2ib9

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{{STRUCTURE_2ib9| PDB=2ib9 | SCENE= }}
 
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===Crystallographic and kinetic studies of human mitochondrial acetoacetyl-CoA thiolase (T2): the importance of potassium and chloride for its structure and function===
 
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{{ABSTRACT_PUBMED_17371050}}
 
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==Disease==
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==Crystallographic and kinetic studies of human mitochondrial acetoacetyl-CoA thiolase (T2): the importance of potassium and chloride for its structure and function==
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[[http://www.uniprot.org/uniprot/THIL_HUMAN THIL_HUMAN]] Defects in ACAT1 are a cause of 3-ketothiolase deficiency (3KTD) [MIM:[http://omim.org/entry/203750 203750]]; also known as alpha-methylacetoaceticaciduria. 3KTD is an inborn error of isoleucine catabolism characterized by intermittent ketoacidotic attacks associated with unconsciousness. Some patients die during an attack or are mentally retarded. Urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, triglylglycine, butanone is increased. It seems likely that the severity of this disease correlates better with the environmental or acquired factors than with the ACAT1 genotype.<ref>PMID:1346617</ref><ref>PMID:1715688</ref><ref>PMID:7728148</ref><ref>PMID:9744475</ref>
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<StructureSection load='2ib9' size='340' side='right'caption='[[2ib9]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2ib9]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IB9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2IB9 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.05&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2ib9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ib9 OCA], [https://pdbe.org/2ib9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ib9 RCSB], [https://www.ebi.ac.uk/pdbsum/2ib9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ib9 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/THIL_HUMAN THIL_HUMAN] Defects in ACAT1 are a cause of 3-ketothiolase deficiency (3KTD) [MIM:[https://omim.org/entry/203750 203750]; also known as alpha-methylacetoaceticaciduria. 3KTD is an inborn error of isoleucine catabolism characterized by intermittent ketoacidotic attacks associated with unconsciousness. Some patients die during an attack or are mentally retarded. Urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, triglylglycine, butanone is increased. It seems likely that the severity of this disease correlates better with the environmental or acquired factors than with the ACAT1 genotype.<ref>PMID:1346617</ref> <ref>PMID:1715688</ref> <ref>PMID:7728148</ref> <ref>PMID:9744475</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/THIL_HUMAN THIL_HUMAN] Plays a major role in ketone body metabolism.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ib/2ib9_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2ib9 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Thiolases are CoA-dependent enzymes which catalyze the formation of a carbon-carbon bond in a Claisen condensation step and its reverse reaction via a thiolytic degradation mechanism. Mitochondrial acetoacetyl-coenzyme A (CoA) thiolase (T2) is important in the pathways for the synthesis and degradation of ketone bodies as well as for the degradation of 2-methylacetoacetyl-CoA. Human T2 deficiency has been identified in more than 60 patients. A unique property of T2 is its activation by potassium ions. High-resolution human T2 crystal structures are reported for the apo form and the CoA complex, with and without a bound potassium ion. The potassium ion is bound near the CoA binding site and the catalytic site. Binding of the potassium ion at this low-affinity binding site causes the rigidification of a CoA binding loop and an active site loop. Unexpectedly, a high-affinity binding site for a chloride ion has also been identified. The chloride ion is copurified, and its binding site is at the dimer interface, near two catalytic loops. A unique property of T2 is its ability to use 2-methyl-branched acetoacetyl-CoA as a substrate, whereas the other structurally characterized thiolases cannot utilize the 2-methylated compounds. The kinetic measurements show that T2 can degrade acetoacetyl-CoA and 2-methylacetoacetyl-CoA with similar catalytic efficiencies. For both substrates, the turnover numbers increase approximately 3-fold when the potassium ion concentration is increased from 0 to 40 mM KCl. The structural analysis of the active site of T2 indicates that the Phe325-Pro326 dipeptide near the catalytic cavity is responsible for the exclusive 2-methyl-branched substrate specificity.
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==Function==
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Crystallographic and kinetic studies of human mitochondrial acetoacetyl-CoA thiolase: the importance of potassium and chloride ions for its structure and function.,Haapalainen AM, Merilainen G, Pirila PL, Kondo N, Fukao T, Wierenga RK Biochemistry. 2007 Apr 10;46(14):4305-21. Epub 2007 Mar 20. PMID:17371050<ref>PMID:17371050</ref>
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[[http://www.uniprot.org/uniprot/THIL_HUMAN THIL_HUMAN]] Plays a major role in ketone body metabolism.
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[2ib9]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IB9 OCA].
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</div>
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<div class="pdbe-citations 2ib9" style="background-color:#fffaf0;"></div>
==See Also==
==See Also==
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*[[Thiolase|Thiolase]]
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*[[Thiolase 3D structures|Thiolase 3D structures]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:017371050</ref><references group="xtra"/><references/>
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__TOC__
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[[Category: Acetyl-CoA C-acetyltransferase]]
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Haapalainen, A M.]]
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[[Category: Large Structures]]
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[[Category: Wierenga, R K.]]
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[[Category: Haapalainen AM]]
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[[Category: Alpha-beta-alpha-beta-alpha layered structure]]
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[[Category: Wierenga RK]]
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[[Category: Beta-alpha-beta-alpha-beta-alpha-beta-beta topology]]
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[[Category: Chloride]]
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[[Category: Potassium ion]]
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[[Category: Thiolase fold]]
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[[Category: Transferase]]
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Current revision

Crystallographic and kinetic studies of human mitochondrial acetoacetyl-CoA thiolase (T2): the importance of potassium and chloride for its structure and function

PDB ID 2ib9

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