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| | ==Crystal structure of heterotetrameric human ketoacyl reductase complexed with NAD== | | ==Crystal structure of heterotetrameric human ketoacyl reductase complexed with NAD== |
| - | <StructureSection load='4cql' size='340' side='right' caption='[[4cql]], [[Resolution|resolution]] 2.85Å' scene=''> | + | <StructureSection load='4cql' size='340' side='right'caption='[[4cql]], [[Resolution|resolution]] 2.85Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4cql]] is a 16 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CQL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CQL FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4cql]] is a 16 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=4CQL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CQL FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</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]] 2.85Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4cqm|4cqm]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/3-oxoacyl-[acyl-carrier-protein]_reductase 3-oxoacyl-[acyl-carrier-protein] reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.100 1.1.1.100] </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=4cql FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cql OCA], [https://pdbe.org/4cql PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cql RCSB], [https://www.ebi.ac.uk/pdbsum/4cql PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cql 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=4cql FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cql OCA], [http://pdbe.org/4cql PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4cql RCSB], [http://www.ebi.ac.uk/pdbsum/4cql PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4cql ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/DHB8_HUMAN DHB8_HUMAN]] NAD-dependent 17-beta-hydroxysteroid dehydrogenase with highest activity towards estradiol. Has very low activity towards testosterone. The heteroteramer with CBR4 has NADH-dependent 3-ketoacyl-acyl carrier protein reductase activity. May play a role in biosynthesis of fatty acids in mitochondria.<ref>PMID:17978863</ref> <ref>PMID:19571038</ref> [[http://www.uniprot.org/uniprot/CBR4_HUMAN CBR4_HUMAN]] The heteroteramer with HSD17B8 has NADH-dependent 3-ketoacyl-acyl carrier protein reductase activity. May play a role in biosynthesis of fatty acids in mitochondria. The homotetramer may act as NADPH-dependent quinone reductase. Has broad substrate specificity and reduces 9,10-phenanthrenequinone, 1,4-benzoquinone and various other o-quinones and p-quinones (in vitro).<ref>PMID:19000905</ref> <ref>PMID:19571038</ref> | + | [https://www.uniprot.org/uniprot/DHB8_HUMAN DHB8_HUMAN] NAD-dependent 17-beta-hydroxysteroid dehydrogenase with highest activity towards estradiol. Has very low activity towards testosterone. The heteroteramer with CBR4 has NADH-dependent 3-ketoacyl-acyl carrier protein reductase activity. May play a role in biosynthesis of fatty acids in mitochondria.<ref>PMID:17978863</ref> <ref>PMID:19571038</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Hydroxysteroid dehydrogenase|Hydroxysteroid dehydrogenase]] | + | *[[Carbonyl reductase 3D structures|Carbonyl reductase 3D structures]] |
| | + | *[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Awoniyi, L O]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Chen, Z]] | + | [[Category: Large Structures]] |
| - | [[Category: Hiltunen, J K]] | + | [[Category: Awoniyi LO]] |
| - | [[Category: Jiang, G]] | + | [[Category: Chen Z]] |
| - | [[Category: Kastaniotis, A J]] | + | [[Category: Hiltunen JK]] |
