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{{STRUCTURE_1dtw|  PDB=1dtw  |  SCENE=  }}
==HUMAN BRANCHED-CHAIN ALPHA-KETO ACID DEHYDROGENASE==
===HUMAN BRANCHED-CHAIN ALPHA-KETO ACID DEHYDROGENASE===
<StructureSection load='1dtw' size='340' side='right' caption='[[1dtw]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
{{ABSTRACT_PUBMED_10745006}}
== Structural highlights ==
 
<table><tr><td colspan='2'>[[1dtw]] is a 2 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=1DTW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1DTW FirstGlance]. <br>
==Disease==
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=TDP:THIAMIN+DIPHOSPHATE'>TDP</scene><br>
[[http://www.uniprot.org/uniprot/ODBA_HUMAN ODBA_HUMAN]] Defects in BCKDHA are a cause of maple syrup urine disease type IA (MSUD1A) [MIM:[http://omim.org/entry/248600 248600]]. MSUD is an autosomal recessive disorder characterized by mental and physical retardation, feeding problems, and a maple syrup odor to the urine.<ref>PMID:2060625</ref><ref>PMID:8037208</ref><ref>PMID:2703538</ref><ref>PMID:2241958</ref><ref>PMID:1867199</ref><ref>PMID:1885764</ref><ref>PMID:8161368</ref><ref>PMID:7883996</ref> [[http://www.uniprot.org/uniprot/ODBB_HUMAN ODBB_HUMAN]] Defects in BCKDHB are the cause of maple syrup urine disease type IB (MSUD1B) [MIM:[http://omim.org/entry/248600 248600]]. MSUD is an autosomal recessive disorder characterized by mental and physical retardation, feeding problems, and a maple syrup odor to the urine.<ref>PMID:8161368</ref><ref>PMID:11509994</ref><ref>PMID:22326532</ref>  
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/3-methyl-2-oxobutanoate_dehydrogenase_(2-methylpropanoyl-transferring) 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.2.4.4 1.2.4.4] </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=1dtw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1dtw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1dtw RCSB], [http://www.ebi.ac.uk/pdbsum/1dtw PDBsum]</span></td></tr>
==Function==
<table>
== Disease ==
[[http://www.uniprot.org/uniprot/ODBA_HUMAN ODBA_HUMAN]] Defects in BCKDHA are a cause of maple syrup urine disease type IA (MSUD1A) [MIM:[http://omim.org/entry/248600 248600]]. MSUD is an autosomal recessive disorder characterized by mental and physical retardation, feeding problems, and a maple syrup odor to the urine.<ref>PMID:2060625</ref> <ref>PMID:8037208</ref> <ref>PMID:2703538</ref> <ref>PMID:2241958</ref> <ref>PMID:1867199</ref> <ref>PMID:1885764</ref> <ref>PMID:8161368</ref> <ref>PMID:7883996</ref> [[http://www.uniprot.org/uniprot/ODBB_HUMAN ODBB_HUMAN]] Defects in BCKDHB are the cause of maple syrup urine disease type IB (MSUD1B) [MIM:[http://omim.org/entry/248600 248600]]. MSUD is an autosomal recessive disorder characterized by mental and physical retardation, feeding problems, and a maple syrup odor to the urine.<ref>PMID:8161368</ref> <ref>PMID:11509994</ref> <ref>PMID:22326532</ref>
== Function ==
[[http://www.uniprot.org/uniprot/ODBA_HUMAN ODBA_HUMAN]] The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO(2). It contains multiple copies of three enzymatic components: branched-chain alpha-keto acid decarboxylase (E1), lipoamide acyltransferase (E2) and lipoamide dehydrogenase (E3). [[http://www.uniprot.org/uniprot/ODBB_HUMAN ODBB_HUMAN]] The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO(2). It contains multiple copies of three enzymatic components: branched-chain alpha-keto acid decarboxylase (E1), lipoamide acyltransferase (E2) and lipoamide dehydrogenase (E3).  
[[http://www.uniprot.org/uniprot/ODBA_HUMAN ODBA_HUMAN]] The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO(2). It contains multiple copies of three enzymatic components: branched-chain alpha-keto acid decarboxylase (E1), lipoamide acyltransferase (E2) and lipoamide dehydrogenase (E3). [[http://www.uniprot.org/uniprot/ODBB_HUMAN ODBB_HUMAN]] The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO(2). It contains multiple copies of three enzymatic components: branched-chain alpha-keto acid decarboxylase (E1), lipoamide acyltransferase (E2) and lipoamide dehydrogenase (E3).  
== 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/dt/1dtw_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 ==
BACKGROUND: Mutations in components of the extraordinarily large alpha-ketoacid dehydrogenase multienzyme complexes can lead to serious and often fatal disorders in humans, including maple syrup urine disease (MSUD). In order to obtain insight into the effect of mutations observed in MSUD patients, we determined the crystal structure of branched-chain alpha-ketoacid dehydrogenase (E1), the 170 kDa alpha(2)beta(2) heterotetrameric E1b component of the branched-chain alpha-ketoacid dehydrogenase multienzyme complex. RESULTS: The 2.7 A resolution crystal structure of human E1b revealed essentially the full alpha and beta polypeptide chains of the tightly packed heterotetramer. The position of two important potassium (K(+)) ions was determined. One of these ions assists a loop that is close to the cofactor to adopt the proper conformation. The second is located in the beta subunit near the interface with the small C-terminal domain of the alpha subunit. The known MSUD mutations affect the functioning of E1b by interfering with the cofactor and K(+) sites, the packing of hydrophobic cores, and the precise arrangement of residues at or near several subunit interfaces. The Tyr--&gt;Asn mutation at position 393-alpha occurs very frequently in the US population of Mennonites and is located in a unique extension of the human E1b alpha subunit, contacting the beta' subunit. CONCLUSIONS: Essentially all MSUD mutations in human E1b can be explained on the basis of the structure, with the severity of the mutations for the stability and function of the protein correlating well with the severity of the disease for the patients. The suggestion is made that small molecules with high affinity for human E1b might alleviate effects of some of the milder forms of MSUD.


