Glucokinase regulatory protein

Last updated
glucokinase (hexokinase 4) regulator
Identifiers
SymbolGCKR
NCBI gene 2646
HGNC 4196
OMIM 600842
RefSeq NM_001486
UniProt Q14397
Other data
Locus Chr. 2 p23
Search for
Structures Swiss-model
Domains InterPro

The glucokinase regulatory protein (GKRP) also known as glucokinase (hexokinase 4) regulator (GCKR) is a protein produced in hepatocytes (liver cells). GKRP binds and moves glucokinase (GK), thereby controlling both activity and intracellular location [1] [2] of this key enzyme of glucose metabolism. [3]

Contents

GKRP is a 68 kD protein of 626 amino acids. It is coded for by a 19 exon gene, GCKR, on the short arm of chromosome 2 (2p23). GKRP was discovered by Emile van Schaftingen and reported in 1989 [4]

Physiological function

Glucokinase (GK) in liver cells phosphorylates glucose, preparing it for incorporation into glycogen or for glycolysis. During periods of ample glucose supply, most GK activity can be found in the peripheral cytoplasm where glycogen synthesis is occurring. [5] As the glucose supply declines during periods of fasting, GK activity in the cytoplasm diminishes. GKRP participates in this modulation of GK activity and location by binding free cytoplasmic GK as glucose levels decline, and moving it into the nucleus, where it is held in reserve in an inactive form. [6] As glucose and insulin levels rise, as during digestion of a meal, GK is released from GKRP and moves back to the cytoplasm, where much of it associates with the bifunctional enzyme. [7]

In hepatocytes of various mammals, GKRP has always been found in molar excess of the amount of GK, but the GKRP:GK ratio varies according to diet, insulin sufficiency, and other factors. Free GKRP shuttles between the nucleus and the cytoplasm. It may be attached to the microfilament cytoskeleton. [8]

GKRP competes with glucose to bind with GK, but inactivates it when bound. In conditions of low glucose, GKRP then pulls the GK into the nucleus. Rising amounts of glucose coming into the hepatocyte prompt the GKRP to rapidly release GK to return to the cytoplasm.

GKRP itself is subject to modulation. Fructose and sorbitol can both be converted to fructose-1-phosphate, which inhibits GKRP and frees GK. [1] Fructose 6-phosphate binds to the same site of GKRP, but enhances the ability of GKRP to bind and inactivate GK. In contrast, phosphorylation of GKRP by AMP-activated protein kinase, induced by elevated levels of AMP, reduces its capacity to inactivate GK. [9]

Presence of GKRP in other organs

A presence and role of GKRP in other organs and tissues beyond the liver remains uncertain. Some researchers have finding small amounts of GKRP, or at least RNA coding for it, in small amounts in certain rat lung cells, in pancreatic islet cells, and in periventricular neurons of the hypothalamus in rats, [10] but physiological function and significance in these organs are unknown.

Species differences

GKRP was originally discovered in rat liver. GKRP was found to serve a similar function in livers of mice and humans as well as other animals. [11] Cats are unusual in lacking GK activity, and have also been found to lack GKRP, though the genes for both GK and GKRP can be identified in the feline genome. [12]

Clinical significance

Many mutant forms of human GK are associated with impaired or amplified insulin secretion or action, resulting in higher or lower blood glucose levels, and either diabetes (MODY2) or hyperinsulinemic hypoglycemia, respectively. Some of these variants have altered interaction with GKRP, which may contribute to the hyperglycemia. [13] [14] [15] [16]

The glucokinase of "knockout mice" who lack GKRP has a reduced expression and is entirely found in the cytoplasm. The knockout mice do not respond rapidly to glucose, exhibiting impaired glucose tolerance. [17] Mutations of the GKRP gene (GCKR) in humans have been sought as possible causes of monogenic diabetes (MODY), but no examples have yet been discovered. However, variant forms of GCKR have been found to be associated with small differences in levels of glucose, insulin, triglycerides, C-reactive protein, and higher or lower risks for type 2 diabetes mellitus. [18] [19] [20] [21]

Activators of GK are being investigated as possible medicines for type 2 diabetes. One of the mechanisms of activation may be protection from binding by GKRP. [22]

Related Research Articles

<span class="mw-page-title-main">Glycolysis</span> Series of interconnected biochemical reactions

Glycolysis is the metabolic pathway that converts glucose into pyruvate, and in most organisms, occurs in the liquid part of cells, the cytosol. The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes.

