5i85: Difference between revisions

Latest revision as of 08:26, 23 August 2023

aSMase with zinc and phosphocholine

Structural highlights

5i85 is a 1 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 2.5Å
Ligands:	BMA, MAN, NAG, PC, SO4, ZN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ASM_HUMAN Niemann-Pick disease type A;Niemann-Pick disease type B. 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

ASM_HUMAN Converts sphingomyelin to ceramide (PubMed:1840600, PubMed:18815062). Also has phospholipase C activities toward 1,2-diacylglycerolphosphocholine and 1,2-diacylglycerolphosphoglycerol.^[1] ^[2] Isoform 2 lacks residues that bind the cofactor Zn(2+) and has no enzyme activity.^[3] Isoform 3 lacks residues that bind the cofactor Zn(2+) and has no enzyme activity.^[4]

Publication Abstract from PubMed

Acid sphingomyelinase (ASM) hydrolyzes sphingomyelin to ceramide and phosphocholine, essential components of myelin in neurons. Genetic alterations in ASM lead to ASM deficiency (ASMD) and have been linked to Niemann-Pick disease types A and B. Olipudase alfa, a recombinant form of human ASM, is being developed as enzyme replacement therapy to treat the non-neurological manifestations of ASMD. Here we present the human ASM holoenzyme and product bound structures encompassing all of the functional domains. The catalytic domain has a metallophosphatase fold, and two zinc ions and one reaction product phosphocholine are identified in a histidine-rich active site. The structures reveal the underlying catalytic mechanism, in which two zinc ions activate a water molecule for nucleophilic attack of the phosphodiester bond. Docking of sphingomyelin provides a model that allows insight into the selectivity of the enzyme and how the ASM domains collaborate to complete hydrolysis. Mapping of known mutations provides a basic understanding on correlations between enzyme dysfunction and phenotypes observed in ASMD patients.

Human acid sphingomyelinase structures provide insight to molecular basis of Niemann-Pick disease.,Zhou YF, Metcalf MC, Garman SC, Edmunds T, Qiu H, Wei RR Nat Commun. 2016 Oct 11;7:13082. doi: 10.1038/ncomms13082. PMID:27725636^[5]

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

References

↑ Schuchman EH, Suchi M, Takahashi T, Sandhoff K, Desnick RJ. Human acid sphingomyelinase. Isolation, nucleotide sequence and expression of the full-length and alternatively spliced cDNAs. J Biol Chem. 1991 May 5;266(13):8531-9. PMID:1840600
↑ Jones I, He X, Katouzian F, Darroch PI, Schuchman EH. Characterization of common SMPD1 mutations causing types A and B Niemann-Pick disease and generation of mutation-specific mouse models. Mol Genet Metab. 2008 Nov;95(3):152-62. doi: 10.1016/j.ymgme.2008.08.004. Epub, 2008 Sep 23. PMID:18815062 doi:https://dx.doi.org/10.1016/j.ymgme.2008.08.004
↑ Schuchman EH, Suchi M, Takahashi T, Sandhoff K, Desnick RJ. Human acid sphingomyelinase. Isolation, nucleotide sequence and expression of the full-length and alternatively spliced cDNAs. J Biol Chem. 1991 May 5;266(13):8531-9. PMID:1840600
↑ Schuchman EH, Suchi M, Takahashi T, Sandhoff K, Desnick RJ. Human acid sphingomyelinase. Isolation, nucleotide sequence and expression of the full-length and alternatively spliced cDNAs. J Biol Chem. 1991 May 5;266(13):8531-9. PMID:1840600
↑ Zhou YF, Metcalf MC, Garman SC, Edmunds T, Qiu H, Wei RR. Human acid sphingomyelinase structures provide insight to molecular basis of Niemann-Pick disease. Nat Commun. 2016 Oct 11;7:13082. doi: 10.1038/ncomms13082. PMID:27725636 doi:https://dx.doi.org/10.1038/ncomms13082

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Schuchman EH, Suchi M, Takahashi T, Sandhoff K, Desnick RJ. Human acid sphingomyelinase. Isolation, nucleotide sequence and expression of the full-length and alternatively spliced cDNAs. J Biol Chem. 1991 May 5;266(13):8531-9. PMID:1840600

