3crl

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===Crystal structure of the PDHK2-L2 complex.===
===Crystal structure of the PDHK2-L2 complex.===
{{ABSTRACT_PUBMED_18387944}}
{{ABSTRACT_PUBMED_18387944}}
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==Disease==
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[[http://www.uniprot.org/uniprot/ODP2_HUMAN ODP2_HUMAN]] Note=Primary biliary cirrhosis is a chronic, progressive cholestatic liver disease characterized by the presence of antimitochondrial autoantibodies in patients' serum. It manifests with inflammatory obliteration of intra-hepatic bile duct, leading to liver cell damage and cirrhosis. Patients with primary biliary cirrhosis show autoantibodies against the E2 component of pyruvate dehydrogenase complex. Defects in DLAT are the cause of pyruvate dehydrogenase E2 deficiency (PDHE2 deficiency) [MIM:[http://omim.org/entry/245348 245348]]; also known as lactic acidemia due to defect of E2 lipoyl transacetylase of the pyruvate dehydrogenase complex. Pyruvate dehydrogenase (PDH) deficiency is a major cause of primary lactic acidosis and neurological dysfunction in infancy and early childhood. In this form of PDH deficiency episodic dystonia is the major neurological manifestation, with other more common features of pyruvate dehydrogenase deficiency, such as hypotonia and ataxia, being less prominent.
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==Function==
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[[http://www.uniprot.org/uniprot/PDK2_RAT PDK2_RAT]] Serine/threonine kinase that plays a key role in the regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism. Mediates cellular responses to insulin. Plays an important role in maintaining normal blood glucose levels and in metabolic adaptation to nutrient availability. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. Plays a role in the regulation of cell proliferation and in resistance to apoptosis under oxidative stress. Plays a role in p53/TP53-mediated apoptosis.<ref>PMID:7961963</ref><ref>PMID:11486000</ref><ref>PMID:14641018</ref><ref>PMID:12573248</ref><ref>PMID:22910903</ref> [[http://www.uniprot.org/uniprot/ODP2_HUMAN ODP2_HUMAN]] The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links the glycolytic pathway to the tricarboxylic cycle.
==About this Structure==
==About this Structure==
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==Reference==
==Reference==
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<ref group="xtra">PMID:018387944</ref><references group="xtra"/>
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<ref group="xtra">PMID:018387944</ref><references group="xtra"/><references/>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Rattus norvegicus]]
[[Category: Rattus norvegicus]]

Revision as of 02:03, 25 March 2013

Template:STRUCTURE 3crl

Contents

Crystal structure of the PDHK2-L2 complex.

Template:ABSTRACT PUBMED 18387944

Disease

[ODP2_HUMAN] Note=Primary biliary cirrhosis is a chronic, progressive cholestatic liver disease characterized by the presence of antimitochondrial autoantibodies in patients' serum. It manifests with inflammatory obliteration of intra-hepatic bile duct, leading to liver cell damage and cirrhosis. Patients with primary biliary cirrhosis show autoantibodies against the E2 component of pyruvate dehydrogenase complex. Defects in DLAT are the cause of pyruvate dehydrogenase E2 deficiency (PDHE2 deficiency) [MIM:245348]; also known as lactic acidemia due to defect of E2 lipoyl transacetylase of the pyruvate dehydrogenase complex. Pyruvate dehydrogenase (PDH) deficiency is a major cause of primary lactic acidosis and neurological dysfunction in infancy and early childhood. In this form of PDH deficiency episodic dystonia is the major neurological manifestation, with other more common features of pyruvate dehydrogenase deficiency, such as hypotonia and ataxia, being less prominent.

Function

[PDK2_RAT] Serine/threonine kinase that plays a key role in the regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism. Mediates cellular responses to insulin. Plays an important role in maintaining normal blood glucose levels and in metabolic adaptation to nutrient availability. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. Plays a role in the regulation of cell proliferation and in resistance to apoptosis under oxidative stress. Plays a role in p53/TP53-mediated apoptosis.[1][2][3][4][5] [ODP2_HUMAN] The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links the glycolytic pathway to the tricarboxylic cycle.

About this Structure

3crl is a 4 chain structure with sequence from Homo sapiens and Rattus norvegicus. Full crystallographic information is available from OCA.

See Also

Reference

  • Green T, Grigorian A, Klyuyeva A, Tuganova A, Luo M, Popov KM. Structural and functional insights into the molecular mechanisms responsible for the regulation of pyruvate dehydrogenase kinase 2. J Biol Chem. 2008 Jun 6;283(23):15789-98. Epub 2008 Apr 3. PMID:18387944 doi:10.1074/jbc.M800311200
  1. ↑ Popov KM, Kedishvili NY, Zhao Y, Gudi R, Harris RA. Molecular cloning of the p45 subunit of pyruvate dehydrogenase kinase. J Biol Chem. 1994 Nov 25;269(47):29720-4. PMID:7961963
  2. ↑ Korotchkina LG, Patel MS. Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase. J Biol Chem. 2001 Oct 5;276(40):37223-9. Epub 2001 Aug 2. PMID:11486000 doi:10.1074/jbc.M103069200
  3. ↑ Mayers RM, Butlin RJ, Kilgour E, Leighton B, Martin D, Myatt J, Orme JP, Holloway BR. AZD7545, a novel inhibitor of pyruvate dehydrogenase kinase 2 (PDHK2), activates pyruvate dehydrogenase in vivo and improves blood glucose control in obese (fa/fa) Zucker rats. Biochem Soc Trans. 2003 Dec;31(Pt 6):1165-7. PMID:14641018 doi:10.1042/
  4. ↑ Boulatnikov I, Popov KM. Formation of functional heterodimers by isozymes 1 and 2 of pyruvate dehydrogenase kinase. Biochim Biophys Acta. 2003 Feb 21;1645(2):183-92. PMID:12573248
  5. ↑ Hurd TR, Collins Y, Abakumova I, Chouchani ET, Baranowski B, Fearnley IM, Prime TA, Murphy MP, James AM. Inactivation of pyruvate dehydrogenase kinase 2 by mitochondrial reactive oxygen species. J Biol Chem. 2012 Oct 12;287(42):35153-60. doi: 10.1074/jbc.M112.400002. Epub, 2012 Aug 21. PMID:22910903 doi:10.1074/jbc.M112.400002

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