5ae2: Difference between revisions

Revision as of 04:53, 25 May 2023

Ether Lipid-Generating Enzyme AGPS in complex with inhibitor 1e

Structural highlights

5ae2 is a 4 chain structure with sequence from Cavia porcellus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	FAD, FYC, SO4
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ADAS_CAVPO Catalyzes the exchange of an acyl for a long-chain alkyl group and the formation of the ether bond in the biosynthesis of ether phospholipids.^[1]

Publication Abstract from PubMed

Dysregulated ether lipid metabolism is an important hallmark of cancer cells. Previous studies have reported that lowering ether lipid levels by genetic ablation of the ether lipid-generating enzyme alkyl-glycerone phosphate synthase (AGPS) lowers key structural and oncogenic ether lipid levels and alters fatty acid, glycerophospholipid, and eicosanoid metabolism to impair cancer pathogenicity, indicating that AGPS may be a potential therapeutic target for cancer. In this study, we have performed a small-molecule screen to identify candidate AGPS inhibitors. We have identified several lead AGPS inhibitors and have structurally characterized their interactions with the enzyme and show that these inhibitors bind to distinct portions of the active site. We further show that the lead AGPS inhibitor 1a selectively lowers ether lipid levels in several types of human cancer cells and impairs their cellular survival and migration. We provide here the first report of in situ-active pharmacological tools for inhibiting AGPS, which may provide chemical scaffolds for future AGPS inhibitor development for cancer therapy.

Discovery of Inhibitors for the Ether Lipid-Generating Enzyme AGPS as Anti-Cancer Agents.,Piano V, Benjamin DI, Valente S, Nenci S, Marrocco B, Mai A, Aliverti A, Nomura DK, Mattevi A ACS Chem Biol. 2015 Sep 4. PMID:26322624^[2]

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

References

↑ Nenci S, Piano V, Rosati S, Aliverti A, Pandini V, Fraaije MW, Heck AJ, Edmondson DE, Mattevi A. Precursor of ether phospholipids is synthesized by a flavoenzyme through covalent catalysis. Proc Natl Acad Sci U S A. 2012 Nov 13;109(46):18791-6. doi:, 10.1073/pnas.1215128109. Epub 2012 Oct 29. PMID:23112191 doi:https://dx.doi.org/10.1073/pnas.1215128109
↑ Piano V, Benjamin DI, Valente S, Nenci S, Marrocco B, Mai A, Aliverti A, Nomura DK, Mattevi A. Discovery of Inhibitors for the Ether Lipid-Generating Enzyme AGPS as Anti-Cancer Agents. ACS Chem Biol. 2015 Sep 4. PMID:26322624 doi:https://dx.doi.org/10.1021/acschembio.5b00466

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OCA

[1] Nenci S, Piano V, Rosati S, Aliverti A, Pandini V, Fraaije MW, Heck AJ, Edmondson DE, Mattevi A. Precursor of ether phospholipids is synthesized by a flavoenzyme through covalent catalysis. Proc Natl Acad Sci U S A. 2012 Nov 13;109(46):18791-6. doi:, 10.1073/pnas.1215128109. Epub 2012 Oct 29. PMID:23112191 doi:https://dx.doi.org/10.1073/pnas.1215128109

[2] Piano V, Benjamin DI, Valente S, Nenci S, Marrocco B, Mai A, Aliverti A, Nomura DK, Mattevi A. Discovery of Inhibitors for the Ether Lipid-Generating Enzyme AGPS as Anti-Cancer Agents. ACS Chem Biol. 2015 Sep 4. PMID:26322624 doi:https://dx.doi.org/10.1021/acschembio.5b00466

[1]

[2]

@@ Line 3: / Line 3: @@
 <StructureSection load='5ae2' size='340' side='right'caption='[[5ae2]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5ae2]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Cavpo Cavpo]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AE2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AE2 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5ae2]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Cavia_porcellus Cavia porcellus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AE2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AE2 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=FYC:3-(2-FLUOROPHENYL)-2-METHYL-N-((2-OXO-2,3-DIHYDRO-1H-BENZO[D]IMIDAZOL-5-YL)METHYL)ACRYLAMIDE'>FYC</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=FYC:3-(2-FLUOROPHENYL)-2-METHYL-N-((2-OXO-2,3-DIHYDRO-1H-BENZO[D]IMIDAZOL-5-YL)METHYL)ACRYLAMIDE'>FYC</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5adz|5adz]], [[5ae1|5ae1]], [[5ae3|5ae3]]</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=5ae2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ae2 OCA], [https://pdbe.org/5ae2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ae2 RCSB], [https://www.ebi.ac.uk/pdbsum/5ae2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ae2 ProSAT]</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=5ae2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ae2 OCA], [http://pdbe.org/5ae2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ae2 RCSB], [http://www.ebi.ac.uk/pdbsum/5ae2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ae2 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/ADAS_CAVPO ADAS_CAVPO]] Catalyzes the exchange of an acyl for a long-chain alkyl group and the formation of the ether bond in the biosynthesis of ether phospholipids.<ref>PMID:23112191</ref>
+[https://www.uniprot.org/uniprot/ADAS_CAVPO ADAS_CAVPO] Catalyzes the exchange of an acyl for a long-chain alkyl group and the formation of the ether bond in the biosynthesis of ether phospholipids.<ref>PMID:23112191</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 22: @@
 __TOC__
 </StructureSection>
-[[Category: Cavpo]]
+[[Category: Cavia porcellus]]
 [[Category: Large Structures]]
-[[Category: Aliverti, A]]
+[[Category: Aliverti A]]
-[[Category: Benjamin, D I]]
+[[Category: Benjamin DI]]
-[[Category: Mai, A]]
+[[Category: Mai A]]
-[[Category: Marrocco, B]]
+[[Category: Marrocco B]]
-[[Category: Mattevi, A]]
+[[Category: Mattevi A]]
-[[Category: Nenci, S]]
+[[Category: Nenci S]]
-[[Category: Nomura, D K]]
+[[Category: Nomura DK]]
-[[Category: Piano, V]]
+[[Category: Piano V]]
-[[Category: Valente, S]]
+[[Category: Valente S]]
-[[Category: Cancer]]
-[[Category: Ether phospholipid]]
-[[Category: Flavin]]
-[[Category: Transferase]]

5ae2: Difference between revisions

Revision as of 04:53, 25 May 2023

Ether Lipid-Generating Enzyme AGPS in complex with inhibitor 1e

Structural highlights

Function

Publication Abstract from PubMed

References

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