<span class="mw-page-title-main">Hexokinase</span> Class of enzymes

A hexokinase is an enzyme that irreversibly phosphorylates hexoses, forming hexose phosphate. In most organisms, glucose is the most important substrate for hexokinases, and glucose-6-phosphate is the most important product. Hexokinase possesses the ability to transfer an inorganic phosphate group from ATP to a substrate.

Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.

<span class="mw-page-title-main">AMP-activated protein kinase</span> Class of enzymes

5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. It belongs to a highly conserved eukaryotic protein family and its orthologues are SNF1 in yeast, and SnRK1 in plants. It consists of three proteins (subunits) that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. In response to binding AMP and ADP, the net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, inhibition of adipocyte lipolysis, and modulation of insulin secretion by pancreatic β-cells.

<span class="mw-page-title-main">Glucokinase</span> Enzyme participating to the regulation of carbohydrate metabolism

Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas 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.

<span class="mw-page-title-main">Pyruvate carboxylase</span> Enzyme

Pyruvate carboxylase (PC) encoded by the gene PC is an enzyme of the ligase class that catalyzes the physiologically irreversible carboxylation of pyruvate to form oxaloacetate (OAA).

<span class="mw-page-title-main">Phosphofructokinase 2</span> Class of enzymes

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. It catalyzes formation and degradation of a significant allosteric regulator, fructose-2,6-bisphosphate (Fru-2,6-P2) from substrate fructose-6-phosphate. Fru-2,6-P2 contributes to the rate-determining step of glycolysis as it activates enzyme phosphofructokinase 1 in the glycolysis pathway, and inhibits fructose-1,6-bisphosphatase 1 in gluconeogenesis. Since Fru-2,6-P2 differentially regulates glycolysis and gluconeogenesis, it can act as a key signal to switch between the opposing pathways. Because PFK-2 produces Fru-2,6-P2 in response to hormonal signaling, metabolism can be more sensitively and efficiently controlled to align with the organism's glycolytic needs. This enzyme participates in fructose and mannose metabolism. The enzyme is important in the regulation of hepatic carbohydrate metabolism and is found in greatest quantities in the liver, kidney and heart. In mammals, several genes often encode different isoforms, each of which differs in its tissue distribution and enzymatic activity. The family described here bears a resemblance to the ATP-driven phospho-fructokinases, however, they share little sequence similarity, although a few residues seem key to their interaction with fructose 6-phosphate.

In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride synthesis, with the latter being the process by which fatty acids are esterified to glycerol before being packaged into very-low-density lipoprotein (VLDL). Fatty acids are produced in the cytoplasm of cells by repeatedly adding two-carbon units to acetyl-CoA. Triacylglycerol synthesis, on the other hand, occurs in the endoplasmic reticulum membrane of cells by bonding three fatty acid molecules to a glycerol molecule. Both processes take place mainly in liver and adipose tissue. Nevertheless, it also occurs to some extent in other tissues such as the gut and kidney. A review on lipogenesis in the brain was published in 2008 by Lopez and Vidal-Puig. After being packaged into VLDL in the liver, the resulting lipoprotein is then secreted directly into the blood for delivery to peripheral tissues.

Glucose transporter type 4 (GLUT4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the SLC2A4 gene. GLUT4 is the insulin-regulated glucose transporter found primarily in adipose tissues and striated muscle. The first evidence for this distinct glucose transport protein was provided by David James in 1988. The gene that encodes GLUT4 was cloned and mapped in 1989.