| - | [[Category: Prus, P]] | + | [[Category: Jiang G]] |
| - | [[Category: Sah-Teli, S K]] | + | [[Category: Kastaniotis AJ]] |
| - | [[Category: Venkatesan, R]] | + | [[Category: Prus P]] |
| - | [[Category: Wierenga, R K]] | + | [[Category: Sah-Teli SK]] |
| - | [[Category: 17-beta hydroxysteroid dehydrogenase]]
| + | [[Category: Venkatesan R]] |
| - | [[Category: 3-ketoacyl-acp reductase]]
| + | [[Category: Wierenga RK]] |
| - | [[Category: 3r- hydroxyacyl-coa dehydrogenase]]
| + | |
| - | [[Category: Carbobyl reductase type4]]
| + | |
| - | [[Category: Hetero tetramer]]
| + | |
| - | [[Category: Hsd17b8]]
| + | |
| - | [[Category: Hsd8]]
| + | |
| - | [[Category: Kar]]
| + | |
| - | [[Category: Nadh]]
| + | |
| - | [[Category: Nadp]]
| + | |
| - | [[Category: Nadph]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
Function
DHB8_HUMAN NAD-dependent 17-beta-hydroxysteroid dehydrogenase with highest activity towards estradiol. Has very low activity towards testosterone. The heteroteramer with CBR4 has NADH-dependent 3-ketoacyl-acyl carrier protein reductase activity. May play a role in biosynthesis of fatty acids in mitochondria.[1] [2]
Publication Abstract from PubMed
Mitochondrial fatty acid synthesis (mtFAS) is essential for respiratory growth in yeast and mammalian embryonic survival. The human 3-ketoacyl-acyl carrier protein (ACP) reductase (KAR) of mtFAS is a heterotetrameric alpha2beta2-assembly composed of 17beta-hydroxysteroid dehydrogenase type-8 (HSD17B8, alpha-subunit) and carbonyl reductase type-4 (CBR4, beta-subunit). Here we provide a structural explanation for the stability of the heterotetramer from the crystal structure with NAD(+) and NADP(+) bound to the HSD17B8 and CBR4 subunits, respectively, and show that the catalytic activity of the NADPH- and ACP-dependent CBR4 subunit is crucial for a functional HsKAR. Therefore, mtFAS is NADPH- and ACP dependent, employing the 3R-hydroxyacyl-ACP intermediate. HSD17B8 assists in the formation of the competent HsKAR assembly. The intrinsic NAD(+)- and CoA-dependent activity of the HSD17B8 subunit on the 3R-hydroxyacyl-CoA intermediates may indicate a role for this subunit in routing 3R-hydroxyacyl-CoA esters, potentially arising from the metabolism of unsaturated fatty acids, into the mitochondrial beta-oxidation pathway.
Insights into mitochondrial fatty acid synthesis from the structure of heterotetrameric 3-ketoacyl-ACP reductase/3R-hydroxyacyl-CoA dehydrogenase.,Venkatesan R, Sah-Teli SK, Awoniyi LO, Jiang G, Prus P, Kastaniotis AJ, Hiltunen JK, Wierenga RK, Chen Z Nat Commun. 2014 Sep 9;5:4805. doi: 10.1038/ncomms5805. PMID:25203508[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ohno S, Nishikawa K, Honda Y, Nakajin S. Expression in E. coli and tissue distribution of the human homologue of the mouse Ke 6 gene, 17beta-hydroxysteroid dehydrogenase type 8. Mol Cell Biochem. 2008 Feb;309(1-2):209-15. Epub 2007 Nov 3. PMID:17978863 doi:http://dx.doi.org/10.1007/s11010-007-9637-9
- ↑ Chen Z, Kastaniotis AJ, Miinalainen IJ, Rajaram V, Wierenga RK, Hiltunen JK. 17beta-hydroxysteroid dehydrogenase type 8 and carbonyl reductase type 4 assemble as a ketoacyl reductase of human mitochondrial FAS. FASEB J. 2009 Nov;23(11):3682-91. Epub 2009 Jul 1. PMID:19571038 doi:http://dx.doi.org/fj.09-133587
- ↑ Venkatesan R, Sah-Teli SK, Awoniyi LO, Jiang G, Prus P, Kastaniotis AJ, Hiltunen JK, Wierenga RK, Chen Z. Insights into mitochondrial fatty acid synthesis from the structure of heterotetrameric 3-ketoacyl-ACP reductase/3R-hydroxyacyl-CoA dehydrogenase. Nat Commun. 2014 Sep 9;5:4805. doi: 10.1038/ncomms5805. PMID:25203508 doi:http://dx.doi.org/10.1038/ncomms5805
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