A cell-permeable racemic mixture of Halofuginone, a halogenated derivative of the Dichroa febriguga alkaloid Febrifugine, whose D-(+)/(2R, 3S) enantiomer serves as the active inhibitor against ProRS- (prolyl-tRNA synthetase) mediated aminoacylation by simultaneously targeting/blocking ProRS Proline-binding pocket with its hydroxypiperidine and tRNA 3′ end adenosine-binding site with its halogenated 4-quinazolinone, preventing not only ProRS-catalyzed prolyl adenylation (Pro-AMP formation), but also the subsequent Pro transfer from Pro-AMP to tRNAPro. Consistently, only proline, but not other NEAA, is able to reverse the inhibitory effect of HF in in vitro rabbit reticulocyte lysate translations (1 µM HF; 1 mM Pro) and prevent HF-induced cellular AAR (amino acid response) pathway activation (100 nM HF/2 mM Pro/MEF; 10 nM HF/1 mM Pro/Murine CD4+ CD25- T cells). Shown to inhibit bFGF-induced neovascularization in a murine corneal angiogenesis model (5 mg/kg/day via food intake) and significantly reduce the severity of myelin antigen MOG33-55-induced autoimmune EAE/encephalomyelitis in mice (2 µg/mouse/day i.p.) in vivo. Unlike AA-AMP mimetics, HF does not compete against ATP for ProRS binding. ATP, in its ProRS bound state, actually helps stabilize HF via hydrogen bond interactions.
生化／生理作用
Primary Target prolyl-tRNA synthetase
包裝
Packaged under inert gas
警告
Toxicity: Standard Handling (A)
重構
Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 3 months at -20°C.
其他說明
Zhou, H., et al. 2013, Nature494, 121.
Keller, T.L., et al. 2012, Nat. Chem. Biol.12, 311.
Sundrud, M.S., et al. 2009, Science324, 1334. Elkin, M., et al. 2000, FASEB J.14, 2477. Elkin, M., et al. 1999, Clin. Cancer Res.5, 1982.
法律資訊
CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany
