Ubiquitin carboxy-terminal hydrolase L1 (UCHL1)

Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is an enzyme that acts as a deubiquitinating enzyme (DUB), specifically hydrolyzing peptide bonds at the C-terminal end of ubiquitin to release active ubiquitin monomers. It is a member of the peptidase C12 family of thiol proteases and is highly expressed in neurons (comprising 1–2% of soluble brain protein) and neuroendocrine cells, and to a lesser extent in testis and ova. UCHL1 is crucial for neuronal maintenance, protein homeostasis, and the regulation of the ubiquitin-proteasome system. Dysfunction or abnormal expression of UCHL1 has been implicated in several diseases, including Parkinson’s disease (loss-of-function mutations), multiple cancers (aberrant/ectopic expression), axonal degeneration, reproductive disorders, and glomerulonephritis. UCHL1 is validated as a therapeutic target in oncology and neuroprotection. Examples of inhibitors include the highly selective IMP-1710, which covalently modifies the active site. As a biomarker, "PGP 9.5" is used to identify neurons and neuroendocrine lineage cells in diagnostics and pathology. Current therapeutic challenges involve achieving selective inhibition in cancer without disrupting essential neuronal functions.

Other names

UCH-L1PARK5PGP 9.5HEL-117NDGOAPGP9.5PGP95Uch-L1HEL-S-53SPG79UCHL-1ubiquitin C-terminal hydrolase L1

Covalent and reversible inhibition of UCHL1 enzymatic activity by binding catalytic cysteine; Competitive inhibition by active-site directed agents