinemic hypoglycemia, which include the underlying mutation of maturity-onset diabetes of the young type 2 ( 3 ). Evidence for deletion of the gene is strongest in birds, while the failure to find a GCKR gene in some of the other species could be due to gaps in the current genome assemblies. But the mutation of the residues N166 to arginine and N180 to aspartic acid was less effective with respect to the interaction properties to the GRP. glucokinase enzyme Learn about this topic in these articles: role in metabolism In metabolism: Glycolysis addition, the liver contains a glucokinase, which requires a much greater concentration of glucose before it reacts. The results indicate that the L58/N204 motif in the hinge region confers binding to GRP, while the L355/N350 motif may modulate the binding affinity for GRP. Witting SR Glucokinase functions as the glucose sensor in the beta cell by controlling the rate of entry of glucose into the glycolytic pathway (glucose phosphorylation)and its subsequent metabolism. Glycolytic Metabolism, Brain Resilience, and Alzheimer's Disease. , Potential pseudogenes were identified as sequences that failed to predict open reading frames due to the presence of base changes that either introduced stop codons, created frame shifts that disrupted the coding sequence, or disrupted splicing consensus sequences. In mammalian hepatocytes, glucokinase is bound to the GRP and mainly localized in the nucleus at basal low-glucose concentrations. , et al. B: The nuclear-to-cytoplasmatic fluorescence intensity ratio was calculated from 20 nuclear and 20 cytoplasmic pixel measurements (cellR software; Olympus BioSystems) of each image. Newton-Cheh C The zebrafish genome also predicts an IFT172-like gene in a position orthologous to the human IFT172 gene, and a PTK6/SRMS6-like gene in a position orthologous to that found in the coelacanth genome (Figure 1). Importance of selected ABCB1 SNPs for the level of severity of depressive symptoms and effectiveness of recurrent depressive disorder therapy. The L309R glucokinase mutant showed a loss of GRP binding in yeast two-hybrid studies and of nuclear localization in COS-1 cells. Cell viability tested by trypan blue staining was at least 80%. In enzyme activity studies, the double-mutant glucokinase protein L58R/N204Y, as well as the single-mutant proteins L58R and N204Y, showed a complete loss of glucokinase activity. In addition, asparagine N350 exists exclusively in the glucokinase sequence. Tlmaque-Potts S Searches of the mammalian (shrew and platypus) and the reptilian (anole lizard) genomes resulted in identifying only short genomic fragments encoding sequences similar to FNDC4 and ZNF512, with none of these genomic fragments encoding any additional genes (results not shown). The short-term activity of hepatic GCK is under control of the competitive inhibitor GCK regulatory protein (GKRP). The lines indicate the linear regression between the parameters. The C16:0/C18:2 fatty acid ratio or de novo lipogenesis index (DNL) index has been established as a tool to estimate de novo lipogenesis (15, 16). , Schick F What's the function of glucokinase? Details are provided in the Supplemental Material. Molecular physiology of mammalian glucokinase. Another study with glucokinase-hexokinase chimeras postulated a large interface in the glucokinase protein for GRP binding (22). Hring HU Hyperinsulinism due to glucokinase deficiency - About the Disease In pancreatic -cells, GCK serves as a sensor of blood glucose that regulates insulin secretion. Kuser PR, Krauchenco S, Antunes OA, Polikarpov I: The high resolution crystal structure of yeast hexokinase PII with the correct primary sequence provides new insights into its mechanism of action. 1975 Feb 28;6(2):109-26. doi: 10.1007/BF01732005. The enzyme shows a sigmoidal saturation curve and a low affinity for glucose. Glucokinase functions as the glucose sensor in the beta cell by controlling the rate of entry of glucose into the glycolytic pathway (glucose phosphorylation) and its subsequent metabolism. Cells were seeded at a density of 2 104 cells on three glass cover slips stored in a 35-mm dish, and transfection was performed the day thereafter with 1 g plasmid DNA and 2 l jetPEI (Qbiogene, Montreal, Canada) according to the manufacturers instructions. , Department of Pharmacology, Peking University, Health Science Center, Beijing, China, , Protein expression of wild-type and mutant glucokinase was confirmed by Western blot analyses (data not shown). Genes similar to FNDC4 and LDLRAP1 (low density lipoprotein receptor adaptor protein 1) are found 5 to the coelacanth GCKR gene, while genes similar to PTK6/SRMS (protein tyrosine kinase 6/src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites) and BLK (B lymphoid tyrosine kinase) were found 3 (Figure 1). quently activate liver-type glucokinase and GLUT2. The main function of glucokinase (GCK) is to regulate carbohydrate metabolism. Nuclear-to-cytoplasmic glucokinase ratio in COS-1 cells transfected with EYFP-GRP and ECFP-GK wild-type and mutant proteins. , Allosteric activators of glucokinase: potential role in diabetes therapy. STATE-OF-THE-ART REVIEW Targeting hepatocyte carbohydrate transport to As indicated above, mice with a targeted disruption of the GCKR gene show a specific deficiency of GCK activity in their liver [24], [25]. , Anatomy Backward effects of left-sided heart failure include: A. The selection of peptides able to bind to the GRP was performed with the Ph.D.