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<span class="mw-page-title-main">Fructokinase</span> Class of enzymes

Fructokinase, also known as D-fructokinase or D-fructose (D-mannose) kinase, is an enzyme of the liver, intestine, and kidney cortex. Fructokinase is in a family of enzymes called transferases, meaning that this enzyme transfers functional groups; it is also considered a phosphotransferase since it specifically transfers a phosphate group. Fructokinase specifically catalyzes the transfer of a phosphate group from adenosine triphosphate to fructose as the initial step in its utilization. The main role of fructokinase is in carbohydrate metabolism, more specifically, sucrose and fructose metabolism. The reaction equation is as follows:

<span class="mw-page-title-main">Enzyme activator</span> Molecules which increase enzyme activity

Enzyme activators are molecules that bind to enzymes and increase their activity. They are the opposite of enzyme inhibitors. These molecules are often involved in the allosteric regulation of enzymes in the control of metabolism. An example of an enzyme activator working in this way is fructose 2,6-bisphosphate, which activates phosphofructokinase 1 and increases the rate of glycolysis in response to the hormone glucagon. In some cases, when a substrate binds to one catalytic subunit of an enzyme, this can trigger an increase in the substrate affinity as well as catalytic activity in the enzyme's other subunits, and thus the substrate acts as an activator.

<span class="mw-page-title-main">Carbohydrate-responsive element-binding protein</span> Protein-coding gene in the species Homo sapiens

Carbohydrate-responsive element-binding protein (ChREBP) also known as MLX-interacting protein-like (MLXIPL) is a protein that in humans is encoded by the MLXIPL gene. The protein name derives from the protein's interaction with carbohydrate response element sequences of DNA.

Fructolysis refers to the metabolism of fructose from dietary sources. Though the metabolism of glucose through glycolysis uses many of the same enzymes and intermediate structures as those in fructolysis, the two sugars have very different metabolic fates in human metabolism. Unlike glucose, which is directly metabolized widely in the body, fructose is almost entirely metabolized in the liver in humans, where it is directed toward replenishment of liver glycogen and triglyceride synthesis. Under one percent of ingested fructose is directly converted to plasma triglyceride. 29% - 54% of fructose is converted in liver to glucose, and about a quarter of fructose is converted to lactate. 15% - 18% is converted to glycogen. Glucose and lactate are then used normally as energy to fuel cells all over the body.

<span class="mw-page-title-main">Forkhead box protein O1</span> Protein

Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the FOXO1 gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glycogenolysis by insulin signaling, and is also central to the decision for a preadipocyte to commit to adipogenesis. It is primarily regulated through phosphorylation on multiple residues; its transcriptional activity is dependent on its phosphorylation state.

<span class="mw-page-title-main">MODY 1</span> Medical condition

MODY 1 or HNF4A-MODY is a form of maturity onset diabetes of the young.

Pyruvate cycling commonly refers to an intracellular loop of spatial movements and chemical transformations involving pyruvate. Spatial movements occur between mitochondria and cytosol and chemical transformations create various Krebs cycle intermediates. In all variants, pyruvate is imported into the mitochondrion for processing through part of the Krebs cycle. In addition to pyruvate, alpha-ketoglutarate may also be imported. At various points, the intermediate product is exported to the cytosol for additional transformations and then re-imported. Three specific pyruvate cycles are generally considered, each named for the principal molecule exported from the mitochondrion: malate, citrate, and isocitrate. Other variants may exist, such as dissipative or "futile" pyruvate cycles.

The insulin transduction pathway is a biochemical pathway by which insulin increases the uptake of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver and hence is involved in maintaining glucose homeostasis. This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones.

<span class="mw-page-title-main">Glucokinase regulator</span> Protein-coding gene in the species Homo sapiens

Glucokinase regulator is a protein that in humans is encoded by the GCKR gene.

Hepatokines are proteins produced by liver cells (hepatocytes) that are secreted into the circulation and function as hormones across the organism. Research is mostly focused on hepatokines that play a role in the regulation of metabolic diseases such as diabetes and fatty liver and include: Adropin, ANGPTL4, Fetuin-A, Fetuin-B, FGF-21, Hepassocin, LECT2, RBP4,Selenoprotein P, Sex hormone-binding globulin.

