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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== | |||
<StructureSection load='2ib8' size='340' side='right' caption='[[2ib8]], [[Resolution|resolution]] 1.85Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2ib8]] 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=2IB8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2IB8 FirstGlance]. <br> | |||
==Disease== | </td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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><br> | ||
[[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> | <tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2ib7|2ib7]], [[2ib9|2ib9]], [[2ibu|2ibu]], [[2ibw|2ibw]], [[2iby|2iby]]</td></tr> | ||
<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ACAT1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | |||
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Acetyl-CoA_C-acetyltransferase Acetyl-CoA C-acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.9 2.3.1.9] </span></td></tr> | |||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ib8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ib8 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2ib8 RCSB], [http://www.ebi.ac.uk/pdbsum/2ib8 PDBsum]</span></td></tr> | |||
<table> | |||
== Disease == | |||
[[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> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/THIL_HUMAN THIL_HUMAN]] Plays a major role in ketone body metabolism. | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ib/2ib8_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</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/chain_selection.php?pdb_ID=2ata ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
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> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Thiolase|Thiolase]] | *[[Thiolase|Thiolase]] | ||
== References == | |||
== | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Acetyl-CoA C-acetyltransferase]] | [[Category: Acetyl-CoA C-acetyltransferase]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||