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

J. Biol. Chem., Vol. 279, Issue 14, 13976-13983, April 2, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/14/13976    most recent M307756200v1 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 Petrolonis, A. J. Articles by Hong, S.-B. Search for Related Content PubMed PubMed Citation Articles by Petrolonis, A. J. Articles by Hong, S.-B. Social Bookmarking                      What's this?

Enzymatic Characterization of the Pancreatic Islet-specific Glucose-6-Phosphatase-related Protein (IGRP)^*

Anthony J. Petrolonis, Qing Yang, Peter J. Tummino, Susan M. Fish, Andrea E. Prack, Sadhana Jain, Thomas F. Parsons, Ping Li, Natalie A. Dales, Lin Ge, Steven P. Langston, Alwin G. P. Schuller, W. Frank An, Louis A. Tartaglia, Hong Chen, and Suk-Bong Hong

From the Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139

Glucose is the main physiological stimulus for insulin biosynthesis and secretion by pancreatic -cells. Glucose-6-phosphatase (G-6-Pase) catalyzes the dephosphorylation of glucose-6-phosphate to glucose, an opposite process to glucose utilization. G-6-Pase activity in pancreatic islets could therefore be an important factor in the control of glucose metabolism and, consequently, of glucose-dependent insulin secretion. While G-6-Pase activity has been shown to be present in pancreatic islets, the gene responsible for this activity has not been conclusively identified. A homolog of liver glucose-6-phosphatase (LG-6-Pase) specifically expressed in islets was described earlier; however, the authors could not demonstrate enzymatic activity for this protein. Here we present evidence that the previously identified islet-specific glucose-6-phosphatase-related protein (IGRP) is indeed the major islet glucose-6-phosphatase. IGRP overexpressed in insect cells possesses enzymatic activity comparable to the previously described G-6-Pase activity in islets. The K_m and V_max values determined using glucose-6-phosphate as the substrate were 0.45 mM and 32 nmol/mg/min by malachite green assay, and 0.29 mM and 77 nmol/mg/min by glucose oxidase/peroxidase coupling assay, respectively. High-throughput screening of a small molecule library led to the identification of an active compound that specifically inhibits IGRP enzymatic activity. Interestingly, this inhibitor did not affect LG-6-Pase activity, while conversely LG-6-Pase inhibitors did not affect IGRP activity. These data demonstrate that IGRP is likely the authentic islet-specific glucose-6-phosphatase catalytic subunit, and selective inhibitors to this molecule can be obtained. IGRP inhibitors may be an attractive new approach for the treatment of insulin secretion defects in type 2 diabetes.

Received for publication, July 17, 2003 , and in revised form, January 7, 2004.

^* 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.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Wyeth Research, 200 Cambridge Park Dr., Cambridge, MA 02140. Tel.: 617-665-5292; Fax: 617-665-5386; E-mail: shong{at}wyeth.com.

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

This article has been cited by other articles:

				C. Dos Santos, P. Bougneres, and D. Fradin A Single-Nucleotide Polymorphism in a Methylatable Foxa2 Binding Site of the G6PC2 Promoter Is Associated With Insulin Secretion In Vivo and Increased Promoter Activity In Vitro Diabetes, February 1, 2009; 58(2): 489 - 492. [Abstract] [Full Text] [PDF]

				K. Boztug, G. Appaswamy, A. Ashikov, A. A. Schaffer, U. Salzer, J. Diestelhorst, M. Germeshausen, G. Brandes, J. Lee-Gossler, F. Noyan, et al. A Syndrome with Congenital Neutropenia and Mutations in G6PC3 N. Engl. J. Med., January 1, 2009; 360(1): 32 - 43. [Abstract] [Full Text] [PDF]

				C. C Martin, B. P Flemming, Y. Wang, J. K Oeser, and R. M O'Brien Foxa2 and MafA regulate islet-specific glucose-6-phosphatase catalytic subunit-related protein gene expression J. Mol. Endocrinol., November 1, 2008; 41(5): 315 - 328. [Abstract] [Full Text] [PDF]

				Y. Wang, B. P. Flemming, C. C. Martin, S. R. Allen, J. Walters, J. K. Oeser, J. C. Hutton, and R. M. O'Brien Long-Range Enhancers Are Required to Maintain Expression of the Autoantigen Islet-Specific Glucose-6-Phosphatase Catalytic Subunit Related Protein in Adult Mouse Islets In Vivo Diabetes, January 1, 2008; 57(1): 133 - 141. [Abstract] [Full Text] [PDF]

				Y. Wang, J. K. Oeser, C. Yang, S. Sarkar, S. I. Hackl, A. H. Hasty, O. P. McGuinness, W. Paradee, J. C. Hutton, D. R. Powell, et al. Deletion of the Gene Encoding the Ubiquitously Expressed Glucose-6-phosphatase Catalytic Subunit-related Protein (UGRP)/Glucose-6-phosphatase Catalytic Subunit-beta Results in Lowered Plasma Cholesterol and Elevated Glucagon J. Biol. Chem., December 29, 2006; 281(52): 39982 - 39989. [Abstract] [Full Text] [PDF]

				J. Yang, N. A. Danke, D. Berger, S. Reichstetter, H. Reijonen, C. Greenbaum, C. Pihoker, E. A. James, and W. W. Kwok Islet-Specific Glucose-6-Phosphatase Catalytic Subunit-Related Protein-Reactive CD4+ T Cells in Human Subjects. J. Immunol., March 1, 2006; 176(5): 2781 - 2789. [Abstract] [Full Text] [PDF]

				C. C. Martin, J. K. Oeser, and R. M. O'Brien Differential Regulation of Islet-specific Glucose-6-phosphatase Catalytic Subunit-related Protein Gene Transcription by Pax-6 and Pdx-1 J. Biol. Chem., August 13, 2004; 279(33): 34277 - 34289. [Abstract] [Full Text] [PDF]