1siq: Difference between revisions

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-[[Image:1siq.gif|left|200px]]<br /><applet load="1siq" size="350" color="white" frame="true" align="right" spinBox="true"
-caption="1siq, resolution 2.10&Aring;" />
-'''The Crystal Structure and Mechanism of Human Glutaryl-CoA Dehydrogenase'''<br />
-==Overview==
+==The Crystal Structure and Mechanism of Human Glutaryl-CoA Dehydrogenase==
-Acyl-CoA dehydrogenases (ACDs) are a family of flavoenzymes that metabolize fatty acids and some amino acids. Of nine known ACDs, glutaryl-CoA dehydrogenase (GCD) is unique: in addition to the alpha,beta-dehydrogenation reaction, common to all ACDs, GCD catalyzes decarboxylation of glutaryl-CoA to produce CO(2) and crotonyl-CoA. Crystal structures of GCD and its complex with 4-nitrobutyryl-CoA have been determined to 2.1 and 2.6 A, respectively. The overall polypeptide folds are the same and similar to the structures of other family members. The active site of the unliganded structure is filled with water molecules that are displaced when enzyme binds the substrate. The structure strongly suggests that the mechanism of dehydrogenation is the same as in other ACDs. The substrate binds at the re side of the FAD ring. Glu370 abstracts the C2 pro-R proton, which is acidified by the polarization of the thiolester carbonyl oxygen through hydrogen bonding to the 2'-OH of FAD and the amide nitrogen of Glu370. The C3 pro-R proton is transferred to the N(5) atom of FAD. The structures indicate a plausible mechanism for the decarboxylation reaction. The carbonyl polarization initiates decarboxylation, and Arg94 stabilizes the transient crotonyl-CoA anion. Protonation of the crotonyl-CoA anion occurs by a 1,3-prototropic shift catalyzed by the conjugated acid of the general base, Glu370. A tight hydrogen-bonding network involving gamma-carboxylate of the enzyme-bound glutaconyl-CoA, with Tyr369, Glu87, Arg94, Ser95, and Thr170, optimizes orientation of the gamma-carboxylate for decarboxylation. Some pathogenic mutations are explained by the structure. The mutations affect protein folding, stability, and/or substrate binding, resulting in inefficient/inactive enzyme.
+<StructureSection load='1siq' size='340' side='right'caption='[[1siq]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1siq]] is a 1 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=1SIQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1SIQ FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1siq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1siq OCA], [https://pdbe.org/1siq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1siq RCSB], [https://www.ebi.ac.uk/pdbsum/1siq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1siq ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/GCDH_HUMAN GCDH_HUMAN] Defects in GCDH are the cause of glutaric aciduria type 1 (GA1) [MIM:[https://omim.org/entry/231670 231670]. GA1 is an autosomal recessive metabolic disorder characterized by progressive dystonia and athetosis due to gliosis and neuronal loss in the basal ganglia.<ref>PMID:18775954</ref> <ref>PMID:8541831</ref> <ref>PMID:9600243</ref> <ref>PMID:8900227</ref> <ref>PMID:8900228</ref> <ref>PMID:14707522</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/GCDH_HUMAN GCDH_HUMAN] Catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism. It uses electron transfer flavoprotein as its electron acceptor. Isoform Short is inactive.
+== 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/si/1siq_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/main_output.php?pdb_ID=1siq ConSurf].
+<div style="clear:both"></div>
-==Disease==
+==See Also==
-Known disease associated with this structure: Glutaricaciduria, type I OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608801 608801]]
+*[[Acyl-CoA dehydrogenase 3D structures|Acyl-CoA dehydrogenase 3D structures]]
+*[[Glutaryl-CoA dehydrogenase|Glutaryl-CoA dehydrogenase]]
-==About this Structure==
+== References ==
-SIQ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=FAD:'>FAD</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Glutaryl-CoA_dehydrogenase Glutaryl-CoA dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.99.7 1.3.99.7] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1SIQ OCA].
+<references/>
+__TOC__
-==Reference==
+</StructureSection>
-Crystal structures of human glutaryl-CoA dehydrogenase with and without an alternate substrate: structural bases of dehydrogenation and decarboxylation reactions., Fu Z, Wang M, Paschke R, Rao KS, Frerman FE, Kim JJ, Biochemistry. 2004 Aug 3;43(30):9674-84. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15274622 15274622]
-[[Category: Glutaryl-CoA dehydrogenase]]
 [[Category: Homo sapiens]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Frerman, F E.]]
+[[Category: Frerman FE]]
-[[Category: Fu, Z.]]
+[[Category: Fu Z]]
-[[Category: Goodman, S.]]
+[[Category: Goodman S]]
-[[Category: Kim, J J.]]
+[[Category: Kim JJ]]
-[[Category: Paschke, R.]]
+[[Category: Paschke R]]
-[[Category: Wang, M.]]
+[[Category: Wang M]]
-[[Category: FAD]]
-[[Category: acyl-coa dehydrogenase]]
-[[Category: decarboxylation]]
-[[Category: flavin protein]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:01:54 2008''