Abstract
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.
Highlights
Pyruvate dehydrogenase complex (PDC),2 an enzyme at the interface between glycolysis and the citric acid cycle, is influ
Effect of Liver inositol phosphoglycan P-type (IPG-P) and Inositol phosphoglycans (IPGs)-A on PDC—The effects of IPG-P isolated from liver on PDP and PDK are shown in the Fig. 3, a and b
The regulatory effect of the contrast between the linear activation of PDP and sigmoidal inhibition of PDK, the latter been manifest at higher concentration of IPG-P, is for a push-pull system that will magnify the response of PDC to moderate changes in IPG-P, a highly sensitive system at critical tissue concentrations of IPG-P
Summary
Pyruvate dehydrogenase complex (PDC), an enzyme at the interface between glycolysis and the citric acid cycle, is influ-. Adaptive changes due to altered hormonal or dietary states, such as diabetes, starvation, or high fat/high carbohydrate diets, and related changes in the expression of isoforms of PDK and PDP in a tissue-specific manner regulate the phosphorylation state of the PDC [2, 7,8,9,10,11,12]. The main objective of this study was to establish whether IPG-P extracted from liver and, critically, whether synthetic inositol hexosamine derivatives had reciprocal effects on PDP and PDK and played a dual role by activating the dephosphorylation and inhibiting the rephosphorylation of PDC, in effect a “push-pull” mechanism facilitating rapid alterations in PDC activity. Control Pyruvate Dehydrogenase Complex that IPG-P played a significant role in regulating glucose metabolism at the PDC stage by sigmoidal inhibition of PDK in addition to the linear activation of PDP. In the light of evidence for the release of IPGs from membrane preparations by insulin (15, 26 –28), it is suggested that a short term effect of insulin on PDC may be mediated, in part, by the reciprocal control of PDP and PDK, an effective push-pull system
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