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Glucokinase Edit Wikipedia article
|, FGQTL3, GK, GLK, HHF3, HK4, HKIV, HXKP, LGLK, MODY2, glucokinase|
|Genetically Related Diseases|
|Maturity onset diabetes of the young||
|RNA expression pattern|
|View/Edit Human||View/Edit Mouse|
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
Glucokinase (EC 220.127.116.11) is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver, pancreas, gut, and brain of humans and most other vertebrates. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising or falling levels of glucose, such as occur after a meal or when fasting. Mutations of the gene for this enzyme can cause unusual forms of diabetes or hypoglycemia.
Glucokinase (GK) is a hexokinase isozyme, related homologously to at least three other hexokinases. All of the hexokinases can mediate phosphorylation of glucose to glucose-6-phosphate (G6P), which is the first step of both glycogen synthesis and glycolysis. However, glucokinase is coded by a separate gene and its distinctive kinetic properties allow it to serve a different set of functions. Glucokinase has a lower affinity for glucose than the other hexokinases do, and its activity is localized to a few cell types, leaving the other three hexokinases as more important preparers of glucose for glycolysis and glycogen synthesis for most tissues and organs. Because of this reduced affinity, the activity of glucokinase, under usual physiological conditions, varies substantially according to the concentration of glucose.
- 1 Nomenclature
- 2 Catalysis
- 3 Structure
- 4 Genetics
- 5 Distribution among organ systems
- 6 Distribution among species
- 7 Function and regulation
- 8 Clinical significance
- 9 As a drug target
- 10 References
- 11 External links
Alternative names for this enzyme are: human hexokinase IV, hexokinase D, and ATP:D-hexose 6-phosphotransferase, EC 18.104.22.168 (previously 22.214.171.124). The common name, glucokinase, is derived from its relative specificity for glucose under physiologic conditions.
Some biochemists have argued that the name glucokinase should be abandoned as misleading, as this enzyme can phosphorylate other hexoses in the right conditions, and there are distantly related enzymes in bacteria with more absolute specificity for glucose that better deserve the name and the EC 126.96.36.199. Nevertheless, glucokinase remains the name preferred in the contexts of medicine and mammalian physiology.
Another mammalian glucose kinase, ADP-specific glucokinase, was discovered in 2004. The gene is distinct and similar to that of primitive organisms. It is dependent on ADP rather than ATP (suggesting the possibility of more effective function during hypoxia), and the metabolic role and importance remain to be elucidated.
Substrates and products
The principal substrate of physiologic importance of glucokinase is glucose, and the most important product is glucose-6-phosphate (G6P). The other necessary substrate, from which the phosphate is derived, is adenosine triphosphate (ATP), which is converted to adenosine diphosphate (ADP) when the phosphate is removed. The reaction catalyzed by glucokinase is:
ATP participates in the reaction in a form complexed to magnesium (Mg) as a cofactor. Furthermore, under certain conditions, glucokinase, like other hexokinases, can induce phosphorylation of other hexoses (6 carbon sugars) and similar molecules. Therefore, the general glucokinase reaction is more accurately described as:
Two important kinetic properties distinguish glucokinase from the other hexokinases, allowing it to function in a special role as glucose sensor.
- Glucokinase has a lower affinity for glucose than the other hexokinases. Glucokinase changes conformation and/or function in parallel with rising glucose concentrations in the physiologically important range of 4–10 mmol/L (72–180 mg/dl). It is half-saturated at a glucose concentration of about 8 mmol/L (144 mg/dl).
- Glucokinase is not inhibited by its product, glucose-6-phosphate. This allows continued signal output (e.g., to trigger insulin release) amid significant amounts of its product
These two features allow it to regulate a "supply-driven" metabolic pathway. That is, the rate of reaction is driven by the supply of glucose, not by the demand for end products.
Another distinctive property of glucokinase is its moderate cooperativity with glucose, with a Hill coefficient (nH) of about 1.7. Glucokinase has only a single binding site for glucose and is the only monomeric regulatory enzyme known to display substrate cooperativity. The nature of the cooperativity has been postulated to involve a "slow transition" between two different enzyme states with different rates of activity. If the dominant state depends upon glucose concentration, it would produce an apparent cooperativity similar to that observed.
