| Physiological control of liver glycogen metabolism: lessons from novel glycogen phosphorylase inhibitors. | |
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MedLine Citation:
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PMID: 20716056 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Liver glycogen is synthesized in the postprandial state in response to elevated concentrations of glucose and insulin or by activation of neuroendocrine signals and it is degraded in the postabsorptive state in response to changes in the concentrations of insulin and counter-regulatory hormones. Dysregulation of either glycogen degradation or synthesis through changes in allosteric control or covalent modification of glycogen phosphorylase and glycogen synthase leads to disturbance of blood glucose homeostasis. Liver glycogen phosphorylase has a dual role in the control of glycogen metabolism by regulation of both glycogen degradation and synthesis. The phosphorylated form (GPa) is the active form and determines the rate of degradation of glycogen and it is also a potent allosteric inhibitor of the protein complex, involving the glycogen targeting protein G(L) and protein phosphatase-1, which catalyses dephosphorylation (activation) of glycogen synthase. Drug discovery programmes exploring the validity of glycogen phosphorylase as a therapeutic target for type 2 diabetes have generated a wide array of selective phosphorylase ligands that modulate the catalytic activity and / or the phosphorylation state (interconversion of GPa and GPb) as well as the binding of GPa to the allosteric site of G(L). Glycogen phosphorylase inhibitors that act in hepatocytes either exclusively by dephosphorylating GPa (e.g. indole carboxamides) or by allosteric inhibition of GPa (1,4-dideoxy-1,4-D-arabinitol) are very powerful experimental tools to determine the relative roles of covalent modification of glycogen phosphorylase and/or cycling between glycogen synthesis and degradation in the mechanism(s) by which insulin and neurotransmitters regulate hepatic glycogen metabolism. |
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Authors:
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Loranne Agius |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Review |
Journal Detail:
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Title: Mini reviews in medicinal chemistry Volume: 10 ISSN: 1875-5607 ISO Abbreviation: Mini Rev Med Chem Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-11-16 Completed Date: 2011-03-01 Revised Date: 2011-12-07 |
Medline Journal Info:
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Nlm Unique ID: 101094212 Medline TA: Mini Rev Med Chem Country: Netherlands |
Other Details:
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Languages: eng Pagination: 1175-87 Citation Subset: IM |
Affiliation:
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Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne NE24HH, UK. Loranne.Agius@ncl.ac.uk |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Allosteric Site Enzyme Inhibitors / chemistry*, pharmacology Glycogen / metabolism* Glycogen Phosphorylase / antagonists & inhibitors*, metabolism, physiology Humans Indoles / chemistry, pharmacology Liver / enzymology, metabolism* Phosphorylation |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Indoles; 9005-79-2/Glycogen; EC 2.4.1.-/Glycogen Phosphorylase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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