1olx: Difference between revisions

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==~~Roles of His291-alpha and His146-beta' in the reductive acylation reaction catalyzed by human branched-chain alpha-ketoacid dehydrogenase~~==

====

== Structural highlights ==

<table><tr><td colspan='2'>~~[[1olx]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human].~~ Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=~~1OLX~~ OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=~~1OLX~~ FirstGlance]. <br>

<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=TDP:THIAMIN+DIPHOSPHATE'>TDP</scene></td></tr>

</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=1olx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1olx OCA], [https://pdbe.org/1olx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1olx RCSB], [https://www.ebi.ac.uk/pdbsum/1olx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1olx ProSAT]</span></td></tr>

~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1dtw|1dtw]], [[1ols|1ols]], [[1olu|1olu]]</td></tr>~~

<tr id='activity'><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 id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=1olx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1olx OCA], [~~http~~://pdbe.org/1olx PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=1olx RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/1olx PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=1olx ProSAT]</span></td></tr>

</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).

== Evolutionary Conservation ==

[[Image:Consurf_key_small.gif|200px|right]]

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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=1olx ConSurf].

~~<div style="background-color:#fffaf0;">~~

~~== Publication Abstract from PubMed ==~~

We report here that alterations of either His291-alpha or His146-beta' in the active site of human branched-chain alpha-ketoacid dehydrogenase (E1b) impede both the decarboxylation and the reductive acylation reactions catalyzed by E1b as well as the binding of cofactor thiamin diphosphate (ThDP). In a refined human E1b active-site structure, His291-alpha, which aligns with His407 in Escherichia coli pyruvate dehydrogenase and His263 in yeast transketolase, is on a largely ordered phosphorylation loop. The imidazole ring of His291-alpha in E1b coordinates to the terminal phosphate oxygen atoms of bound ThDP. The N3 atom of wild-type His146-beta', which can be protonated, binds a water molecule and points toward the aminopyrimidine ring of ThDP. Remarkably, the H291A-alpha mutation results in a complete order-to-disorder transition of the loop region, which precludes the binding of the substrate lipoyl-bearing domain to E1b. The H146A-beta' mutation, on the other hand, does not alter the loop structure, but nullifies the reductive acylation activity of E1b. Our results suggest that: 1) His291-alpha plays a structural rather than a catalytic role in the binding of cofactor ThDP and the lipoyl-bearing domain to E1b, and 2) His146-beta' is an essential catalytic residue, probably functioning as a proton donor in the reductive acylation of lipoamide on the lipoyl-bearing domain.

Roles of His291-alpha and His146-beta' in the reductive acylation reaction catalyzed by human branched-chain alpha-ketoacid dehydrogenase: refined phosphorylation loop structure in the active site.,Wynn RM, Machius M, Chuang JL, Li J, Tomchick DR, Chuang DT J Biol Chem. 2003 Oct 31;278(44):43402-10. Epub 2003 Aug 5. PMID:12902323<ref>PMID:12902323</ref>

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

~~</div>~~

~~<div class="pdbe-citations 1olx" style="background-color:#fffaf0;"></div>~~

~~==See Also==~~

*[[2-oxoisovalerate dehydrogenase 3D structures|2-oxoisovalerate dehydrogenase 3D structures]]

~~== References ==~~

~~<references/>~~

__TOC__

</StructureSection>

~~[[Category: Human]]~~

[[Category: Large Structures]]

[[Category: ~~Chuang, D T]]~~

[[Category: Z-disk]]

~~[[Category: Chuang, J L]]~~

~~[[Category: Li, J]]~~

~~[[Category: Machius, M]]~~

~~[[Category: Tomchick, D R]]~~

~~[[Category: Wynn, R M]]~~

~~[[Category: Acylation]]~~

~~[[Category: Branched~~-~~chain]]~~

~~[[Category: Ketoacid dehydrogenase]]~~

~~[[Category: Maple syrup urine disease]]~~

~~[[Category: Multi-enzyme complex]]~~

~~[[Category: Oxidative decarboxylation oxidoreductase]]~~

~~[[Category: Oxidoreductase]]~~

~~[[Category: Thiamine phosphate~~]]