Because of this cooperativity, the kinetic interaction of glucokinase with glucose does not follow classical Michaelis-Menten kinetics. Rather than a Km for glucose, it is more accurate to describe a half-saturation level S0.5, which is the concentration at which the enzyme is 50% saturated and active.
The S0.5 and nH extrapolate to an "inflection point" of the curve describing enzyme activity as a function of glucose concentration at about 4 mmol/L. In other words, at a glucose concentration of about 72 mg/dl, which is near the low end of the normal range, glucokinase activity is most sensitive to small changes in glucose concentration.
The kinetic relationship with the other substrate, MgATP, can be described by classical Michaelis-Menten kinetics, with an affinity at about 0.3–0.4 mmol/L, well below a typical intracellular concentration of 2.5 mmol/L. The fact that there is nearly always an excess of ATP available implies that ATP concentration rarely influences glucokinase activity.
The maximum specific activity (kcat, also known as the turnover rate) of glucokinase when saturated with both substrates is 62/s.
A "minimal mathematical model" has been devised based on the above kinetic information to predict the beta cell glucose phosphorylation rate (BGPR) of normal ("wild type") glucokinase and the known mutations. The BGPR for wild type glucokinase is about 28% at a glucose concentration of 5 mmol/l, indicating that the enzyme is running at 28% of capacity at the usual threshold glucose for triggering insulin release.
The sulfhydryl groups of several cysteines surround the glucose binding site. All except cys 230 are essential for the catalytic process, forming multiple disulfide bridges during interaction with the substrates and regulators. At least in the beta cells, the ratio of active to inactive glucokinase molecules is at least partly determined by the balance of oxidation of sulfhydryl groups or reduction of disulfide bridges.
These sulfhydryl groups are quite sensitive to the oxidation status of the cells, making glucokinase one of the components most vulnerable to oxidative stress, especially in the beta cells.
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534".
Glucokinase is a monomeric protein of 465 amino acids and a molecular weight of about 50 kD. There are at least two clefts, one for the active site, binding glucose and MgATP, and the other for a putative allosteric activator that has not yet been identified.
This is about half the size of the other mammalian hexokinases, which retain a degree of dimeric structure. Several sequences and the three-dimensional structure of the key active sites. The ATP binding domain, for example, are shared with hexokinases, bacterial glucokinases, and other proteins, and the common structure is termed an actin fold.
A distinctive feature of the gene is that it begins with two promoter regions. The first exon from the 5' end contains two tissue-specific promoter regions. Transcription can begin at either promoter (depending on the tissue) so that the same gene can produce a slightly different molecule in liver and in other tissues. The two isoforms of glucokinase differ only by 13–15 amino acids at the N-terminal end of the molecule, which produces only a minimal difference in structure. The two isoforms have the same kinetic and functional characteristics.
The first promoter from the 5' end, referred to as the "upstream" or neuroendocrine promoter, is active in pancreatic islet cells, neural tissue, and enterocytes (small intestine cells) to produce the "neuroendocrine isoform" of glucokinase. The second promoter, the "downstream" or liver promoter, is active in hepatocytes and directs production of the "liver isoform". The two promoters have little or no sequence homology and are separated by a 30 kbp sequence which has not yet been shown to incur any functional differences between isoforms. The two promoters are functionally exclusive and governed by distinct sets of regulatory factors, so that glucokinase expression can be regulated separately in different tissue types. The two promoters correspond to two broad categories of glucokinase function: In liver, glucokinase acts as the gateway for the "bulk processing" of available glucose, while, in the neuroendocrine cells, it acts as a sensor, triggering cell responses that affect body-wide carbohydrate metabolism.
Distribution among organ systems
Glucokinase has been discovered in specific cells in four types of mammalian tissue: liver, pancreas, small intestine, and brain. All play crucial roles in responding to rising or falling levels of blood glucose.
