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PDBsum entry 5ae3
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PDB id:
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Transferase
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Title:
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Ether lipid-generating enzyme agps in complex with antimycin a
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Structure:
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Alkyldihydroxyacetonephosphate synthase, peroxisomal. Chain: a, b, c, d. Synonym: alkyl-dhap synthase, alkylglycerone-phosphate synthase, alkyl-dhap synthase, alkylglycerone-phosphate synthase, alkyl-dihydro xyacetonephosphate synthase. Engineered: yes
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Source:
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Cavia porcellus. Domestic guinea pig. Organism_taxid: 10141. Expressed in: escherichia coli. Expression_system_taxid: 511693.
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Resolution:
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2.18Å
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R-factor:
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0.192
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R-free:
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0.259
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Authors:
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V.Piano,D.I.Benjamin,S.Valente,S.Nenci,B.Marrocco,A.Mai,A.Aliverti, D.K.Nomura,A.Mattevi
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Key ref:
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V.Piano
et al.
(2015).
Discovery of Inhibitors for the Ether Lipid-Generating Enzyme AGPS as Anti-Cancer Agents.
Acs Chem Biol,
10,
2589-2597.
PubMed id:
DOI:
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Date:
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25-Aug-15
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Release date:
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09-Sep-15
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PROCHECK
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Headers
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References
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P97275
(ADAS_CAVPO) -
Alkyldihydroxyacetonephosphate synthase, peroxisomal from Cavia porcellus
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Seq:
Struc:
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658 a.a.
539 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.2.5.1.26
- alkylglycerone-phosphate synthase.
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Reaction:
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a long chain fatty alcohol + a 1-acylglycerone 3-phosphate = a 1-O- alkylglycerone 3-phosphate + a long-chain fatty acid + H+
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long chain fatty alcohol
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+
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1-acylglycerone 3-phosphate
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=
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1-O- alkylglycerone 3-phosphate
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+
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long-chain fatty acid
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Acs Chem Biol
10:2589-2597
(2015)
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PubMed id:
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Discovery of Inhibitors for the Ether Lipid-Generating Enzyme AGPS as Anti-Cancer Agents.
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V.Piano,
D.I.Benjamin,
S.Valente,
S.Nenci,
B.Marrocco,
A.Mai,
A.Aliverti,
D.K.Nomura,
A.Mattevi.
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ABSTRACT
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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.
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Links