[2] Jones I, He X, Katouzian F, Darroch PI, Schuchman EH. Characterization of common SMPD1 mutations causing types A and B Niemann-Pick disease and generation of mutation-specific mouse models. Mol Genet Metab. 2008 Nov;95(3):152-62. doi: 10.1016/j.ymgme.2008.08.004. Epub, 2008 Sep 23. PMID:18815062 doi:https://dx.doi.org/10.1016/j.ymgme.2008.08.004

[3] Schuchman EH, Suchi M, Takahashi T, Sandhoff K, Desnick RJ. Human acid sphingomyelinase. Isolation, nucleotide sequence and expression of the full-length and alternatively spliced cDNAs. J Biol Chem. 1991 May 5;266(13):8531-9. PMID:1840600

[4] Schuchman EH, Suchi M, Takahashi T, Sandhoff K, Desnick RJ. Human acid sphingomyelinase. Isolation, nucleotide sequence and expression of the full-length and alternatively spliced cDNAs. J Biol Chem. 1991 May 5;266(13):8531-9. PMID:1840600

[5] Zhou YF, Metcalf MC, Garman SC, Edmunds T, Qiu H, Wei RR. Human acid sphingomyelinase structures provide insight to molecular basis of Niemann-Pick disease. Nat Commun. 2016 Oct 11;7:13082. doi: 10.1038/ncomms13082. PMID:27725636 doi:https://dx.doi.org/10.1038/ncomms13082

[1]

[2]

[3]

[4]

[5]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5i85 is ON HOLD
+==aSMase with zinc and phosphocholine==
+<StructureSection load='5i85' size='340' side='right'caption='[[5i85]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5i85]] is a 1 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=5I85 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5I85 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</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=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PC:PHOSPHOCHOLINE'>PC</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=5i85 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i85 OCA], [https://pdbe.org/5i85 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5i85 RCSB], [https://www.ebi.ac.uk/pdbsum/5i85 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5i85 ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/ASM_HUMAN ASM_HUMAN] Niemann-Pick disease type A;Niemann-Pick disease type B. 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/ASM_HUMAN ASM_HUMAN] Converts sphingomyelin to ceramide (PubMed:1840600, PubMed:18815062). Also has phospholipase C activities toward 1,2-diacylglycerolphosphocholine and 1,2-diacylglycerolphosphoglycerol.<ref>PMID:1840600</ref> <ref>PMID:18815062</ref>   Isoform 2 lacks residues that bind the cofactor Zn(2+) and has no enzyme activity.<ref>PMID:1840600</ref>   Isoform 3 lacks residues that bind the cofactor Zn(2+) and has no enzyme activity.<ref>PMID:1840600</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Acid sphingomyelinase (ASM) hydrolyzes sphingomyelin to ceramide and phosphocholine, essential components of myelin in neurons. Genetic alterations in ASM lead to ASM deficiency (ASMD) and have been linked to Niemann-Pick disease types A and B. Olipudase alfa, a recombinant form of human ASM, is being developed as enzyme replacement therapy to treat the non-neurological manifestations of ASMD. Here we present the human ASM holoenzyme and product bound structures encompassing all of the functional domains. The catalytic domain has a metallophosphatase fold, and two zinc ions and one reaction product phosphocholine are identified in a histidine-rich active site. The structures reveal the underlying catalytic mechanism, in which two zinc ions activate a water molecule for nucleophilic attack of the phosphodiester bond. Docking of sphingomyelin provides a model that allows insight into the selectivity of the enzyme and how the ASM domains collaborate to complete hydrolysis. Mapping of known mutations provides a basic understanding on correlations between enzyme dysfunction and phenotypes observed in ASMD patients.
-Authors: Zhou, Y.F., Wei, R.R.
+Human acid sphingomyelinase structures provide insight to molecular basis of Niemann-Pick disease.,Zhou YF, Metcalf MC, Garman SC, Edmunds T, Qiu H, Wei RR Nat Commun. 2016 Oct 11;7:13082. doi: 10.1038/ncomms13082. PMID:27725636<ref>PMID:27725636</ref>
-Description: aSMase with zinc and phosphocholine
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Wei, R.R]]
+<div class="pdbe-citations 5i85" style="background-color:#fffaf0;"></div>
-[[Category: Zhou, Y.F]]
+==See Also==
+*[[Sphingomyelinase|Sphingomyelinase]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Wei RR]]
+[[Category: Zhou YF]]

5i85: Difference between revisions

Latest revision as of 08:26, 23 August 2023

aSMase with zinc and phosphocholine

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

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