- The predominant cells of the liver are the hepatocytes, and GK is found exclusively in these cells. During digestion of a carbohydrate meal, when blood glucose is plentiful and insulin levels are high, hepatocytes remove glucose from the blood and store it as glycogen. After completion of digestion and absorption, the liver manufactures glucose from both non-glucose substrates (gluconeogenesis) and glycogen (glycogenolysis), and exports it into the blood, to maintain adequate blood glucose levels during fasting. Because GK activity rises rapidly as the glucose concentration rises, it serves as a central metabolic switch to shift hepatic carbohydrate metabolism between fed and fasting states. Phosphorylation of glucose to glucose-6-phosphate by GK facilitates storage of glucose as glycogen and disposal by glycolysis. The separate liver promoter allows glucokinase to be regulated differently in hepatocytes than in the neuroendocrine cells.
- Neuroendocrine cells of the pancreas, gut, and brain share some common aspects of glucokinase production, regulation, and function. These tissues are collectively referred to as "neuroendocrine" cells in this context.
- Beta cells and alpha cells of the pancreatic islets
- Beta cells release insulin in response to rising levels of glucose. Insulin enables many types of cells to import and use glucose, and signals the liver to synthesize glycogen. Alpha cells produce less glucagon in response to rising glucose levels, and more glucagon if blood glucose is low. Glucagon serves as a signal to the liver to break down glycogen and release glucose into the blood. Glucokinase in beta cells serves as a glucose sensor, amplifying insulin secretion as blood glucose rises.
- Glucose-sensitive neurons of the hypothalamus
- In response to rising or falling levels of glucose, cells in the hypothalamus polarize or depolarize. Among the neuroendocrine reactions of the central nervous system to hypoglycemia is activation of the adrenergic responses of the autonomic nervous system. Glucokinase likely serves as a glucose signal here as well. Glucokinase has also been found in cells of the anterior pituitary.
- Enterocytes of the small intestine
- This is the least-understood of the glucokinase sensor systems. It seems likely that responses to incoming glucose during digestion play a role in the incretin amplification of insulin secretion during a meal, or in the generation of satiety signals from gut to brain.
- Beta cells and alpha cells of the pancreatic islets
Distribution among species
Liver glucokinase occurs widely but not universally throughout vertebrate species. The gene structure and amino acid sequence are highly conserved among most mammals (e.g., rat and human glucokinase is more than 80% homologous). However, there are some unusual exceptions: For example, it has not been discovered in cats and bats, though some reptiles, birds, amphibians, and fish have it. Whether glucokinase occurs similarly in the pancreas and other organs has not yet been determined. It has been postulated that the presence of glucokinase in liver reflects the ease with which carbohydrates can be included in the animals' diets.
Function and regulation
Most of the glucokinase in a mammal is found in the liver, and glucokinase provides approximately 95% of the hexokinase activity in hepatocytes. Phosphorylation of glucose to glucose-6-phosphate (G6P) by glucokinase is the first step of both glycogen synthesis and glycolysis in the liver.
When ample glucose is available, glycogen synthesis proceeds at the periphery of the hepatocytes until the cells are replete with glycogen. Excess glucose is then increasingly converted into triglycerides for export and storage in adipose tissue. Glucokinase activity in the cytoplasm rises and falls with available glucose.
G6P, the product of glucokinase, is the principal substrate of glycogen synthesis, and glucokinase has a close functional and regulatory association with glycogen synthesis. When maximally active, GK and glycogen synthase appears to be located in the same peripheral areas of hepatocyte cytoplasm in which glycogen synthesis occurs. The supply of G6P affects the rate of glycogen synthesis not only as the primary substrate, but by direct stimulation of glycogen synthase and inhibition of glycogen phosphorylase.
Glucokinase activity can be rapidly amplified or damped in response to changes in the glucose supply, typically resulting from eating and fasting. Regulation occurs at several levels and speeds, and is influenced by many factors that affect mainly two general mechanisms:
- Glucokinase activity can be amplified or reduced in minutes by actions of the glucokinase regulatory protein (GKRP). The actions of this protein are influenced by small molecules such as glucose and fructose.
- The amount of glucokinase can be increased by synthesis of new protein. Insulin is the principal signal for increased transcription, operating mainly by way of a transcription factor called sterol regulatory element binding protein-1c (SREBP1c) except in the liver. This occurs within an hour after a rise in insulin levels, as after a carbohydrate meal.
