5AE3

Ether Lipid-Generating Enzyme AGPS in complex with antimycin A

5AE3 の概要

• エントリーDOI: 10.2210/pdb5ae3/pdb
• 関連するPDBエントリー: 5ADZ 5AE1 5AE2
• 分子名称: ALKYLDIHYDROXYACETONEPHOSPHATE SYNTHASE, PEROXISOMAL, [(2R,3S,6S,7R,8R)-3-[(3-formamido-2-oxidanyl-phenyl)carbonylamino]-8-hexyl-2,6-dimethyl-4,9-bis(oxidanylidene)-1,5-dioxonan-7-yl] 3-methylbutanoate, FLAVIN-ADENINE DINUCLEOTIDE, ... (5 entities in total)
• 機能のキーワード: transferase, ether phospholipid, cancer, flavin
• 由来する生物種: CAVIA PORCELLUS (DOMESTIC GUINEA PIG)
• 細胞内の位置: Peroxisome: P97275
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 297379.67

構造登録者

Piano, V.,Benjamin, D.I.,Valente, S.,Nenci, S.,Marrocco, B.,Mai, A.,Aliverti, A.,Nomura, D.K.,Mattevi, A. (登録日: 2015-08-25, 公開日: 2015-09-09, 最終更新日: 2024-01-10)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.18 Å)