Reciprocal Control of Pyruvate Dehydrogenase Kinase and Phosphatase by Inositol Phosphoglycans DYNAMIC STATE SET BY "PUSH-PULL" SYSTEM
Reciprocal Control of Pyruvate Dehydrogenase Kinase and Phosphatase by Inositol Phosphoglycans DYNAMIC STATE SET BY "PUSH-PULL" SYSTEM
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DOI：
10.1074/jbc.m801781200
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发表时间：
2008-11-28
影响因子：
4.8
通讯作者：
Rademacher, Thomas W.
中科院分区：
文献类型：
--
作者：
McLean, Patricia;Kunjara, Sirilaksana;Rademacher, Thomas W.
蛋白质的可逆磷酸化调节了细胞功能的许多方面，异常磷酸化是许多疾病的原因。丙酮酸脱氢酶复合物（PDC）是调节葡萄糖稳态的核心。PDC存在于丙酮酸脱氢酶磷酸酶（PDP1,2）和丙酮酸脱氢酶激酶（PDK1-4）控制的去磷酸（活性）和磷酸化（非活性）形式之间的动态平衡中。与PDC的磷酸化/去磷酸化循环的相互调节以及PDK和PDP同工型的表达水平受激素和饮食调节相反，很少有证据表明调节因子在体内作为相互的“开关”开关起作用。本研究表明，假定的胰岛素介质肌醇磷酸聚糖p型（IPG-P）除了已知的线性刺激PDP外，还具有对PDK的s型抑制作用。因此，在IPG-P达到临界水平时，这种s型/线性模型显著增强了PDC从无活性到活性形式的转换，这是一种“推拉”系统，结合IPG-P的发育和激素控制，表明其强大的调节功能。胰岛素从细胞膜释放IPGs与糖尿病有重要关系。IPGs与Mn2+和Zn2+的螯合作用表明IPGs具有“催化螯合剂”的作用，可以协调细胞内金属离子的运输。合成肌醇己糖胺类似物对PDC具有类似的线性/s型相互作用，施加推拉效应，表明其治疗代谢紊乱（包括糖尿病）的潜力。
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.