Insulin acting via the sterol regulatory element binding protein-1c (SREBP1c) is thought to be the most important direct activator of glucokinase gene transcription in hepatocytes. SREBP1c is a basic helix-loop-helix zipper (bHLHZ) transactivator. This class of transactivators bind to the "E box" sequence of genes for a number of regulatory enzymes. The liver promoter in the first exon of the glucokinase gene includes such an E box, which appears to be the principal insulin-response element of the gene in hepatocytes. It was previously thought that SREBP1c must be present for transcription of glucokinase in hepatocytes however, it was recently shown that glucokinase transcription was carried out normally in SREBP1c knock out mice. SREBP1c increases in response to a high-carbohydrate diet, presumed as a direct effect of frequent insulin elevation. Increased transcription can be detected in less than an hour after hepatocytes are exposed to rising insulin levels.
2) also stimulates GK transcription, it seems by way of Akt2 rather than SREBP1c. It is not known whether this effect is one of the downstream effects of activation of insulin receptors or independent of insulin action. Levels of F2,6P
2 play other amplifying roles in glycolysis in hepatocytes.
Other transacting factors suspected of playing a role in liver cell transcription regulation include:
- Hepatic nuclear factor-4-alpha (HNF4α) is an orphan nuclear receptor important in the transcription of many genes for enzymes of carbohydrate and lipid metabolism. It activates GCK transcription.
- Upstream stimulatory factor 1 (USF1) is another basic helix-loop-helix zipper (bHLHZ) transactivator.
- Hepatic nuclear factor 6 (HNF6) is a homeodomain transcriptional regulator of the "one-cut class." HNF6 is also involved in regulation of transcription of gluconeogenic enzymes such as glucose-6-phosphatase and phosphoenolpyruvate carboxykinase.
Hormonal and dietary
Insulin is by far the most important of the hormones that have direct or indirect effects on glucokinase expression and activity in the liver. Insulin appears to affect both glucokinase transcription and activity through multiple direct and indirect pathways. While rising portal vein glucose levels increase glucokinase activity, the concomitant rise of insulin amplifies this effect by induction of glucokinase synthesis. Glucokinase transcription begins to rise within an hour of rising insulin levels. Glucokinase transcription becomes nearly undetectable in prolonged starvation, severe carbohydrate deprivation, or untreated insulin-deficient diabetes.
The mechanisms by which insulin induces glucokinase may involve both of the major intracellular pathways of insulin action, the extracellular signal-regulated kinase (ERK 1/2) cascade, and the phosphoinositide 3-kinase (PI3-K) cascade. The latter may operate via the FOXO1 transactivator.
However, as would be expected given its antagonistic effect on glycogen synthesis, glucagon and its intracellular second messenger cAMP suppresses glucokinase transcription and activity, even in the presence of insulin.
Other hormones such as triiodothyronine (T
3) and glucocorticoids provide permissive or stimulatory effects on glucokinase in certain circumstances. Biotin and retinoic acid increase GCK mRNA transcription as well as GK activity. Fatty acids in significant amounts amplify GK activity in the liver, while long chain acyl CoA inhibits it.
Glucokinase can be rapidly activated and inactivated in hepatocytes by a novel regulatory protein (glucokinase regulatory protein), which operates to maintain an inactive reserve of GK, which can be made quickly available in response to rising levels of portal vein glucose.
GKRP moves between nucleus and cytoplasm of the hepatocytes and may be tethered to the microfilament cytoskeleton. It forms reversible 1:1 complexes with GK, and can move it from the cytoplasm into the nucleus. It acts as a competitive inhibitor with glucose, such that the enzyme activity is reduced to near-zero while bound. GK:GKRP complexes are sequestered in the nucleus while glucose and fructose levels are low. Nuclear sequestration may serve to protect GK from degradation by cytoplasmic proteases. GK can be rapidly released from GKRP in response to rising levels of glucose. Unlike GK in beta cells, GK in hepatocytes is not associated with mitochondria.
