Ubiquitin-proteasome is one of the important ways to "digest" protein in cells, and it can regulate many important life activities, such as cell proliferation, differentiation, apoptosis, DNA repair and so on. In recent years, people gradually realize that the abnormality in the ubiquitin-proteasome system is closely related to many different diseases, including neurodegenerative disease Alzheimer's disease, Huntington's disease, cancer, cardiovascular disease, respiratory disease and so on. In neurodegenerative disease, exogenous or endogenous factors can cause the misfolding of protein inside and outside nerve cells, affecting the degradation function of ubiquitin-proteasome and leading to abnormal accumulation of many proteins and even cell death. The occurrence of tumor is related to the excessive proliferation of cells and the enhancement of anti-apoptosis ability. Ubiquitin-proteasome affects the survival of tumor cells through promoting the degradation of cancer suppressor proteins such as P53 or blocking the degradation of oncogenic proteins. As a great protein machine, ubiquitin-proteasome has become an important target for scientists to develop potentially effective drugs for diseases in recent decades of research.
Mechanism of action of ubiquitin-proteasome pathway
Ubiquitin-proteasome pathway needs the participation of ubiquitin (Ub), ubiquitin-activating enzyme (E1), ubiquitin polymerase (ubiquitin-carrier protein) (E2), ubiquitin-ligating enzyme (E3), 26S proteasomes, deubiquitinating enzymes (DUBs) and other related substances.
Ubiquitin-proteasome pathway is made of 2 processes: substrate protein ubiquitination and substrate degradation by proteasome. Ubiquitin is a highly conserved polypeptide chain consisting of 76 amino acids. It has two forms, one is free ubiquitin, and the other is ubiquitin covalently binding to the receptor protein. Ubiquitin is covalently bound to ε-amino group of lysine side chain or α-amino group of N-terminal of receptor protein through its C-terminal, which is called ubiquitination. Ubiquitination is a multi-enzyme cascade reaction mediated by ubiquitin-activating enzyme E1, ubiquitin polymerase E2, ubiquitin-ligating enzyme E3, etc.
![Ubiquitin-proteasome pathway (Source [1])](https://eimg.pharmasources.com/upload/image/20230710/dnKpDl2TH8PllAj7Gscu9bCNAqLjdgzuonrFVoG0.png "Ubiquitin-proteasome pathway (Source [1])")
Ub: Ubiquitin; E1: Ubiquitin-activating enzyme; E2: Ubiquitin-carrier protein; E3: Ubiquitin-ligating enzyme; DUB: Deubiquitinating enzyme
Ubiquitin-proteasome and drug R&D
At present, many reported human diseases are related to the abnormality of proteasome pathway. The approved proteasome inhibitors have been used to treat multiple myeloma, mantle cell lymphoma and other cancers successfully, and some drugs under research, which target different components of ubiquitin-proteasome pathway, including preclinical trial drugs such as deubiquitinating enzyme inhibitor and clinical trial drugs such as ubiquitinating enzyme regulator and new proteasome inhibitor, have shown a more anticipated curative effect.
1. Proteasome inhibitor
At present, there are more than 10 kinds of drugs reported to have a good anti-tumor effect, and proteasome inhibitors are most commonly used in clinical treatment. Bortezomib (PS-341) is the first proteasome inhibitor drug approved by FDA which targets ubiquitin-proteasome pathway. Bortezomib, a kind of boracic acid dipeptide, can effectively inhibit chymotrypsin activity by specifically binding to the active site of threonine at β5 subunit of 20S proteasome. It can also inhibit Caspase activity by binding to the active site of threonine at β1 subunit. Bortezomib is a reversible inhibitor with a high selectivity and a drug approved for treating multiple myeloma. Exposure to Bortezomib can st...
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