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New page: left|200px<br /> <applet load="1siq" size="450" color="white" frame="true" align="right" spinBox="true" caption="1siq, resolution 2.10Å" /> '''The Crystal Structu...
 
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[[Image:1siq.gif|left|200px]]<br />
<applet load="1siq" size="450" 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 ==
1SIQ 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 FAD 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://ispc.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: 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://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 19:14:18 2007''

Latest revision as of 11:30, 14 February 2024

The Crystal Structure and Mechanism of Human Glutaryl-CoA DehydrogenaseThe Crystal Structure and Mechanism of Human Glutaryl-CoA Dehydrogenase

Structural highlights

1siq is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.1Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

GCDH_HUMAN Defects in GCDH are the cause of glutaric aciduria type 1 (GA1) [MIM:231670. GA1 is an autosomal recessive metabolic disorder characterized by progressive dystonia and athetosis due to gliosis and neuronal loss in the basal ganglia.[1] [2] [3] [4] [5] [6]

Function

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

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

References

  1. ↑ Keyser B, Muhlhausen C, Dickmanns A, Christensen E, Muschol N, Ullrich K, Braulke T. Disease-causing missense mutations affect enzymatic activity, stability and oligomerization of glutaryl-CoA dehydrogenase (GCDH). Hum Mol Genet. 2008 Dec 15;17(24):3854-63. doi: 10.1093/hmg/ddn284. Epub 2008 Sep, 5. PMID:18775954 doi:10.1093/hmg/ddn284
  2. ↑ Goodman SI, Kratz LE, DiGiulio KA, Biery BJ, Goodman KE, Isaya G, Frerman FE. Cloning of glutaryl-CoA dehydrogenase cDNA, and expression of wild type and mutant enzymes in Escherichia coli. Hum Mol Genet. 1995 Sep;4(9):1493-8. PMID:8541831
  3. ↑ Schwartz M, Christensen E, Superti-Furga A, Brandt NJ. The human glutaryl-CoA dehydrogenase gene: report of intronic sequences and of 13 novel mutations causing glutaric aciduria type I. Hum Genet. 1998 Apr;102(4):452-8. PMID:9600243
  4. ↑ Biery BJ, Stein DE, Morton DH, Goodman SI. Gene structure and mutations of glutaryl-coenzyme A dehydrogenase: impaired association of enzyme subunits that is due to an A421V substitution causes glutaric acidemia type I in the Amish. Am J Hum Genet. 1996 Nov;59(5):1006-11. PMID:8900227
  5. ↑ Anikster Y, Shaag A, Joseph A, Mandel H, Ben-Zeev B, Christensen E, Elpeleg ON. Glutaric aciduria type I in the Arab and Jewish communities in Israel. Am J Hum Genet. 1996 Nov;59(5):1012-8. PMID:8900228
  6. ↑ Muhlhausen C, Christensen E, Schwartz M, Muschol N, Ullrich K, Lukacs Z. Severe phenotype despite high residual glutaryl-CoA dehydrogenase activity: a novel mutation in a Turkish patient with glutaric aciduria type I. J Inherit Metab Dis. 2003;26(7):713-4. PMID:14707522

1siq, resolution 2.10Å

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