6mhm: Difference between revisions

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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6mhm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mhm OCA], [https://pdbe.org/6mhm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mhm RCSB], [https://www.ebi.ac.uk/pdbsum/6mhm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mhm 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=6mhm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mhm OCA], [https://pdbe.org/6mhm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mhm RCSB], [https://www.ebi.ac.uk/pdbsum/6mhm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mhm ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/ASAH1_HUMAN ASAH1_HUMAN] Farber disease;Spinal muscular atrophy-progressive myoclonic epilepsy syndrome. The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/ASAH1_HUMAN ASAH1_HUMAN] Lysosomal ceramidase that hydrolyzes sphingolipid ceramides into sphingosine and free fatty acids at acidic pH (PubMed:10610716, PubMed:7744740, PubMed:15655246, PubMed:11451951). Ceramides, sphingosine, and its phosphorylated form sphingosine-1-phosphate are bioactive lipids that mediate cellular signaling pathways regulating several biological processes including cell proliferation, apoptosis and differentiation (PubMed:10610716). Has a higher catalytic efficiency towards C12-ceramides versus other ceramides (PubMed:7744740, PubMed:15655246). Also catalyzes the reverse reaction allowing the synthesis of ceramides from fatty acids and sphingosine (PubMed:12764132, PubMed:12815059). For the reverse synthetic reaction, the natural sphingosine D-erythro isomer is more efficiently utilized as a substrate compared to D-erythro-dihydrosphingosine and D-erythro-phytosphingosine, while the fatty acids with chain lengths of 12 or 14 carbons are the most efficiently used (PubMed:12764132). Has also an N-acylethanolamine hydrolase activity (PubMed:15655246). By regulating the levels of ceramides, sphingosine and sphingosine-1-phosphate in the epidermis, mediates the calcium-induced differentiation of epidermal keratinocytes (PubMed:17713573). Also indirectly regulates tumor necrosis factor/TNF-induced apoptosis (By similarity). By regulating the intracellular balance between ceramides and sphingosine, in adrenocortical cells, probably also acts as a regulator of steroidogenesis (PubMed:22261821).[UniProtKB:Q9WV54]<ref>PMID:10610716</ref> <ref>PMID:11451951</ref> <ref>PMID:12764132</ref> <ref>PMID:12815059</ref> <ref>PMID:15655246</ref> <ref>PMID:17713573</ref> <ref>PMID:22261821</ref> <ref>PMID:7744740</ref> <ref>PMID:10610716</ref>  Isoform 2: May directly regulate steroidogenesis by binding the nuclear receptor NR5A1 and negatively regulating its transcriptional activity.<ref>PMID:22927646</ref>
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== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==

Latest revision as of 11:08, 17 October 2024

Crystal structure of human acid ceramidase in covalent complex with carmofurCrystal structure of human acid ceramidase in covalent complex with carmofur

Structural highlights

6mhm is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.743Å
Ligands:, , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

Human acid ceramidase (AC) is a lysosomal cysteine amidase, which has received a great deal of interest in recent years as a potential target for the development of new therapeutics against melanoma and glioblastoma tumors. Despite the strong interest in obtaining structural information, only the structures of the apo-AC enzyme in its zymogen and activated conformations are available. In this work, the crystal structure of AC in complex with the covalent carmofur inhibitor is presented. Carmofur is an antineoplastic drug containing an electrophilic carbonyl reactive group that targets the catalytic cysteine. This novel structural data explains the basis of the AC inhibition, provides insights into the enzymatic properties of the protein, and is a great aid toward the structure-based drug design of potent inhibitors for AC, providing the detailed mechanism, which has eluded the scientific community for more than 30 years, of carmofur's mysterious 5-fluorouracil-independent antitumor activity.

Molecular Mechanism of Inhibition of Acid Ceramidase by Carmofur.,Dementiev A, Joachimiak A, Nguyen H, Gorelik A, Illes K, Shabani S, Gelsomino M, Ahn EE, Nagar B, Doan N J Med Chem. 2019 Jan 24;62(2):987-992. doi: 10.1021/acs.jmedchem.8b01723. Epub, 2018 Dec 19. PMID:30525581[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Dementiev A, Joachimiak A, Nguyen H, Gorelik A, Illes K, Shabani S, Gelsomino M, Ahn EE, Nagar B, Doan N. Molecular Mechanism of Inhibition of Acid Ceramidase by Carmofur. J Med Chem. 2019 Jan 24;62(2):987-992. doi: 10.1021/acs.jmedchem.8b01723. Epub, 2018 Dec 19. PMID:30525581 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b01723

6mhm, resolution 2.74Å

Drag the structure with the mouse to rotate

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OCA
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