Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:6.3.2.19 (
ubiquitin-protein ligase
)
799
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Protein ubiquitination plays an important role in the regulation of almost every aspect of eukaryotic cellular function; therefore, its destabilization is often observed in most human diseases and cancers. Consequently, developing inhibitors of the ubiquitination system for the treatment of cancer has been a recent area of interest. Currently, only a few classes of compounds have been discovered to inhibit the
ubiquitin-activating enzyme
(E1) and only one class is relatively selective in E1 inhibition in cells. We now report that Largazole and its ester and ketone analogs selectively inhibit ubiquitin conjugation to p27(Kip1) and TRF1 in vitro. The inhibitory activity of these small molecules on ubiquitin conjugation has been traced to their inhibition of the ubiquitin E1 enzyme. To further dissect the mechanism of E1 inhibition, we analyzed the effects of these inhibitors on each of the two steps of E1 activation. We show that Largazole and its derivatives specifically inhibit the adenylation step of the E1 reaction while having no effect on thioester bond formation between ubiquitin and E1. E1 inhibition appears to be specific to human E1 as Largazole ketone fails to inhibit the activation of Uba1p, a homolog of E1 in Schizosaccharomyces pombe. Moreover, Largazole analogs do not significantly inhibit
SUMO
E1. Thus, Largazole and select analogs are a novel class of ubiquitin E1 inhibitors and valuable tools for studying ubiquitination in vitro. This class of compounds could be further developed and potentially be a useful tool in cells.
...
PMID:Largazole and its derivatives selectively inhibit ubiquitin activating enzyme (e1). 2227 28
Voltage-gated sodium channel Na
v
1.5 is critical for generation and conduction of cardiac action potentials. Mutations and expression level changes of Na
v
1.5 are associated with cardiac arrhythmias and sudden death. The ubiquitin (Ub) conjugation machinery utilizes three enzyme activities, E1, E2, and E3, to regulate protein degradation. Previous studies from us and others showed that Nedd4-2 acts as an E3
ubiquitin-protein ligase
involved in ubiquitination and degradation of Na
v
1.5, however, more key regulators remain to be identified. In this study, we show that UBC9, a
SUMO
-conjugating enzyme, regulates ubiquitination and degradation of Na
v
1.5. Overexpression of UBC9 significantly decreased Na
v
1.5 expression and reduced sodium current densities, whereas knockdown of UBC9 expression significantly enhanced Na
v
1.5 expression and increased sodium current densities, in both HEK293 cells and primary neonatal cardiomyocytes. Overexpression of UBC9 increased ubiquitination of Na
v
1.5, and proteasome inhibitor MG132 blocked the effect of UBC9 overexpression on Na
v
1.5 degradation. Co-immunoprecipitation showed that UBC9 interacts with Nedd4-2. UBC9 with mutation C93S, which suppresses
SUMO
-conjugating activity of UBC9, was as active as wild type UBC9 in regulating Na
v
1.5 levels, suggesting that UBC9 regulates Na
v
1.5 expression levels in a SUMOylation-independent manner. Our findings thus identify a key structural element of the ubiquitin-conjugation machinery for Na
v
1.5 and provide important insights into the regulatory mechanism for ubiquitination and turnover of Na
v
1.5.
...
PMID:UBC9 regulates cardiac sodium channel Na
v
1.5 ubiquitination, degradation and sodium current density. 3077 77
