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== 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> | [[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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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. | ||
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| + | 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<ref>PMID:26190575</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 08:48, 12 August 2015
Crystal structure of human neutral ceramidase with Zn-bound phosphate
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Categories: Ceramidase | Airola, M V | Hannun, Y A | Obeid, L M | Pulkoski-Gross, M J | Amidase | Hydrolase | Phosphate | Zinc