References

  1. 1 2 Van Schaftingen E (September 1994). "Short-term regulation of glucokinase". Diabetologia. 37 (Suppl 2): S43-7. doi: 10.1007/bf00400825 . PMID   7821739.
  2. ↑ de la Iglesia N, Veiga-da-Cunha M, Van Schaftingen E, Guinovart JJ, Ferrer JC (August 1999). "Glucokinase regulatory protein is essential for the proper subcellular localisation of liver glucokinase". FEBS Letters. 456 (2): 332–8. doi: 10.1016/S0014-5793(99)00971-0 . PMID   10456334. S2CID   11923216.
  3. ↑ Iynedjian PB (January 2009). "Molecular physiology of mammalian glucokinase". Cellular and Molecular Life Sciences. 66 (1): 27–42. doi:10.1007/s00018-008-8322-9. PMC   2780631 . PMID   18726182.
  4. ↑ Van Schaftingen E (January 1989). "A protein from rat liver confers to glucokinase the property of being antagonistically regulated by fructose 6-phosphate and fructose 1-phosphate". European Journal of Biochemistry. 179 (1): 179–84. doi:10.1111/j.1432-1033.1989.tb14538.x. PMID   2917560.
  5. ↑ Jetton TL, Shiota M, Knobel SM, Piston DW, Cherrington AD, Magnuson MA (2001). "Substrate-induced nuclear export and peripheral compartmentalization of hepatic glucokinase correlates with glycogen deposition". International Journal of Experimental Diabetes Research. 2 (3): 173–86. doi: 10.1155/EDR.2001.173 . PMC   2478546 . PMID   12369705.
  6. ↑ Shiota C, Coffey J, Grimsby J, Grippo JF, Magnuson MA (December 1999). "Nuclear import of hepatic glucokinase depends upon glucokinase regulatory protein, whereas export is due to a nuclear export signal sequence in glucokinase". The Journal of Biological Chemistry. 274 (52): 37125–30. doi: 10.1074/jbc.274.52.37125 . PMID   10601273.
  7. ↑ Payne VA, Arden C, Wu C, Lange AJ, Agius L (July 2005). "Dual role of phosphofructokinase-2/fructose bisphosphatase-2 in regulating the compartmentation and expression of glucokinase in hepatocytes". Diabetes. 54 (7): 1949–57. doi: 10.2337/diabetes.54.7.1949 . PMID   15983194.
  8. ↑ van Schaftingen EF, Veiga da Cunha M (2004). "Discovery and role of glucokinase regulatory protein". In Matschinsky M (ed.). in Glucokinase And Glycemic Disease: From Basics to Novel Therapeutics (Frontiers in Diabetes). S. Karger AG (Switzerland). pp. 197–307. ISBN   978-3-8055-7744-1.
  9. ↑ Mukhtar MH, Payne VA, Arden C, Harbottle A, Khan S, Lange AJ, Agius L (March 2008). "Inhibition of glucokinase translocation by AMP-activated protein kinase is associated with phosphorylation of both GKRP and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 294 (3): R766-74. doi:10.1152/ajpregu.00593.2007. PMID   18199594.
  10. ↑ Alvarez E, Roncero I, Chowen JA, Vázquez P, Blázquez E (January 2002). "Evidence that glucokinase regulatory protein is expressed and interacts with glucokinase in rat brain". Journal of Neurochemistry. 80 (1): 45–53. doi: 10.1046/j.0022-3042.2001.00677.x . PMID   11796742. S2CID   46075589.
  11. ↑ Polakof S, Míguez JM, Soengas JL (July 2009). "A hepatic protein modulates glucokinase activity in fish and avian liver: a comparative study". Journal of Comparative Physiology B: Biochemical, Systemic, and Environmental Physiology. 179 (5): 643–52. doi:10.1007/s00360-009-0346-4. PMID   19247671. S2CID   38796726.
  12. ↑ Hiskett EK, Suwitheechon OU, Lindbloom-Hawley S, Boyle DL, Schermerhorn T (March 2009). "Lack of glucokinase regulatory protein expression may contribute to low glucokinase activity in feline liver". Veterinary Research Communications. 33 (3): 227–40. doi:10.1007/s11259-008-9171-6. PMID   18780155. S2CID   11115622.
