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| | <StructureSection load='4wgk' size='340' side='right'caption='[[4wgk]], [[Resolution|resolution]] 2.58Å' scene=''> | | <StructureSection load='4wgk' size='340' side='right'caption='[[4wgk]], [[Resolution|resolution]] 2.58Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4wgk]] 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=4WGK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WGK FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4wgk]] 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=4WGK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WGK FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ASAH2, HNAC1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4wgk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wgk OCA], [https://pdbe.org/4wgk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wgk RCSB], [https://www.ebi.ac.uk/pdbsum/4wgk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wgk ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Ceramidase Ceramidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.23 3.5.1.23] </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=4wgk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wgk OCA], [http://pdbe.org/4wgk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4wgk RCSB], [http://www.ebi.ac.uk/pdbsum/4wgk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4wgk ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ASAH2_HUMAN ASAH2_HUMAN]] Hydrolyzes the sphingolipid ceramide into sphingosine and free fatty acid at an optimal pH of 6.5-8.5. Acts as a key regulator of sphingolipid signaling metabolites by generating sphingosine at the cell surface. Acts as a repressor of apoptosis both by reducing C16-ceramide, thereby preventing ceramide-induced apoptosis, and generating sphingosine, a precursor of the antiapoptotic factor sphingosine 1-phosphate. Probably involved in the digestion of dietary sphingolipids in intestine by acting as a key enzyme for the catabolism of dietary sphingolipids and regulating the levels of bioactive sphingolipid metabolites in the intestinal tract.<ref>PMID:15946935</ref> <ref>PMID:16061940</ref> | + | [https://www.uniprot.org/uniprot/ASAH2_HUMAN ASAH2_HUMAN] Hydrolyzes the sphingolipid ceramide into sphingosine and free fatty acid at an optimal pH of 6.5-8.5. Acts as a key regulator of sphingolipid signaling metabolites by generating sphingosine at the cell surface. Acts as a repressor of apoptosis both by reducing C16-ceramide, thereby preventing ceramide-induced apoptosis, and generating sphingosine, a precursor of the antiapoptotic factor sphingosine 1-phosphate. Probably involved in the digestion of dietary sphingolipids in intestine by acting as a key enzyme for the catabolism of dietary sphingolipids and regulating the levels of bioactive sphingolipid metabolites in the intestinal tract.<ref>PMID:15946935</ref> <ref>PMID:16061940</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4wgk" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4wgk" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Ceramidase|Ceramidase]] |
| | + | *[[Ceramidase 3D PDB structures|Ceramidase 3D PDB structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Ceramidase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Airola, M V]] | + | [[Category: Airola MV]] |
| - | [[Category: Hannun, Y A]] | + | [[Category: Hannun YA]] |
| - | [[Category: Obeid, L M]] | + | [[Category: Obeid LM]] |
| - | [[Category: Pulkoski-Gross, M J]] | + | [[Category: Pulkoski-Gross MJ]] |
| - | [[Category: Amidase]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Phosphate]]
| + | |
| - | [[Category: Zinc]]
| + | |
| Structural highlights
4wgk 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: | , , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
ASAH2_HUMAN Hydrolyzes the sphingolipid ceramide into sphingosine and free fatty acid at an optimal pH of 6.5-8.5. Acts as a key regulator of sphingolipid signaling metabolites by generating sphingosine at the cell surface. Acts as a repressor of apoptosis both by reducing C16-ceramide, thereby preventing ceramide-induced apoptosis, and generating sphingosine, a precursor of the antiapoptotic factor sphingosine 1-phosphate. Probably involved in the digestion of dietary sphingolipids in intestine by acting as a key enzyme for the catabolism of dietary sphingolipids and regulating the levels of bioactive sphingolipid metabolites in the intestinal tract.[1] [2]
Publication Abstract from PubMed
Neutral ceramidase (nCDase) catalyzes conversion of the apoptosis-associated lipid ceramide to sphingosine, the precursor for the proliferative factor sphingosine-1-phosphate. As an enzyme regulating the balance of ceramide and sphingosine-1-phosphate, nCDase is emerging as a therapeutic target for cancer. Here, we present the 2.6-A crystal structure of human nCDase in complex with phosphate that reveals a striking, 20-A deep, hydrophobic active site pocket stabilized by a eukaryotic-specific subdomain not present in bacterial ceramidases. Utilizing flexible ligand docking, we predict a likely binding mode for ceramide that superimposes closely with the crystallographically observed transition state analog phosphate. Our results suggest that nCDase uses a new catalytic strategy for Zn(2+)-dependent amidases, and generates ceramide specificity by sterically excluding sphingolipids with bulky headgroups and specifically recognizing the small hydroxyl head group of ceramide. Together, these data provide a foundation to aid drug development and establish common themes for how proteins recognize the bioactive lipid ceramide.
Structural Basis for Ceramide Recognition and Hydrolysis by Human Neutral Ceramidase.,Airola MV, Allen WJ, Pulkoski-Gross MJ, Obeid LM, Rizzo RC, Hannun YA Structure. 2015 Aug 4;23(8):1482-91. doi: 10.1016/j.str.2015.06.013. Epub 2015, Jul 16. PMID:26190575[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Osawa Y, Uchinami H, Bielawski J, Schwabe RF, Hannun YA, Brenner DA. Roles for C16-ceramide and sphingosine 1-phosphate in regulating hepatocyte apoptosis in response to tumor necrosis factor-alpha. J Biol Chem. 2005 Jul 29;280(30):27879-87. Epub 2005 Jun 9. PMID:15946935 doi:http://dx.doi.org/10.1074/jbc.M503002200
- ↑ Tani M, Sano T, Ito M, Igarashi Y. Mechanisms of sphingosine and sphingosine 1-phosphate generation in human platelets. J Lipid Res. 2005 Nov;46(11):2458-67. Epub 2005 Aug 1. PMID:16061940 doi:http://dx.doi.org/M500268-JLR200
- ↑ Airola MV, Allen WJ, Pulkoski-Gross MJ, Obeid LM, Rizzo RC, Hannun YA. Structural Basis for Ceramide Recognition and Hydrolysis by Human Neutral Ceramidase. Structure. 2015 Aug 4;23(8):1482-91. doi: 10.1016/j.str.2015.06.013. Epub 2015, Jul 16. PMID:26190575 doi:http://dx.doi.org/10.1016/j.str.2015.06.013
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