Reciprocal Control of Pyruvate Dehydrogenase Kinase and Phosphatase by Inositol Phosphoglycans: Dynamic State Set by “Push-Pull” System

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 Mn 2؉ and Zn 2؉ 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. Pyruvate dehydrogenase complex (PDC),2 an enzyme at the interface between glycolysis and the citric acid cycle, is influenced by dietary and hormonal control and by phosphorylation/dephosphorylation reactions, the former regulated by pyruvate dehydrogenase kinases (PDK1-4) and the latter by dedicated mitochondrial pyruvate dehydrogenase phosphatases (PDP1,2) (1-4). Phosphorylation forms the basis of the dynamic state of cell cycling networks, thus the balance between the active (de-phospho-) and the inactive (phospho-) forms of PDC is dependent upon the regulation of PDK and PDP (2,5,6). Cycling between two phosphorylated states is, classically, one mode of control, permitting rapid alterations in catalytic activity, e.g. in response to insulin, adrenaline, shifts in Ca 2ϩ distribution, and effector molecules. In addition, 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, 7-12). The profile of the regulation of PDK1-4 to activation by NADH and to NADH plus acetyl CoA and ATP, together with differences in the apparent K i values for ADP, confers upon tissues individual patterns of response to alterations in metabolite profile linked to hormonal and dietary changes (2, 3, 9 -12).Inositol phosphoglycans (IPGs) are bro...

D-Chiro-Inositol Glycans in Insulin Signaling and Insulin Resistance

“…Furthermore, a pseudodisaccharide lacking the amine moiety from the galactosamine in INS-2 was synthesized and it showed a complete lack of activation of both PP2Cα and PDHP (24 chelate is required for bioactivity with PDHP (10), which suggests differential glycan availability to the bimetallic center in the two enzymes. The lack of activation of PDHP by unchelated INS-2 has been independently observed and noted (25). Unchelated INS-2 is biologically active in H4IIE hepatoma cells and in STZ diabetic rats (10) to sensitize insulin stimulation of glycogen synthesis (10), as well as in STZ diabetic rats to reduce hyperglycemia (11).…”

“…McLean et al (25) synthesized 23 inositol-glycan pseudodisaccharides containing myo-inositol and/or DCI and glucosamine and/or galactosamine, assaying their activity in vitro. Active compounds had reciprocal actions to stimulate PDHP and to inhibit PDH kinase.…”

Herbal constituent sequoyitol improves hyperglycemia and glucose intolerance by targeting hepatocytes, adipocytes, and β-cells

“…IPGs, endogenous inositol derivatives, are believed to act as intracellular mediator of insulin metabolic action (7,21,23,29,36). IPGs appear to regulate glucose metabolism by activating pyruvate dehydrogenase phosphatases and protein phosphatase 2C (5,13,23,25,27). Sequoyitol (5-O-methyl-myo-inositol) may promote IPG production by serving as a precursor or a regulator.…”

Ethanol and Normobaric Oxygen

“…5 Specifically, targeted regulation of PDHC occurs primarily via site-specific phosphorylation. 6 After ischemic stroke, a severe oxygen deprivation leads to a large impairment of oxidative phosphorylation, thus limiting the production of ATP. This, in turn, raises the production of ROS after reperfusion which exacerbates cell and tissue injuries.…”

“…Conversely, PDP removes the phosphate group off the serine residues and thus activates the enzyme. 6 Ultimately, PDHC, PDK, and PDP changes after stroke would provide important indexes to assess oxidative metabolism underlying ischemic injury after stroke.…”