HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 14, 14105-14113, April 8, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/14/14105    most recent M413146200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gloyn, A. L. Articles by Matschinsky, F. M. Search for Related Content PubMed PubMed Citation Articles by Gloyn, A. L. Articles by Matschinsky, F. M. Social Bookmarking                      What's this?

Insights into the Structure and Regulation of Glucokinase from a Novel Mutation (V62M), Which Causes Maturity-onset Diabetes of the Young^*

From the ^aDiabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, United Kingdom, the ^bInstitute of Biomedical and Clinical Science, Peninsula Medical School, Exeter EX2 5DW, United Kingdom, the ^dDepartment of Biochemistry & Biophysics and Diabetes Research Center, University of Pennsylvania School of Medicine, Philadelphia 19104, the ^eDepartment of Molecular Biophysics and Physiology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615, the ^fDepartment of Pediatrics, University of Genoa, G. Gaslini Institute, Genoa 16147, Italy, the ^gDivision of Endocrinology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, the ⁱLaboratorie de Chimie Physiologique, Christan de Duve Institute of Cellular Pathology and Universite Catholique de Louvain, Brussels BE-1200, Belgium, the ^kIstituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesu, Rome 81 001323, Italy, and the ^lDepartment of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, New Jersey 07110

Glucokinase (GCK) serves as the pancreatic glucose sensor. Heterozygous inactivating GCK mutations cause hyperglycemia, whereas activating mutations cause hypoglycemia. We studied the GCK V62M mutation identified in two families and co-segregating with hyperglycemia to understand how this mutation resulted in reduced function. Structural modeling locates the mutation close to five naturally occurring activating mutations in the allosteric activator site of the enzyme. Recombinant glutathionyl S-transferase-V62M GCK is paradoxically activated rather than inactivated due to a decreased S_0.5 for glucose compared with wild type (4.88 versus 7.55 mM). The recently described pharmacological activator (RO0281675) interacts with GCK at this site. V62M GCK does not respond to RO0281675, nor does it respond to the hepatic glucokinase regulatory protein (GKRP). The enzyme is also thermally unstable, but this lability is apparently less pronounced than in the proven instability mutant E300K. Functional and structural analysis of seven amino acid substitutions at residue Val⁶² has identified a non-linear relationship between activation by the pharmacological activator and the van der Waals interactions energies. Smaller energies allow a hydrophobic interaction between the activator and glucokinase, whereas larger energies prohibit the ligand from fitting into the binding pocket. We conclude that V62M may cause hyperglycemia by a complex defect of GCK regulation involving instability in combination with loss of control by a putative endogenous activator and/or GKRP. This study illustrates that mutations that cause hyperglycemia are not necessarily kinetically inactivating but may exert their effects by other complex mechanisms. Elucidating such mechanisms leads to a deeper understanding of the GCK glucose sensor and the biochemistry of -cells and hepatocytes.

Received for publication, November 22, 2004 , and in revised form, January 20, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact..

^c A Diabetes UK RD Lawrence Research Fellow. Supported by a European Foundation for the Study of Diabetes Travel Fellowship and by NIDDK Grant 22122 from the National Institutes of Health (to F. M. M.).

^h Funded by National Institutes of Health Grant RO1-DK53013.

^j A chercheur qualifie of the Belgian Fonds National de la Rescherche Scientifique.

^m A Wellcome Trust Clinical Research Leave Fellow.

ⁿ To whom correspondence should be addressed: Diabetes Research Center, Rm. 510, Stemmler Hall, 36th and Hamilton Walk, University of Pennsylvania, Philadelphia, PA 19104. Tel.: 215-898-4365; Fax: 215-898-2178; E-mail: matsch{at}mail.med.upenn.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. Sayed, D. R. Langdon, S. Odili, P. Chen, C. Buettger, A. B. Schiffman, M. Suchi, R. Taub, J. Grimsby, F. M. Matschinsky, et al. Extremes of Clinical and Enzymatic Phenotypes in Children With Hyperinsulinism Caused by Glucokinase Activating Mutations Diabetes, June 1, 2009; 58(6): 1419 - 1427. [Abstract] [Full Text] [PDF]

