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| | ==Crystal structure of the D444V disease-causing mutant of the human dihydrolipoamide dehydrogenase== | | ==Crystal structure of the D444V disease-causing mutant of the human dihydrolipoamide dehydrogenase== |
| - | <StructureSection load='5j5z' size='340' side='right' caption='[[5j5z]], [[Resolution|resolution]] 1.84Å' scene=''> | + | <StructureSection load='5j5z' size='340' side='right'caption='[[5j5z]], [[Resolution|resolution]] 1.84Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5j5z]] 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=5J5Z OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J5Z FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5j5z]] is a 2 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=5J5Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5J5Z FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.84Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DLD, GCSL, LAD, PHE3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydrolipoyl_dehydrogenase Dihydrolipoyl dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.8.1.4 1.8.1.4] </span></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=5j5z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j5z OCA], [https://pdbe.org/5j5z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5j5z RCSB], [https://www.ebi.ac.uk/pdbsum/5j5z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5j5z ProSAT]</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=5j5z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j5z OCA], [http://pdbe.org/5j5z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j5z RCSB], [http://www.ebi.ac.uk/pdbsum/5j5z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j5z ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/DLDH_HUMAN DLDH_HUMAN]] Note=Defects in DLD are involved in the development of congenital infantile lactic acidosis. Defects in DLD are a cause of maple syrup urine disease (MSUD) [MIM:[http://omim.org/entry/248600 248600]]. MSUD is characterized by mental and physical retardation, feeding problems and a maple syrup odor to the urine. The keto acids of the branched-chain amino acids are present in the urine, resulting from a block in oxidative decarboxylation. | + | [https://www.uniprot.org/uniprot/DLDH_HUMAN DLDH_HUMAN] Note=Defects in DLD are involved in the development of congenital infantile lactic acidosis. Defects in DLD are a cause of maple syrup urine disease (MSUD) [MIM:[https://omim.org/entry/248600 248600]. MSUD is characterized by mental and physical retardation, feeding problems and a maple syrup odor to the urine. The keto acids of the branched-chain amino acids are present in the urine, resulting from a block in oxidative decarboxylation. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/DLDH_HUMAN DLDH_HUMAN]] Lipoamide dehydrogenase is a component of the glycine cleavage system as well as of the alpha-ketoacid dehydrogenase complexes. Involved in the hyperactivation of spermatazoa during capacitation and in the spermatazoal acrosome reaction. | + | [https://www.uniprot.org/uniprot/DLDH_HUMAN DLDH_HUMAN] Lipoamide dehydrogenase is a component of the glycine cleavage system as well as of the alpha-ketoacid dehydrogenase complexes. Involved in the hyperactivation of spermatazoa during capacitation and in the spermatazoal acrosome reaction. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Dihydrolipoyl dehydrogenase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Adam-Vizi, V]] | + | [[Category: Adam-Vizi V]] |
| - | [[Category: Ambrus, A]] | + | [[Category: Ambrus A]] |
| - | [[Category: Mizsei, R]] | + | [[Category: Mizsei R]] |
| - | [[Category: Szabo, E]] | + | [[Category: Szabo E]] |
| - | [[Category: Torocsik, B]] | + | [[Category: Torocsik B]] |
| - | [[Category: Weiss, M S]] | + | [[Category: Weiss MS]] |
| - | [[Category: Zambo, Z]] | + | [[Category: Zambo Z]] |
| - | [[Category: Dihydrolipoamide dehydrogenase]]
| + | |
| - | [[Category: Disease-causing mutant]]
| + | |
| - | [[Category: E3 deficiency]]
| + | |
| - | [[Category: E3 subunit]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
Disease
DLDH_HUMAN Note=Defects in DLD are involved in the development of congenital infantile lactic acidosis. Defects in DLD are a cause of maple syrup urine disease (MSUD) [MIM:248600. MSUD is characterized by mental and physical retardation, feeding problems and a maple syrup odor to the urine. The keto acids of the branched-chain amino acids are present in the urine, resulting from a block in oxidative decarboxylation.
Function
DLDH_HUMAN Lipoamide dehydrogenase is a component of the glycine cleavage system as well as of the alpha-ketoacid dehydrogenase complexes. Involved in the hyperactivation of spermatazoa during capacitation and in the spermatazoal acrosome reaction.
Publication Abstract from PubMed
We report the crystal structures of the human (dihydro)lipoamide dehydrogenase (hLADH, hE3) and its disease-causing homodimer interface mutant D444V-hE3 at 2.27 and 1.84A resolution, respectively. The wild type structure is a unique uncomplexed, unliganded hE3 structure with the true canonical sequence. Based on the structural information a novel molecular pathomechanism is proposed for the impaired catalytic activity and enhanced capacity for reactive oxygen species generation of the pathogenic mutant. The mechanistic model involves a previously much ignored solvent accessible channel leading to the active site that might be perturbed also by other disease-causing homodimer interface substitutions of this enzyme.
Crystal structures of the disease-causing D444V mutant and the relevant wild type human dihydrolipoamide dehydrogenase.,Szabo E, Mizsei R, Wilk P, Zambo Z, Torocsik B, Weiss MS, Adam-Vizi V, Ambrus A Free Radic Biol Med. 2018 Jun 20;124:214-220. doi:, 10.1016/j.freeradbiomed.2018.06.008. PMID:29908278[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Szabo E, Mizsei R, Wilk P, Zambo Z, Torocsik B, Weiss MS, Adam-Vizi V, Ambrus A. Crystal structures of the disease-causing D444V mutant and the relevant wild type human dihydrolipoamide dehydrogenase. Free Radic Biol Med. 2018 Jun 20;124:214-220. doi:, 10.1016/j.freeradbiomed.2018.06.008. PMID:29908278 doi:http://dx.doi.org/10.1016/j.freeradbiomed.2018.06.008
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