Fructose in tiny (micromolar) amounts (after phosphorylation by ketohexokinase to fructose-1-phosphate (F1P)) accelerates release of GK from GKRP. This sensitivity to the presence of small amounts of fructose allows GKRP, GK, and ketohexokinase to act as a "fructose sensing system," which signals that a mixed carbohydrate meal is being digested, and accelerates the utilization of glucose. However, fructose 6-phosphate (F6P) potentiates binding of GK by GKRP. F6P decreases phosphorylation of glucose by GK when glycogenolysis or gluconeogenesis are underway. F1P and F6P both bind to the same site on GKRP. It is postulated that they produce 2 different conformations of GKRP, one able to bind GK and the other not.
Although most of the glucokinase in the body is in the liver, smaller amounts in the beta and alpha cells of the pancreas, certain hypothalamic neurons, and specific cells (enterocytes) of the gut play an increasingly appreciated role in regulation of carbohydrate metabolism. In the context of glucokinase function, these cell types are collectively referred to as neuroendocrine tissues, and they share some aspects of glucokinase regulation and function, especially the common neuroendocrine promoter. Of the neuroendocrine cells, the beta cells of the pancreatic islets are the most-studied and best-understood. It is likely that many of the regulatory relationships discovered in the beta cells will also exist in the other neuroendocrine tissues with glucokinase.
A signal for insulin
In islet beta cells, glucokinase activity serves as a principal control for the secretion of insulin in response to rising levels of blood glucose. As G6P is consumed, increasing amounts of ATP initiate a series of processes that result in release of insulin. One of the immediate consequences of increased cellular respiration is a rise in the NADH and NADPH concentrations (collectively referred to as NAD(P)H). This shift in the redox status of the beta cells results in rising intracellular calcium levels, closing of the KATP channels, depolarization of the cell membrane, merging of the insulin secretory granules with the membrane, and release of insulin into the blood.
It is as a signal for insulin release that glucokinase exerts the largest effect on blood sugar levels and overall direction of carbohydrate metabolism. Glucose, in turn, influences both the immediate activity and the amount of glucokinase produced in the beta cells.
Regulation in beta cells
Glucose immediately amplifies glucokinase activity by the cooperativity effect.
A second important rapid regulator of glucokinase activity in beta cells occurs by direct protein-protein interaction between glucokinase and the "bifunctional enzyme" (phosphofructokinase-2/fructose-2,6-bisphosphatase), which also plays a role in the regulation of glycolysis. This physical association stabilizes glucokinase in a catalytically favorable conformation (somewhat opposite the effect of GKRP binding) that enhances its activity.
In as little as 15 minutes, glucose can stimulate GCK transcription and glucokinase synthesis by way of insulin. Insulin is produced by the beta cells, but some of it acts on beta cell B-type insulin receptors, providing an autocrine positive-feedback amplification of glucokinase activity. Further amplification occurs by insulin action (via A-type receptors) to stimulate its own transcription.
Transcription of the GCK gene is initiated through the "upstream," or neuroendocrine, promoter. This promoter, in contrast to the liver promoter, has elements homologous to other insulin-induced gene promoters. Among the probable transacting factors are Pdx-1 and PPARγ. Pdx-1 is a homeodomain transcription factor involved in the differentiation of the pancreas. PPARγ is a nuclear receptor that responds to glitazone drugs by enhancing insulin sensitivity.
Association with insulin secretory granules
Much, but not all, of the glucokinase found in the cytoplasm of beta cells is associated with insulin secretory granules and with mitochondria. The proportion thus "bound" falls rapidly in response to rising glucose and insulin secretion. It has been suggested that binding serves a purpose similar to the hepatic glucokinase regulatory protein—protecting glucokinase from degradation so that it is rapidly available as the glucose rises. The effect is to amplify the glucokinase response to glucose more rapidly than transcription could do so.
Suppression of glucagon in alpha cells
It has also been proposed that glucokinase plays a role in the glucose sensing of the pancreatic alpha cells, but the evidence is less consistent, and some researchers have found no evidence of glucokinase activity in these cells. Alpha cells occur in pancreatic islets, mixed with beta and other cells. While beta cells respond to rising glucose levels by secreting insulin, alpha cells respond by reducing glucagon secretion. When blood glucose concentration falls to hypoglycemic levels, alpha cells release glucagon. Glucagon is a protein hormone that blocks the effect of insulin on hepatocytes, inducing glycogenolysis, gluconeogenesis, and reduced glucokinase activity in hepatocytes. The degree to which glucose suppression of glucagon is a direct effect of glucose via glucokinase in alpha cells, or an indirect effect mediated by insulin or other signals from beta cells, is still uncertain.
While all neurons use glucose for fuel, certain glucose-sensing neurons alter their firing rates in response to rising or falling levels of glucose. These glucose-sensing neurons are concentrated primarily in the ventromedial nucleus and arcuate nucleus of the hypothalamus, which regulate many aspects of glucose homeostasis (especially the response to hypoglycemia), fuel utilization, satiety and appetite, and weight maintenance. These neurons are most sensitive to glucose changes in the 0.5–3.5 mmol/L glucose range.
Glucokinase has been found in the brain in largely the same areas that contain glucose-sensing neurons, including both of the hypothalamic nuclei. Inhibition of glucokinase abolishes the ventromedial nucleus response to a meal. However, brain glucose levels are lower than plasma levels, typically 0.5–3.5 mmol/L. Although this range is matches the sensitivity of the glucose-sensing neurons, it is below the optimal inflection sensitivity for glucokinase. The presumption, based on indirect evidence and speculation, is that neuronal glucokinase is somehow exposed to plasma glucose levels even in the neurons.
Enterocytes and incretin
While glucokinase has been shown to occur in certain cells (enterocytes) of the small intestine and stomach, its function and regulation have not been worked out. It has been suggested that here, also, glucokinase serves as a glucose sensor, allowing these cells to provide one of the earliest metabolic responses to incoming carbohydrates. It is suspected that these cells are involved in incretin functions.
Because insulin is one of, if not the most important, regulators of glucokinase synthesis, diabetes mellitus of all types diminishes glucokinase synthesis and activity by a variety of mechanisms. Glucokinase activity is sensitive to oxidative stress of cells, especially the beta cells.
Around 200 mutations of the human glucokinase gene GCK have been discovered, that can change the efficiency of glucose binding and phosphorylation, increasing or decreasing the sensitivity of beta cell insulin secretion in response to glucose, and producing clinically significant hyperglycemia or hypoglycemia.
Over 190 of these mutations reduce the functional efficiency of the glucokinase molecule. Heterozygosity for alleles with reduced enzyme activity results in a higher threshold for insulin release and persistent, mild hyperglycemia. This condition is referred to as maturity onset diabetes of the young, type 2 (MODY2).
As of 2004, 5 mutations have been found to enhance insulin secretion. Heterozygosity for gain of function mutations reduces the threshold glucose that triggers insulin release. This creates hypoglycemia of varying patterns, including transient or persistent congenital hyperinsulinism, or fasting or reactive hypoglycemia appearing at an older age.
Homozygosity for gain of function mutations has not been found.
As a drug target
Several laboratories sponsored by pharmaceutical companies are researching molecules that activate glucokinase in hope that it will be useful in the treatment of type 2 diabetes. Potential glucokinase activator MK-0941 led to unsustained glycemic improvements, as well as increased blood pressure and hypoglycemia risk.
- Kawai S, Mukai T, Mori S, Mikami B, Murata K (April 2005). "Hypothesis: structures, evolution, and ancestor of glucose kinases in the hexokinase family". J. Biosci. Bioeng. 99 (4): 320–30. doi:10.1263/jbb.99.320. PMID 16233797.
- Iynedjian PB (January 2009). "Molecular physiology of mammalian glucokinase". Cell. Mol. Life Sci. 66 (1): 27–42. doi:10.1007/s00018-008-8322-9. PMC 2780631. PMID 18726182.
- Cardenas, M.L. (2004). "Comparative biochemistry of glucokinase". In Matschinsky, F.M.; Magnuson, M.A. Glucokinase And Glycemic Disease: From Basics to Novel Therapeutics (Frontiers in Diabetes). Basel: S. Karger AG (Switzerland). pp. 31–41. ISBN 3-8055-7744-3.
- Ronimus RS, Morgan HW (March 2004). "Cloning and biochemical characterization of a novel mouse ADP-dependent glucokinase". Biochem. Biophys. Res. Commun. 315 (3): 652–8. doi:10.1016/j.bbrc.2004.01.103. PMID 14975750.
