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J. Biol. Chem., Vol. 278, Issue 47, 47098-47103, November 21, 2003

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A Glucose-6-phosphate Hydrolase, Widely Expressed Outside the Liver, Can Explain Age-dependent Resolution of Hypoglycemia in Glycogen Storage Disease Type Ia^*

Jeng-Jer Shieh, Chi-Jiunn Pan, Brian C. Mansfield, and Janice Yang Chou

From the Section on Cellular Differentiation, Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

A fine control of the blood glucose level is essential to avoid hyper- or hypo-glycemic shocks associated with many metabolic disorders, including diabetes mellitus and type I glycogen storage disease. Between meals, the primary source of blood glucose is gluconeogenesis and glycogenolysis. In the final step of both pathways, glucose-6-phosphate (G6P) is hydrolyzed to glucose by the glucose-6-phosphatase (G6Pase) complex. Because G6Pase (renamed G6Pase-) is primarily expressed only in the liver, kidney, and intestine, it has implied that most other tissues cannot contribute to interprandial blood glucose homeostasis. We demonstrate that a novel, widely expressed G6Pase-related protein, PAP2.8/UGRP, renamed here G6Pase-, is an acid-labile, vanadate-sensitive, endoplasmic reticulum-associated phosphohydrolase, like G6Pase-. Both enzymes have the same active site structure, exhibit a similar K_m toward G6P, but the V_max of G6Pase- is 6-fold greater than that of G6Pase-. Most importantly, G6Pase- couples with the G6P transporter to form an active G6Pase complex that can hydrolyze G6P to glucose. Our findings challenge the current dogma that only liver, kidney, and intestine can contribute to blood glucose homeostasis and explain why type Ia glycogen storage disease patients, lacking a functional liver/kidney/intestine G6Pase complex, are still capable of endogenous glucose production.

Received for publication, August 26, 2003 , and in revised form, September 12, 2003.

^* 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.

To whom correspondence should be addressed: National Institutes of Health, Building 10, Room 9S241, 9000 Rockville Pike, Bethesda, MD 20892-1830. Tel.: 301-496-1094; Fax: 301-402-6035; E-mail: chouja{at} mail.nih.gov.

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