==About this Structure==
Crystal structure of human branched-chain alpha-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease.,AEvarsson A, Chuang JL, Wynn RM, Turley S, Chuang DT, Hol WG Structure. 2000 Mar 15;8(3):277-91. PMID:10745006<ref>PMID:10745006</ref>
[[1dtw]] is a 2 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=1DTW OCA].


==Reference==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
<ref group="xtra">PMID:010745006</ref><ref group="xtra">PMID:011509994</ref><ref group="xtra">PMID:012651851</ref><references group="xtra"/><references/>
</div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: AEvarsson, A.]]
[[Category: AEvarsson, A.]]

Revision as of 19:25, 29 September 2014

HUMAN BRANCHED-CHAIN ALPHA-KETO ACID DEHYDROGENASEHUMAN BRANCHED-CHAIN ALPHA-KETO ACID DEHYDROGENASE

Structural highlights

1dtw is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, ,
Activity:3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring), with EC number 1.2.4.4
Resources:FirstGlance, OCA, RCSB, PDBsum

Disease

[ODBA_HUMAN] Defects in BCKDHA are a cause of maple syrup urine disease type IA (MSUD1A) [MIM:248600]. MSUD is an autosomal recessive disorder characterized by mental and physical retardation, feeding problems, and a maple syrup odor to the urine.[1] [2] [3] [4] [5] [6] [7] [8] [ODBB_HUMAN] Defects in BCKDHB are the cause of maple syrup urine disease type IB (MSUD1B) [MIM:248600]. MSUD is an autosomal recessive disorder characterized by mental and physical retardation, feeding problems, and a maple syrup odor to the urine.[9] [10] [11]

Function

[ODBA_HUMAN] The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO(2). It contains multiple copies of three enzymatic components: branched-chain alpha-keto acid decarboxylase (E1), lipoamide acyltransferase (E2) and lipoamide dehydrogenase (E3). [ODBB_HUMAN] The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO(2). It contains multiple copies of three enzymatic components: branched-chain alpha-keto acid decarboxylase (E1), lipoamide acyltransferase (E2) and lipoamide dehydrogenase (E3).

Evolutionary Conservation

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

Publication Abstract from PubMed

BACKGROUND: Mutations in components of the extraordinarily large alpha-ketoacid dehydrogenase multienzyme complexes can lead to serious and often fatal disorders in humans, including maple syrup urine disease (MSUD). In order to obtain insight into the effect of mutations observed in MSUD patients, we determined the crystal structure of branched-chain alpha-ketoacid dehydrogenase (E1), the 170 kDa alpha(2)beta(2) heterotetrameric E1b component of the branched-chain alpha-ketoacid dehydrogenase multienzyme complex. RESULTS: The 2.7 A resolution crystal structure of human E1b revealed essentially the full alpha and beta polypeptide chains of the tightly packed heterotetramer. The position of two important potassium (K(+)) ions was determined. One of these ions assists a loop that is close to the cofactor to adopt the proper conformation. The second is located in the beta subunit near the interface with the small C-terminal domain of the alpha subunit. The known MSUD mutations affect the functioning of E1b by interfering with the cofactor and K(+) sites, the packing of hydrophobic cores, and the precise arrangement of residues at or near several subunit interfaces. The Tyr-->Asn mutation at position 393-alpha occurs very frequently in the US population of Mennonites and is located in a unique extension of the human E1b alpha subunit, contacting the beta' subunit. CONCLUSIONS: Essentially all MSUD mutations in human E1b can be explained on the basis of the structure, with the severity of the mutations for the stability and function of the protein correlating well with the severity of the disease for the patients. The suggestion is made that small molecules with high affinity for human E1b might alleviate effects of some of the milder forms of MSUD.

