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J. Biol. Chem., Vol. 283, Issue 48, 33428-33436, November 28, 2008

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Reciprocal Control of Pyruvate Dehydrogenase Kinase and Phosphatase by Inositol Phosphoglycans

DYNAMIC STATE SET BY "PUSH-PULL" SYSTEM^*

Patricia McLean, Sirilaksana Kunjara, A. Leslie Greenbaum, Khalid Gumaa^¶, Javier López-Prados^||, Manuel Martin-Lomas^||, and Thomas W. Rademacher¹

From the Division of Infection and Immunity, University College London Medical School, London W1T 4JF, United Kingdom, Sylus Pharmaceuticals, Oxford OX13 6BH, United Kingdom, ^||Consejo Superior de Investigaciones Científicas Instituto de Investigaciones Quimicas, Seville 41092, Spain, and the ^¶College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain

Reversible phosphorylation of proteins regulates numerous aspects of cell function, and abnormal phosphorylation is causal in many diseases. Pyruvate dehydrogenase complex (PDC) is central to the regulation of glucose homeostasis. PDC exists in a dynamic equilibrium between de-phospho-(active) and phosphorylated (inactive) forms controlled by pyruvate dehydrogenase phosphatases (PDP1,2) and pyruvate dehydrogenase kinases (PDK1–4). In contrast to the reciprocal regulation of the phospho-/de-phospho cycle of PDC and at the level of expression of the isoforms of PDK and PDP regulated by hormones and diet, there is scant evidence for regulatory factors acting in vivo as reciprocal "on-off" switches. Here we show that the putative insulin mediator inositol phosphoglycan P-type (IPG-P) has a sigmoidal inhibitory action on PDK in addition to its known linear stimulation of PDP. Thus, at critical levels of IPG-P, this sigmoidal/linear model markedly enhances the switchover from the inactive to the active form of PDC, a "push-pull" system that, combined with the developmental and hormonal control of IPG-P, indicates their powerful regulatory function. The release of IPGs from cell membranes by insulin is significant in relation to diabetes. The chelation of IPGs with Mn²⁺ and Zn²⁺ suggests a role as "catalytic chelators" coordinating the traffic of metal ions in cells. Synthetic inositol hexosamine analogues are shown here to have a similar linear/sigmoidal reciprocal action on PDC exerting push-pull effects, suggesting their potential for treatment of metabolic disorders, including diabetes.

Received for publication, March 5, 2008 , and in revised form, September 3, 2008.

^* This work was supported in part by grants from the Medical Research Council and the Basil Samuel Charitable Trust. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental text and additional references.

¹ To whom correspondence should be addressed: Division of Infection and Immunity, University College London, Windeyer Bldg., 46 Cleveland St., London, W1T 4JF. Tel.: 44-207-679-9373; Fax: 44-207-679-9497; E-mail: t.rademacher{at}ucl.ac.uk.

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