5AE1

Ether Lipid-Generating Enzyme AGPS in complex with inhibitor ZINC69435460

Summary for 5AE1

• Entry DOI: 10.2210/pdb5ae1/pdb
• Related: 5ADZ 5AE2 5AE3
• Descriptor: ALKYLDIHYDROXYACETONEPHOSPHATE SYNTHASE, PEROXISOMAL, (3-(2-FLUOROPHENYL)-N-(1-(2-OXO-2,3-DIHYDRO-1H-BENZO[D]IMIDAZOL-5-YL)ETHYL)BUTANAMIDE), FLAVIN-ADENINE DINUCLEOTIDE, ... (5 entities in total)
• Functional Keywords: transferase, ether phospholipid, cancer, flavin
• Biological source: CAVIA PORCELLUS (DOMESTIC GUINEA PIG)
• Cellular location: Peroxisome: P97275
• Total number of polymer chains: 4
• Total formula weight: 296646.75

Authors

Piano, V.,Benjamin, D.I.,Valente, S.,Nenci, S.,Marrocco, B.,Mai, A.,Aliverti, A.,Nomura, D.K.,Mattevi, A. (deposition date: 2015-08-25, release date: 2015-09-09, Last modification date: 2024-01-10)

Primary citation

Piano, V.,Benjamin, D.I.,Valente, S.,Nenci, S.,Marrocco, B.,Mai, A.,Aliverti, A.,Nomura, D.K.,Mattevi, A.
Discovery of Inhibitors for the Ether Lipid-Generating Enzyme Agps as Anti-Cancer Agents.
Acs Chem.Biol., 10:2589-, 2015

PubMed Abstract: 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.

PubMed: 26322624
DOI: 10.1021/ACSCHEMBIO.5B00466

Experimental method

X-RAY DIFFRACTION (2.1 Å)