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Glucokinase regulatory protein

April 12, 2024

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]

glucokinase (hexokinase 4) regulator
Identifiers
SymbolGCKR
NCBI gene2646
HGNC4196
OMIM600842
RefSeqNM_001486
UniProtQ14397
Other data
LocusChr. 2 p23
Search for
StructuresSwiss-model
DomainsInterPro

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 edit

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 edit

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 edit

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 edit

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]

References edit

  1. ^ a b 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.

April 12, 2024
glucokinase, regulatory, protein, glucokinase, regulatory, protein, gkrp, also, known, glucokinase, hexokinase, regulator, gckr, protein, produced, hepatocytes, liver, cells, gkrp, binds, moves, glucokinase, thereby, controlling, both, activity, intracellular,. 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 glucokinase hexokinase 4 regulatorIdentifiersSymbolGCKRNCBI gene2646HGNC4196OMIM600842RefSeqNM 001486UniProtQ14397Other dataLocusChr 2 p23Search forStructuresSwiss modelDomainsInterProGKRP 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 Contents 1 Physiological function 2 Presence of GKRP in other organs 3 Species differences 4 Clinical significance 5 ReferencesPhysiological function editGlucokinase 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 editA 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 editGKRP 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 editMany 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 References edit a b Van Schaftingen E September 1994 Short term regulation of glucokinase Diabetologia 37 Suppl 2 S43 7 doi 10 1007 bf00400825 PMID 7821739 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 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 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 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 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 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 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 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 Alvarez E Roncero I Chowen JA Vazquez P Blazquez 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 Polakof S Miguez 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 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 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 Garcia Herrero CM Galan M Vincent O Flandez B Gargallo M Delgado Alvarez E Blazquez 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 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 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 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 Koster 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 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 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 Bi M Kao WH Boerwinkle E Hoogeveen RC Rasmussen Torvik LJ Astor BC North KE Coresh J Kottgen 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 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 Retrieved from https en wikipedia org w index php title Glucokinase regulatory protein amp oldid 1190808747, wikipedia, wiki, book, books, library,

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