Description
The ubiquitin C-terminal hydrolase L1 (UCH-L1) is a member of a family of de-ubiquitinating enzymes that can generate free ubiquitin from ubiquitin precursors
via its ubiquitin ligase activity. By associating with free ubiquitin, it also prevents its degradation. Neuronal UCH-L1 has been linked to Parkinson’s disease, the development of tumors, and neuropathic pain. LDN-57444 is an inhibitor of UCH-L1 activity (IC
50 = 0.88, K
i = 0.4 μM) that demonstrates selectivity for UCH-L1 compared to UCH-L3 (IC
50 = 25 μM). Loss of UCH-L1 activity causes cell death through the apoptosis pathway due to an impaired ubiquitin-proteasome pathway. LDN-57444-induced reduction of free ubiquitin has been shown to create dramatic alterations in synaptic structure and function, increasing spine size while decreasing spine density in hippocampal neurons.
Uses
LDN 57444 is an inhibitor of UCH-L1, an enzyme expressed by certain lung tumor-derived cell lines, suggesting that this enzyme plays a role in tumor progression.
Biochem/physiol Actions
LDN-57444 is a potent, reversible, competitive and active site-directed inhibitor of UCHL1
in vivo
LDN-57444 (0.4 mg/kg, i.p.) blocks the beneficial effect of V-Uch-L1, and worsens contextual conditioning performance as the mice are exposed to the context at 1, 7, 14, and 21 days after training[2].
References
[1] YICHIN LIU. Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line.[J]. Chemistry & biology, 2003, 10 9: 837-846. DOI:
10.1016/j.chembiol.2003.08.010[2] YU-YAN TAN. Endoplasmic reticulum stress contributes to the cell death induced by UCH-L1 inhibitor.[J]. Molecular and Cellular Biochemistry, 2008, 318 1-2: 109-115. DOI:
10.1007/s11010-008-9862-x[3] ANNA E CARTIER. Regulation of synaptic structure by ubiquitin C-terminal hydrolase L1.[J]. Journal of Neuroscience, 2009, 29 24: 7857-7868. DOI:
10.1523/jneurosci.1817-09.2009