- Magnuson, M.A.; Matschinsky, F.M. (2004). "Glucokinase as a glucose sensor: past, present, and future". In Matschinsky, F.M.; Magnuson, M.A. Glucokinase And Glycemic Disease: From Basics to Novel Therapeutics (Frontiers in Diabetes). Basel: S. Karger AG (Switzerland). pp. 18–30. ISBN 3-8055-7744-3.
- Bell, G.I.; Cuesta-Munoz, A.; Matschinsky, F.M. (2002). "Glucokinase". Encyclopedia of Molecular Medicine. Hoboken: John Wiley & Sons. ISBN 978-0-471-37494-7.
- Matschinsky FM (February 1996). "Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm". Diabetes 45 (2): 223–41. doi:10.2337/diabetes.45.2.223. PMID 8549869.
- Heredia VV, Thomson J, Nettleton D, Sun S (June 2006). "Glucose-induced conformational changes in glucokinase mediate allosteric regulation: transient kinetic analysis". Biochemistry 45 (24): 7553–62. doi:10.1021/bi060253q. PMID 16768451.
- Matschinsky FM, Glaser B, Magnuson MA (March 1998). "Pancreatic beta-cell glucokinase: closing the gap between theoretical concepts and experimental realities". Diabetes 47 (3): 307–15. doi:10.2337/diabetes.47.3.307. PMID 9519733.
- Lunin VV, Li Y, Schrag JD, Iannuzzi P, Cygler M, Matte A (October 2004). "Crystal structures of Escherichia coli ATP-dependent glucokinase and its complex with glucose". J. Bacteriol. 186 (20): 6915–27. doi:10.1128/JB.186.20.6915-6927.2004. PMC 522197. PMID 15466045.
- Mahalingam B, Cuesta-Munoz A, Davis EA, Matschinsky FM, Harrison RW, Weber IT (September 1999). "Structural model of human glucokinase in complex with glucose and ATP: implications for the mutants that cause hypo- and hyperglycemia". Diabetes 48 (9): 1698–705. doi:10.2337/diabetes.48.9.1698. PMID 10480597.
- Kamata K, Mitsuya M, Nishimura T, Eiki J, Nagata Y (March 2004). "Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase". Structure 12 (3): 429–38. doi:10.1016/j.str.2004.02.005. PMID 15016359.
Beautiful structural pictures illustrating the conformational changes and potential regulatory mechanisms
- Matsutani A, Janssen R, Donis-Keller H, Permutt MA (February 1992). "A polymorphic (CA)n repeat element maps the human glucokinase gene (GCK) to chromosome 7p". Genomics 12 (2): 319–25. doi:10.1016/0888-7543(92)90380-B. PMID 1740341.
- Stoffel M, Froguel P, Takeda J, Zouali H, Vionnet N, Nishi S, Weber IT, Harrison RW, Pilkis SJ, Lesage S (August 1992). "Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus". Proc. Natl. Acad. Sci. U.S.A. 89 (16): 7698–702. doi:10.1073/pnas.89.16.7698. PMC 49778. PMID 1502186.
- Wilson, J.E. (2004). "The hexokinase gene family". In Matschinsky, F.M.; Magnuson, M.A. Glucokinase And Glycemic Disease: From Basics to Novel Therapeutics (Frontiers in Diabetes). Basel: S. Karger AG (Switzerland). pp. 18–30. ISBN 3-8055-7744-3.
- Iynedjian PB, Pilot PR, Nouspikel T, et al. (October 1989). "Differential expression and regulation of the glucokinase gene in liver and islets of Langerhans". Proc. Natl. Acad. Sci. U.S.A. 86 (20): 7838–42. doi:10.1073/pnas.86.20.7838. PMC 298166. PMID 2682629.
- Iynedjian PB, Jotterand D, Nouspikel T, Asfari M, Pilot PR (December 1989). "Transcriptional induction of glucokinase gene by insulin in cultured liver cells and its repression by the glucagon-cAMP system". J. Biol. Chem. 264 (36): 21824–9. PMID 2557341.
- Jetton TL, Liang Y, Pettepher CC, et al. (February 1994). "Analysis of upstream glucokinase promoter activity in transgenic mice and identification of glucokinase in rare neuroendocrine cells in the brain and gut". J. Biol. Chem. 269 (5): 3641–54. PMID 8106409.