-12 Phage Display Peptide Library (New England Biolabs) according to the manufacturers instructions. Liver-specific GCK expression is absolutely dependent upon the presence of insulin and is repressed by glucagon [3], [6][8]. In addition, in multiple mammalian genomes, whereas GCKR-like gene sequences could be identified, these genes could not predict a functional protein. Glucokinase Glucokinase ( EC 2.7.1.2) is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Bengtsson Bostrm K Liver Glucokinase Can Be Activated by Peroxisome Proliferator-Activated With an influx of glucose, GCK within the nucleus is re-activated and returns to the cytoplasm [20][22]. GCKR genes, though, have only been identified or characterized in a few species [34][36]. While in COS-1 cells the cellular distribution of the glucokinase single mutants N350Y and L355R was comparable to that of wild-type glucokinase, the double mutation showed an additive effect with strong nuclear localization both at high and low glucose concentrations. PAS Kinase deficiency alters the glucokinase function and hepatic 6A) appears similar to the corresponding conformation of yeast hexokinase II (Fig. Marcus L Media and supplements for culture of yeast were from Clontech (Palo Alto, CA). Glucokinase acts as a sensor, recognizing when the level of glucose in the blood rises and helping stimulate the release of insulin from beta cells to control it. The ECFP-N350Y/L355R glucokinase mutant showed a distinct fluorescence in the nucleus at low and high glucose concentrations (Fig. bc higher influx of glucose going at it; 34. This was demonstrated by a high nuclear-to-cytoplasmic glucokinase ratio of 2.0 at 25 mmol/l glucose compared with 0.7 for the wild type (Table 3). , Searches of the non-redundant and genome databases maintained at the National Center for Biotechnology Information (NCBI, www.ncbi.nlm.nih.gov) were used to complement the genomes gathered from the Ensembl database and aided in the identification of incomplete genes or coding region sequences. While only some of these glucokinase activators increase the Vmax of glucokinase (36,48,50), all of them decrease the S0.5 of the enzyme for the substrate glucose. However, allosteric dual activation of glucokinase by dorzagliatin is completely different from glucokinase activation due to disruption of GKRP. Abstract. Reduced intrapleural pressures B. , Our results show that species deficient in liver GCK activity have mutated or deleted GCKR genes, supporting the hypothesis that the loss of GCKR, and its ability to stabilize GCK, explains the loss of liver-specific GCK activity. GCKR genes and GCKR-like sequences were identified in the genomes of all vertebrate species with available genome sequences. Regulatory proteins that inhibit glucokinase (GK) in pancreatic beta cells and the liver are encircled in green (midnolin and parkin) and blue (GRP), respectively. To test this possibility we first constructed a phylogenetic tree (Figure 3) of the mammalian GCKR protein sequences from species that have full-length sequences, rooted with the sequence from the Tasmanian devil, a marsupial outgroup for placental mammals [47]. 6B). Epub 2021 Mar 23. sharing sensitive information, make sure youre on a federal Therefore, both the intrinsic glucose phosphorylation activity and the GRP-binding affinity were nearly completely abolished in the L58R glucokinase mutant. The wild-type glucokinase showed a strong binding to the GRP with a 10-fold increase of the reporter gene activity compared with background activity by the truncated binding domain interaction (Fig. 1977 Jul 1;165(1):61-9. doi: 10.1042/bj1650061. Insight into the physiological and pathological roles of the aryl Blood glucose is the primary cellular substrate and in vivo must be tightly maintained. Our results suggest that mutation of the GCKR gene leads to hepatic GCK deficiency due to the loss of the stabilizing effect of GCKR. , The Xenopus tropicalis GCKR gene is distributed over four small genomic fragments (Table 1) that do not show similarity to any other gene. Therefore, we investigated the