  13. ↑ Arden C, Trainer A, de la Iglesia N, Scougall KT, Gloyn AL, Lange AJ, Shaw JA, Matschinsky FM, Agius L (July 2007). "Cell biology assessment of glucokinase mutations V62M and G72R in pancreatic beta-cells: evidence for cellular instability of catalytic activity". Diabetes. 56 (7): 1773–82. doi: 10.2337/db06-1151 . PMID   17389332.
  14. ↑ García-Herrero CM, Galán M, Vincent O, Flández B, Gargallo M, Delgado-Alvarez E, Blázquez E, Navas MA (February 2007). "Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity". Diabetologia. 50 (2): 325–33. doi: 10.1007/s00125-006-0542-7 . PMID   17186219.
  15. ↑ Heredia VV, Carlson TJ, Garcia E, Sun S (December 2006). "Biochemical basis of glucokinase activation and the regulation by glucokinase regulatory protein in naturally occurring mutations". The Journal of Biological Chemistry. 281 (52): 40201–7. doi: 10.1074/jbc.M607987200 . PMID   17082186.
  16. ↑ Pino MF, Kim KA, Shelton KD, Lindner J, Odili S, Li C, Collins HW, Shiota M, Matschinsky FM, Magnuson MA (May 2007). "Glucokinase thermolability and hepatic regulatory protein binding are essential factors for predicting the blood glucose phenotype of missense mutations". The Journal of Biological Chemistry. 282 (18): 13906–16. doi: 10.1074/jbc.M610094200 . PMID   17353190.
  17. ↑ Grimsby J, Coffey JW, Dvorozniak MT, Magram J, Li G, Matschinsky FM, Shiota C, Kaur S, Magnuson MA, Grippo JF (March 2000). "Characterization of glucokinase regulatory protein-deficient mice". The Journal of Biological Chemistry. 275 (11): 7826–31. doi: 10.1074/jbc.275.11.7826 . PMID   10713097.
  18. ↑ Køster B, Fenger M, Poulsen P, Vaag A, Bentzen J (December 2005). "Novel polymorphisms in the GCKR gene and their influence on glucose and insulin levels in a Danish twin population". Diabetic Medicine. 22 (12): 1677–82. doi: 10.1111/j.1464-5491.2005.01700.x . PMID   16401311. S2CID   20786263.
  19. ↑ Orho-Melander M, Melander O, Guiducci C, Perez-Martinez P, Corella D, Roos C, et al. (November 2008). "Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations". Diabetes. 57 (11): 3112–21. doi:10.2337/db08-0516. PMC   2570409 . PMID   18678614.
  20. ↑ Tam CH, Ma RC, So WY, Wang Y, Lam VK, Germer S, Martin M, Chan JC, Ng MC (March 2009). "Interaction effect of genetic polymorphisms in glucokinase (GCK) and glucokinase regulatory protein (GCKR) on metabolic traits in healthy Chinese adults and adolescents". Diabetes. 58 (3): 765–9. doi:10.2337/db08-1277. PMC   2646078 . PMID   19073768.
  21. ↑ Bi M, Kao WH, Boerwinkle E, Hoogeveen RC, Rasmussen-Torvik LJ, Astor BC, North KE, Coresh J, Köttgen A (July 2010). "Association of rs780094 in GCKR with metabolic traits and incident diabetes and cardiovascular disease: the ARIC Study". PLOS ONE. 5 (7): e11690. Bibcode:2010PLoSO...511690B. doi: 10.1371/journal.pone.0011690 . PMC   2908550 . PMID   20661421.
  22. ↑ Futamura M, Hosaka H, Kadotani A, Shimazaki H, Sasaki K, Ohyama S, Nishimura T, Eiki J, Nagata Y (December 2006). "An allosteric activator of glucokinase impairs the interaction of glucokinase and glucokinase regulatory protein and regulates glucose metabolism". The Journal of Biological Chemistry. 281 (49): 37668–74. doi: 10.1074/jbc.M605186200 . PMID   17028192.
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