- Cárdenas, María Luz (1995). "Glucokinase": Its Regulation and Role in Liver Metabolism (Molecular Biology Intelligence Unit). R G Landes. ISBN 1-57059-207-1.
This is the most detailed treatment of liver glucokinase
- Arden C, Harbottle A, Baltrusch S, Tiedge M, Agius L (September 2004). "Glucokinase is an integral component of the insulin granules in glucose-responsive insulin secretory cells and does not translocate during glucose stimulation". Diabetes 53 (9): 2346–52. doi:10.2337/diabetes.53.9.2346. PMID 15331544.
- Jain, A. Glucokinase Activators in Diabetes Management
- Matschinsky, Franz (May 2009). "Assessing the potential of glucokinase activators in diabetes therapy" 8 (5): 399–419. doi:10.1038/nrd2850. PMID 19373249.
- Meininger GE, Scott R, Alba M, Shentu Y, Luo E, Amin H, Davies MJ, Kaufman KD, Goldstein BJ (December 2011). "Effects of MK-0941, a novel glucokinase activator, on glycemic control in insulin-treated patients with type 2 diabetes.". Diabetes Care 34 (12): 2560–6. doi:10.2337/dc11-1200. PMID 21994424.
- Glaser, Benjamin (2013-01-24). Familial Hyperinsulinism. PMID 20301549. NBK1375. In Pagon RA, Bird TD, Dolan CR, et al. (eds.). GeneReviews™ [Internet]. Seattle WA: University of Washington, Seattle.
- De León, Diva D; Stanley, Charles A (23 January 2014). Permanent Neonatal Diabetes Mellitus. PMID 20301620. NBK1447. In GeneReviews
- Glucokinase at the US National Library of Medicine Medical Subject Headings (MeSH)
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Glucokinase Provide feedback
This is a family of glucokinases or glucose kinases EC:188.8.131.52. These enzymes phosphorylate glucose using ATP as a donor to give glucose-6-phosphate and ADP.
Internal database links
|SCOOP:||Pan_kinase TCR Hydant_A_N|
|Similarity to PfamA using HHSearch:||ROK|
This tab holds annotation information from the InterPro database.
InterPro entry IPR003836
Glucokinases EC are found in invertebrates and microorganisms and are highly specific for glucose. These enzymes phosphorylate glucose using ATP as a donor to give glucose-6-phosphate and ADP [PUBMED:9023215].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||ATP binding (GO:0005524)|
|glucokinase activity (GO:0004340)|
|Biological process||glucose 6-phosphate metabolic process (GO:0051156)|
|glycolytic process (GO:0006096)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
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The actin-like ATPase domain forms an alpha/beta canonical fold. The domain can be subdivided into 1A, 1B, 2A and 2B subdomains. Subdomains 1A and 1B share the same RNAseH-like fold (a five-stranded beta-sheet decorated by a number of alpha-helices). Domains 1A and 2A are conserved in all members of this superfamily, whereas domain 1B and 2B have a variable structure and are even missing from some homologues . Within the actin-like ATPase domain the ATP-binding site is highly conserved. The phosphate part of the ATP is bound in a cleft between subdomains 1A and 2A, whereas the adenosine moiety is bound to residues from domains 2A and 2B.
The clan contains the following 31 members:Acetate_kinase Actin Actin_micro AnmK BcrAD_BadFG Carbam_trans_N DDR DUF1464 DUF2229 EutA FGGY_C FGGY_N FtsA Fumble GDA1_CD39 Glucokinase Hexokinase_1 Hexokinase_2 HGD-D HSP70 Hydant_A_N Hydantoinase_A MreB_Mbl MutL Pan_kinase Peptidase_M22 PilM_2 Ppx-GppA ROK StbA T2SSL
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Author:||Bashton M, Bateman A|
|Number in seed:||39|
|Number in full:||845|
|Average length of the domain:||308.50 aa|
|Average identity of full alignment:||31 %|
|Average coverage of the sequence by the domain:||89.57 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 17690987 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||14|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There is 1 interaction for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Glucokinase domain has been found. There are 15 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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