				O. Anderka, J. Boyken, U. Aschenbach, A. Batzer, O. Boscheinen, and D. Schmoll Biophysical Characterization of the Interaction between Hepatic Glucokinase and Its Regulatory Protein: IMPACT OF PHYSIOLOGICAL AND PHARMACOLOGICAL EFFECTORS J. Biol. Chem., November 14, 2008; 283(46): 31333 - 31340. [Abstract] [Full Text] [PDF]

				H. B T Christesen, N. D Tribble, A. Molven, J. Siddiqui, T. Sandal, K. Brusgaard, S. Ellard, P. R Njolstad, J. Alm, B. Brock Jacobsen, et al. Activating glucokinase (GCK) mutations as a cause of medically responsive congenital hyperinsulinism: prevalence in children and characterisation of a novel GCK mutation. Eur. J. Endocrinol., July 1, 2008; 159(1): 27 - 34. [Abstract] [Full Text] [PDF]

				C. Arden, A. Trainer, N. de la Iglesia, K. T. Scougall, A. L. Gloyn, A. J. Lange, J. A.M. Shaw, F. M. Matschinsky, and L. Agius Cell Biology Assessment of Glucokinase Mutations V62M and G72R in Pancreatic {beta}-Cells: Evidence for Cellular Instability of Catalytic Activity Diabetes, July 1, 2007; 56(7): 1773 - 1782. [Abstract] [Full Text] [PDF]

				M. F. Pino, K.-A. Kim, K. D. Shelton, J. Lindner, S. Odili, C. Li, H. W. Collins, M. Shiota, F. M. Matschinsky, and M. A. Magnuson Glucokinase Thermolability and Hepatic Regulatory Protein Binding Are Essential Factors for Predicting the Blood Glucose Phenotype of Missense Mutations J. Biol. Chem., May 4, 2007; 282(18): 13906 - 13916. [Abstract] [Full Text] [PDF]

				G. A. Martens, Q. Wang, K. Kerckhofs, G. Stange, Z. Ling, and D. Pipeleers Metabolic Activation of Glucose Low-Responsive {beta}-Cells by Glyceraldehyde Correlates with Their Biosynthetic Activation in Lower Glucose Concentration Range But Not at High Glucose Endocrinology, November 1, 2006; 147(11): 5196 - 5204. [Abstract] [Full Text] [PDF]

				J. Zhang, C. Li, K. Chen, W. Zhu, X. Shen, and H. Jiang Conformational transition pathway in the allosteric process of human glucokinase PNAS, September 5, 2006; 103(36): 13368 - 13373. [Abstract] [Full Text] [PDF]

				J. E. Lindsley and J. Rutter Whence cometh the allosterome? PNAS, July 11, 2006; 103(28): 10533 - 10535. [Abstract] [Full Text] [PDF]

				J. V. Sagen, S. Odili, L. Bjorkhaug, D. Zelent, C. Buettger, J. Kwagh, C. Stanley, K. Dahl-Jorgensen, C. de Beaufort, G. I. Bell, et al. From Clinicogenetic Studies of Maturity-Onset Diabetes of the Young to Unraveling Complex Mechanisms of Glucokinase Regulation Diabetes, June 1, 2006; 55(6): 1713 - 1722. [Abstract] [Full Text] [PDF]

				F. M. Matschinsky, M. A. Magnuson, D. Zelent, T. L. Jetton, N. Doliba, Y. Han, R. Taub, and J. Grimsby The Network of Glucokinase-Expressing Cells in Glucose Homeostasis and the Potential of Glucokinase Activators for Diabetes Therapy Diabetes, January 1, 2006; 55(1): 1 - 12. [Abstract] [Full Text] [PDF]

				R. L. Printz and D. K. Granner Tweaking the Glucose Sensor: Adjusting Glucokinase Activity with Activator Compounds Endocrinology, September 1, 2005; 146(9): 3693 - 3695. [Full Text] [PDF]

				A. M. Efanov, D. G. Barrett, M. B. Brenner, S. L. Briggs, A. Delaunois, J. D. Durbin, U. Giese, H. Guo, M. Radloff, G. S. Gil, et al. A Novel Glucokinase Activator Modulates Pancreatic Islet and Hepatocyte Function Endocrinology, September 1, 2005; 146(9): 3696 - 3701. [Abstract] [Full Text] [PDF]