relationship between hepatic GCK mRNA expression and liver triglyceride content as well as markers of lipogenesis in human liver biopsies. Inactivating mutations must have occurred in the GCKR gene on the lineages leading to: (1) tarsier, (2) ruminant artiodactyls, (3) cat, (4) bats, (5) hedgehog, and (6) common ancestor of Afrotheria and Xenarthra (see Figure 2). Therefore, the enzyme functions as a glucose sensor in pancreatic -cells. To address the hypothesis that liver-specific GCK deficiency is caused by the loss of GCKR, we identified and characterized GCKR genes from the genomes of diverse vertebrate species. LigGrep: a tool for filtering docked poses to improve virtual-screening hit rates. Glucokinase functions as the glucose sensor in the beta cell by controlling the rate of entry of glucose into the glycolytic pathway (glucose phosphorylation) and its subsequent metabolism. So, obviously, glucoskinase is present in the liver and the beta cells of the pancreas but not the rest of the body. Citation: Wang ZY, Jin L, Tan H, Irwin DM (2013) Evolution of Hepatic Glucose Metabolism: Liver-Specific Glucokinase Deficiency Explained by Parallel Loss of the Gene for Glucokinase Regulatory Protein (GCKR). , How Does Glucokinase And Insulin Regulate Blood Glucose Levels? Bader A, Fruhauf N, Tiedge M, Drinkgern M, De Bartolo L, Borlak JT, Steinhoff G, Haverich A: Enhanced oxygen delivery reverses anaerobic metabolic states in prolonged sandwich rat hepatocyte culture. , Hexokinase is an allosteric enzyme with **allosteric site for regulation of enzyme activity. The membranes were stained by Ponceau to verify the transfer of comparable amounts of cellular protein. Relative order and orientation of genes near the GCKR genes in human, chicken, Chinese softshell turtle, coelacanth, zebrafish and takifugu genomes. Glucokinase (GK)the enzyme catalyzing glucose phosphorylation, the rate-limiting step in glycolysis, and a major controller of glycogen synthesis (2, 3)is one such target.Heterozygous inactivating mutations of this enzyme produce an altered set point, increasing the threshold for insulin secretion (), whereas homozygous inactivating mutations produce a more severe phenotype that presents . Search for other works by this author on: Glucokinase as pancreatic cell glucose sensor and diabetes gene. Glucokinase regulatory protein (GCKR) is the most important post-transcriptional regulator of GCK in the liver; it participates in the modulation of GCK activity and location depending upon changes in glucose levels. Funding: This study was supported by a grant from the National Science Foundation of China (NSFC) -Canadian Institutes of Health Research (CIHR) China-Canada Joint Health Research Initiative to HT (81061120525) and DMI (CCI-109605). To determine why some GCKR genes are poorly annotated we used MultiPipMaker [38], [39] to align the genomic sequences of mammalian GCKR genes to the well-characterized human GCKR gene [43]. Storage and release of glucose is a tightly regulated process involving numerous enzymes and regulatory proteins, with glucokinase (GCK) being a key regulatory enzyme [1]. Takeda J, Gidh JM, Xu LZ, Froguel P, Velho G, Vaxillaire M, Cohen D, Shimada F, Makino H, Nishi S, et al. Function. Parnell LD All constructs were verified by sequence analyses. , Hughes TE Effects of glucose metabolism on the regulation of genes of fatty acid synthesis and triglyceride secretion in the liver. , The thermostatically controlled (37C) chamber was filled with 200 l of the appropriate medium and fixed on the stage of an Olympus IX81 inverted microscope (Olympus Optical, Tokyo, Japan) equipped with a PLAPO 60 1.4NA oil-immersion objective (Olympus) and a YFP/CFP dual-band beamsplitter and emitter (AHF Analysentechnik, Tubingen, Germany). Accessibility A group of enzymes that catalyzes the conversion of ATP and D-glucose to ADP and D-glucose 6-phosphate. Glucokinase is a hexokinase isoenzyme. Shown are means SE from five independent experiments. , , Omar Abuzeid*, Mia Heiligenstein, Lama Noureddine, Cassandra Heiselman eCollection 2021. The phylogenetic relationship is from Ensembl (www.ensembl.org). These results indicate that in liver, GCK requires GCKR for stability, and the absence of GCKR leads to GCK degradation. in humans, changes in glucokinase expression and activity are associated with poorly controlled type 2 diabetes and with nonalcoholic fatty liver disease, and a common variant of gkrp with altered binding affinity for glucokinase is associated with increased blood and liver lipids and other metabolic traits that implicate a role for gkrp in The following discussions of glycolysis include the enzymes responsible for the reactions. In experimental models, loss of GCKR has been shown to associate with reduced hepatic GCK protein levels and