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@@ Line 1: / Line 1: @@
-==Roles of His291-alpha and His146-beta' in the reductive acylation reaction catalyzed by human branched-chain alpha-ketoacid dehydrogenase==
+====
-<StructureSection load='1olx' size='340' side='right'caption='[[1olx]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
+<StructureSection load='1olx' size='340' side='right'caption='[[1olx]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1olx]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1OLX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1OLX FirstGlance]. <br>
+<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=TDP:THIAMIN+DIPHOSPHATE'>TDP</scene></td></tr>
+</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=1olx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1olx OCA], [https://pdbe.org/1olx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1olx RCSB], [https://www.ebi.ac.uk/pdbsum/1olx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1olx ProSAT]</span></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1dtw|1dtw]], [[1ols|1ols]], [[1olu|1olu]]</td></tr>
-<tr id='activity'><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 id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1olx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1olx OCA], [http://pdbe.org/1olx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1olx RCSB], [http://www.ebi.ac.uk/pdbsum/1olx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1olx ProSAT]</span></td></tr>
 </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).
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 23: / Line 16: @@
 </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=1olx ConSurf].
 <div style="clear:both"></div>
-<div style="background-color:#fffaf0;">
-== Publication Abstract from PubMed ==
-We report here that alterations of either His291-alpha or His146-beta' in the active site of human branched-chain alpha-ketoacid dehydrogenase (E1b) impede both the decarboxylation and the reductive acylation reactions catalyzed by E1b as well as the binding of cofactor thiamin diphosphate (ThDP). In a refined human E1b active-site structure, His291-alpha, which aligns with His407 in Escherichia coli pyruvate dehydrogenase and His263 in yeast transketolase, is on a largely ordered phosphorylation loop. The imidazole ring of His291-alpha in E1b coordinates to the terminal phosphate oxygen atoms of bound ThDP. The N3 atom of wild-type His146-beta', which can be protonated, binds a water molecule and points toward the aminopyrimidine ring of ThDP. Remarkably, the H291A-alpha mutation results in a complete order-to-disorder transition of the loop region, which precludes the binding of the substrate lipoyl-bearing domain to E1b. The H146A-beta' mutation, on the other hand, does not alter the loop structure, but nullifies the reductive acylation activity of E1b. Our results suggest that: 1) His291-alpha plays a structural rather than a catalytic role in the binding of cofactor ThDP and the lipoyl-bearing domain to E1b, and 2) His146-beta' is an essential catalytic residue, probably functioning as a proton donor in the reductive acylation of lipoamide on the lipoyl-bearing domain.
-Roles of His291-alpha and His146-beta' in the reductive acylation reaction catalyzed by human branched-chain alpha-ketoacid dehydrogenase: refined phosphorylation loop structure in the active site.,Wynn RM, Machius M, Chuang JL, Li J, Tomchick DR, Chuang DT J Biol Chem. 2003 Oct 31;278(44):43402-10. Epub 2003 Aug 5. PMID:12902323<ref>PMID:12902323</ref>
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 1olx" style="background-color:#fffaf0;"></div>
-==See Also==
-*[[2-oxoisovalerate dehydrogenase 3D structures|2-oxoisovalerate dehydrogenase 3D structures]]
-== References ==
-<references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Chuang, D T]]
+[[Category: Z-disk]]
-[[Category: Chuang, J L]]
-[[Category: Li, J]]
-[[Category: Machius, M]]
-[[Category: Tomchick, D R]]
-[[Category: Wynn, R M]]
-[[Category: Acylation]]
-[[Category: Branched-chain]]
-[[Category: Ketoacid dehydrogenase]]
-[[Category: Maple syrup urine disease]]
-[[Category: Multi-enzyme complex]]
-[[Category: Oxidative decarboxylation oxidoreductase]]
-[[Category: Oxidoreductase]]
-[[Category: Thiamine phosphate]]