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| | <StructureSection load='3dop' size='340' side='right'caption='[[3dop]], [[Resolution|resolution]] 2.00Å' scene=''> | | <StructureSection load='3dop' size='340' side='right'caption='[[3dop]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3dop]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3DOP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3DOP FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3dop]] 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=3DOP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3DOP FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BDT:5-BETA-DIHYDROTESTOSTERONE'>BDT</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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]] 2Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3cmf|3cmf]]</div></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BDT:5-BETA-DIHYDROTESTOSTERONE'>BDT</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AKR1D1, SRD5B1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Delta(4)-3-oxosteroid_5-beta-reductase Delta(4)-3-oxosteroid 5-beta-reductase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.3 1.3.1.3] </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=3dop FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3dop OCA], [https://pdbe.org/3dop PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3dop RCSB], [https://www.ebi.ac.uk/pdbsum/3dop PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3dop ProSAT]</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=3dop FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3dop OCA], [https://pdbe.org/3dop PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3dop RCSB], [https://www.ebi.ac.uk/pdbsum/3dop PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3dop ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[https://www.uniprot.org/uniprot/AK1D1_HUMAN AK1D1_HUMAN]] Defects in AKR1D1 are the cause of congenital bile acid synthesis defect type 2 (CBAS2) [MIM:[https://omim.org/entry/235555 235555]]; also known as cholestasis with delta(4)-3-oxosteroid 5-beta-reductase deficiency. Patients with this liver disease show absence or low levels of chenodeoxycholic acid and cholic acid in plasma and urine.<ref>PMID:12970144</ref> <ref>PMID:15030995</ref>
| + | [https://www.uniprot.org/uniprot/AK1D1_HUMAN AK1D1_HUMAN] Defects in AKR1D1 are the cause of congenital bile acid synthesis defect type 2 (CBAS2) [MIM:[https://omim.org/entry/235555 235555]; also known as cholestasis with delta(4)-3-oxosteroid 5-beta-reductase deficiency. Patients with this liver disease show absence or low levels of chenodeoxycholic acid and cholic acid in plasma and urine.<ref>PMID:12970144</ref> <ref>PMID:15030995</ref> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/AK1D1_HUMAN AK1D1_HUMAN]] Efficiently catalyzes the reduction of progesterone, androstenedione, 17-alpha-hydroxyprogesterone and testosterone to 5-beta-reduced metabolites. The bile acid intermediates 7-alpha,12-alpha-dihydroxy-4-cholesten-3-one and 7-alpha-hydroxy-4-cholesten-3-one can also act as substrates.
| + | [https://www.uniprot.org/uniprot/AK1D1_HUMAN AK1D1_HUMAN] Efficiently catalyzes the reduction of progesterone, androstenedione, 17-alpha-hydroxyprogesterone and testosterone to 5-beta-reduced metabolites. The bile acid intermediates 7-alpha,12-alpha-dihydroxy-4-cholesten-3-one and 7-alpha-hydroxy-4-cholesten-3-one can also act as substrates. |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Christianson, D W]] | + | [[Category: Christianson DW]] |
| - | [[Category: Costanzo, L Di]] | + | [[Category: Di Costanzo L]] |
| - | [[Category: Drury, J E]] | + | [[Category: Drury JE]] |
| - | [[Category: Penning, T M]] | + | [[Category: Penning TM]] |
| - | [[Category: Bile acid catabolism]]
| + | |
| - | [[Category: Cytoplasm]]
| + | |
| - | [[Category: Disease mutation]]
| + | |
| - | [[Category: Intrahepatic cholestasis]]
| + | |
| - | [[Category: Lipid metabolism]]
| + | |
| - | [[Category: Nadp]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Product]]
| + | |
| - | [[Category: Steroid metabolism]]
| + | |
| Structural highlights
Disease
AK1D1_HUMAN Defects in AKR1D1 are the cause of congenital bile acid synthesis defect type 2 (CBAS2) [MIM:235555; also known as cholestasis with delta(4)-3-oxosteroid 5-beta-reductase deficiency. Patients with this liver disease show absence or low levels of chenodeoxycholic acid and cholic acid in plasma and urine.[1] [2]
Function
AK1D1_HUMAN Efficiently catalyzes the reduction of progesterone, androstenedione, 17-alpha-hydroxyprogesterone and testosterone to 5-beta-reduced metabolites. The bile acid intermediates 7-alpha,12-alpha-dihydroxy-4-cholesten-3-one and 7-alpha-hydroxy-4-cholesten-3-one can also act as substrates.
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
Human steroid 5beta-reductase (aldo-keto reductase (AKR) 1D1) catalyzes reduction of Delta(4)-ene double bonds in steroid hormones and bile acid precursors. We have reported the structures of an AKR1D1-NADP(+) binary complex, and AKR1D1-NADP(+)-cortisone, AKR1D1-NADP(+)-progesterone and AKR1D1-NADP(+)-testosterone ternary complexes at high resolutions. Recently, structures of AKR1D1-NADP(+)-5beta-dihydroprogesterone complexes showed that the product is bound unproductively. Two quite different mechanisms of steroid double bond reduction have since been proposed. However, site-directed mutagenesis supports only one mechanism. In this mechanism, the 4-pro-R hydride is transferred from the re-face of the nicotinamide ring to C5 of the steroid substrate. E120, a unique substitution in the AKR catalytic tetrad, permits a deeper penetration of the steroid substrate into the active site to promote optimal reactant positioning. It participates with Y58 to create a "superacidic" oxyanion hole for polarization of the C3 ketone. A role for K87 in the proton relay proposed using the AKR1D1-NADP(+)-5beta-dihydroprogesterone structure is not supported.
Structure and catalytic mechanism of human steroid 5beta-reductase (AKR1D1).,Di Costanzo L, Drury JE, Christianson DW, Penning TM Mol Cell Endocrinol. 2008 Sep 19. PMID:18848863[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lemonde HA, Custard EJ, Bouquet J, Duran M, Overmars H, Scambler PJ, Clayton PT. Mutations in SRD5B1 (AKR1D1), the gene encoding delta(4)-3-oxosteroid 5beta-reductase, in hepatitis and liver failure in infancy. Gut. 2003 Oct;52(10):1494-9. PMID:12970144
- ↑ Gonzales E, Cresteil D, Baussan C, Dabadie A, Gerhardt MF, Jacquemin E. SRD5B1 (AKR1D1) gene analysis in delta(4)-3-oxosteroid 5beta-reductase deficiency: evidence for primary genetic defect. J Hepatol. 2004 Apr;40(4):716-8. PMID:15030995 doi:10.1016/j.jhep.2003.12.024
- ↑ Di Costanzo L, Drury JE, Christianson DW, Penning TM. Structure and catalytic mechanism of human steroid 5beta-reductase (AKR1D1). Mol Cell Endocrinol. 2008 Sep 19. PMID:18848863 doi:S0303-7207(08)00411-5
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