activity. In the liver, glucokinase plays a key role in the ability to store glucose as glycogen, particularly in the postprandial state. The sequences of peptides displayed by GRP-binding phages were identified through a selection protocol consisting of three rounds of high-stringency panning from a 12-mer random peitide M13 phage display library. As shown in Table 4, when the dog, panda, horse, and pig sequences were tested against the human sequence, no significant difference in the number of amino acid substitutions was seen on either lineage. , The SNP rs2041547 had no significant effect on GCK mRNA expression; however, the power was limited because of the smaller sample size. Glucokinase functions as the glucose sensor in the beta cell by controlling the rate of entry of glucose into the glycolytic pathway (glucose phosphorylation) and its subsequent metabolism. Efanov AM, Barrett DG, Brenner MB, Briggs SL, Delaunois A, Durbin JD, Giese U, Guo H, Radloff M, Sanz Gil G, Sewing S, Wang Y, Weichert A, Zaliani A, Gromada J: A novel glucokinase activator modulates pancreatic islet and hepatocyte function. After 3 h, the nonadherent cells were removed and attached cells transfected with 2 g plasmid DNA and 6 l jetPEI-Gal (Qbiogene) according to the manufacturers instructions. Background.There is a lack of predictive preclinical animal models combining atherosclerosis and type 2 diabetes. The glucokinase double-mutant L58R/N204Y was found exclusively in the cytoplasm at both high and low glucose concentrations (Fig. Biochem test 2 ONLY questions (for sure) Flashcards Its involvement in the pathogenesis of cancer, cardiovascular diseases, rheumatoid arthritis, and systemic lupus erythematosus have . Similar trees were generated when different protein distance measures, or distance measures based on nonsynonymous distances calculated from aligned DNA sequences, were used or if trees were built by other methods, such as parsimony or maximum likelihood. Vertebrate species that were previously reported to be deficient in hepatic GCK activity were found to have deleted (birds and lizard) or mutated (mammals) GCKR genes. However, the existence of a glucokinase nuclear export signal remains open because nuclear export of glucokinase was not inhibited by leptomycin B (41). Herein we summarize the current knowledge regarding the regulation of hepatic GCK activity. As a key target gene for diabetes mellitus, pharmacological activation of GCK is considered a promising novel strategy for antihyperglycemic drug therapy (3, 4). Riu E 2009 Jan;66(1):27-42. doi: 10.1007/s00018-008-8322-9. Please enable it to take advantage of the complete set of features! 4B and Table 3). An alternative explanation for this distribution of inactivated genes is that all of the Laurasiatherian GCKR genes are pseudogenes, which were generated by a single mutational event that did not disrupt the open reading frame but did disrupt GCKR protein function. The cod genome was also searched with genes that flank the GCKR gene in different fish genomes, and a genomic fragment with some similarity to that seen in coelacanth was found (containing FNDC, LDLRAP1, and BLK-like genes), but different from other ray-finned fish. Smith CI In contrast, large genomic fragments were typically identified from the avian genomes, where the FNDC4 and ZNF512 genes were linked on the same genomic fragment, as shown for the chicken in Figure 1. Wrote the paper: ZYW LJ HT DMI. Two-hundred microliters of the protein solution (200 ng/ml GRP in 0.1 mol/l NaHCO3) were incubated overnight at 4C with gentle agitation in the microplate wells. 2021 Dec 7;33(12):2329-2354. doi: 10.1016/j.cmet.2021.09.010. Tiedge M, Richter T, Lenzen S: Importance of cysteine residues for the stability and catalytic activity of human pancreatic beta cell glucokinase. HHS Vulnerability Disclosure, Help 6C), the helical structure formed by the amino acid residues 344355 is clearly exposed in the super-open conformation of glucokinase (Fig. While transient transfection of EYFP resulted in a uniform cellular distribution of the fluorescence protein, the EYFP-glucokinase construct was exclusively located in the cytoplasm. Francini F, Castro MC, Gagliardino JJ, Massa ML. Frontiers | The Central Role of Glucokinase in Glucose Homeostasis: A Tessari R Alignments of the GCKR gene exons allowed us to identify changes that have occurred in the GCKR gene in each species. Glucose is essential as an energy molecule by many cells in the body such as the neurons [1]; however, import of glucose is not essential for liver cells. Genes of fatty acid synthesis and triglyceride secretion in the cytoplasm at both high low. In the glucokinase sequence high and low glucose concentrations ( Fig emergencies, the! 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