Crystal structure of human branched-chain alpha-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease.,AEvarsson A, Chuang JL, Wynn RM, Turley S, Chuang DT, Hol WG Structure. 2000 Mar 15;8(3):277-91. PMID:10745006[12]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Dariush N, Fisher CW, Cox RP, Chuang DT. Structure of the gene encoding the entire mature E1 alpha subunit of human branched-chain alpha-keto acid dehydrogenase complex. FEBS Lett. 1991 Jun 17;284(1):34-8. PMID:2060625
  2. ↑ Chuang JL, Fisher CR, Cox RP, Chuang DT. Molecular basis of maple syrup urine disease: novel mutations at the E1 alpha locus that impair E1(alpha 2 beta 2) assembly or decrease steady-state E1 alpha mRNA levels of branched-chain alpha-keto acid dehydrogenase complex. Am J Hum Genet. 1994 Aug;55(2):297-304. PMID:8037208
  3. ↑ Zhang B, Edenberg HJ, Crabb DW, Harris RA. Evidence for both a regulatory mutation and a structural mutation in a family with maple syrup urine disease. J Clin Invest. 1989 Apr;83(4):1425-9. PMID:2703538 doi:http://dx.doi.org/10.1172/JCI114033
  4. ↑ Matsuda I, Nobukuni Y, Mitsubuchi H, Indo Y, Endo F, Asaka J, Harada A. A T-to-A substitution in the E1 alpha subunit gene of the branched-chain alpha-ketoacid dehydrogenase complex in two cell lines derived from Menonite maple syrup urine disease patients. Biochem Biophys Res Commun. 1990 Oct 30;172(2):646-51. PMID:2241958
  5. ↑ Fisher CR, Fisher CW, Chuang DT, Cox RP. Occurrence of a Tyr393----Asn (Y393N) mutation in the E1 alpha gene of the branched-chain alpha-keto acid dehydrogenase complex in maple syrup urine disease patients from a Mennonite population. Am J Hum Genet. 1991 Aug;49(2):429-34. PMID:1867199
  6. ↑ Fisher CR, Chuang JL, Cox RP, Fisher CW, Star RA, Chuang DT. Maple syrup urine disease in Mennonites. Evidence that the Y393N mutation in E1 alpha impedes assembly of the E1 component of branched-chain alpha-keto acid dehydrogenase complex. J Clin Invest. 1991 Sep;88(3):1034-7. PMID:1885764 doi:http://dx.doi.org/10.1172/JCI115363
  7. ↑ Nobukuni Y, Mitsubuchi H, Hayashida Y, Ohta K, Indo Y, Ichiba Y, Endo F, Matsuda I. Heterogeneity of mutations in maple syrup urine disease (MSUD): screening and identification of affected E1 alpha and E1 beta subunits of the branched-chain alpha-keto-acid dehydrogenase multienzyme complex. Biochim Biophys Acta. 1993 Nov 25;1225(1):64-70. PMID:8161368
  8. ↑ Chuang JL, Davie JR, Chinsky JM, Wynn RM, Cox RP, Chuang DT. Molecular and biochemical basis of intermediate maple syrup urine disease. Occurrence of homozygous G245R and F364C mutations at the E1 alpha locus of Hispanic-Mexican patients. J Clin Invest. 1995 Mar;95(3):954-63. PMID:7883996 doi:http://dx.doi.org/10.1172/JCI117804
  9. ↑ Nobukuni Y, Mitsubuchi H, Hayashida Y, Ohta K, Indo Y, Ichiba Y, Endo F, Matsuda I. Heterogeneity of mutations in maple syrup urine disease (MSUD): screening and identification of affected E1 alpha and E1 beta subunits of the branched-chain alpha-keto-acid dehydrogenase multienzyme complex. Biochim Biophys Acta. 1993 Nov 25;1225(1):64-70. PMID:8161368
  10. ↑ Edelmann L, Wasserstein MP, Kornreich R, Sansaricq C, Snyderman SE, Diaz GA. Maple syrup urine disease: identification and carrier-frequency determination of a novel founder mutation in the Ashkenazi Jewish population. Am J Hum Genet. 2001 Oct;69(4):863-8. Epub 2001 Aug 16. PMID:11509994 doi:S0002-9297(07)61141-0
  11. ↑ Wang YP, Qi ML, Li TT, Zhao YJ. Two novel mutations in the BCKDHB gene (R170H, Q346R) cause the classic form of maple syrup urine disease (MSUD). Gene. 2012 Apr 25;498(1):112-5. doi: 10.1016/j.gene.2012.01.082. Epub 2012 Feb 3. PMID:22326532 doi:10.1016/j.gene.2012.01.082
  12. ↑ AEvarsson A, Chuang JL, Wynn RM, Turley S, Chuang DT, Hol WG. Crystal structure of human branched-chain alpha-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease. Structure. 2000 Mar 15;8(3):277-91. PMID:10745006

1dtw, resolution 2.70Å

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