UCH-L3 structure and function: Insights about a promising drug target

In the past few years, researchers have shed light on the immense importance of ubiquitin in numerous regulatory pathways. The post-translational addition of mono or poly-ubiquitin molecules namely "ubiquitinoylation" is therefore pivotal to maintain the cell's vitality, maturation, differentiation, and division. Part of conserving homeostasis stems from maintaining the ubiquitin pool in the vicinity of the cell's intracellular environment; this crucial role is played by deubiquitylating enzymes (DUBs) that cleave ubiquitin molecules from target molecules. To date, they are categorized into 7 families with ubiquitin carboxyl c-terminal de-hydrolase family (UCH) as the most common and well-studied. Ubiquitin C-terminal hydrolase L (UCH-L3) is a significant protein in this family as it has been implicated in many molecular and cellular processes with its mRNA identified in a range of body tissues including the brain. It goes without saying that it manifests in maintaining health and when abnormally regulated in disease. As it is an attractive small molecule drug target, scientists have used high throughput screening (HTS) and other drug discovery methods to discover inhibitors for this enzyme for the treatment of cancer and neurodegenerative diseases. In this review we present an overview of UCH-L3 catalytic mechanism, structure, its role in DNA repair and cancer along with the inhibitors discovered so far to halt its activity.