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• Deubiquitylating Enzymes
• E1 Ubiquitin Activating Enzymes
• E2 Ubiquitin Conjugating Enzymes
• E3 Ubiquitin Ligases

As a leading CRO company in the pharmaceutical industry, BOC Sciences have made great efforts to develop the PROTAC^® platform of protein degradation technology to provide research tools in order to better help customers. PROTAC technology mediates the target proteins degradation through the ubiquitin-proteasome system. Among them, ubiquitination and deubiquitination play an important role in targeting of proteins for degradation by the proteasome.

BOC Sciences provides a variety of enzymes of ubiquitination and deubiquitination, including:

• Deubiquitylating Enzymes
• E1 Ubiquitin Activating Enzymes
• E2 Ubiquitin Conjugating Enzymes
• E3 Ubiquitin Ligases

Introduction

Ubiquitination is one of the post-translational modifications, which tagging ubiquitin (Ub) to the target proteins. The ubiquitination process usually requires the synergistic action of three ubiquitin enzymes: E1, E2, and E3. The ubiquitin-proteasome pathway is an important protein degradation regulatory system in cells.

Like other post-translational modifications, ubiquitylation is reversible. Deubiquitylating enzymes (DUBs) can cleave ubiquitin from substrate proteins by hydrolyzing the ester bond, peptide bond or isopeptide bond at the carboxyl end of ubiquitin.

E1 Ubiquitin Activating Enzymes

E1 catalyzes the first step in an ubiquitination reaction. In the presence of ATP, one ubiquitin molecule is acidified by adenosine to form AMP-Ub and binds to E1 via a non-covalent bond. And the carboxyl at the c-terminal glycine (G76) of another Ub molecule binds to the -SH in E1 and forms a thioester, thereby being activated.

E2 Ubiquitin Conjugating Enzymes

E2 is the second step in the ubiquitination process. E1 transfers ubiquitin to the active cysteine site of E2, forming the UB-E2 complex. And further, ubiquitin is then either directly bound to the target protein by binding with the substrate, or interacts with ubiquitin ligase E3 to be transferred to the target protein.

E3 Ubiquitin Ligases

E3 play an important role in the specific recognition of target proteins and the regulation of ubiquitination system activity. Based on their characteristic domains and the mechanism of ubiquitin-delivered target proteins, E3 can be divided into three families: RING E3s, U-box E3s and HECT E3s.

• RING E3s

E3s of the Ring-Finger family all contain similar E2-binding domains, which act as a bridge to transfer activated ubiquitin directly from E2 to the target protein rather than itself interacting with ubiquitin.

• U-box E3s

E3s of the U-box family is required for post-translational quality control of eukaryotic proteins. The U-box domain in E3s may recognize unfolded or misfolded proteins through molecular chaperone, thus playing an important role in protein quality control.

• HECT E3s

The HECT family contains the HECT domain, in which the conserved Cys residue forms a thioester bond with ubiquitin carried by E2. E2 first delivers ubiquitin to HECT E3, which is then delivered to the substrate.

Deubiquitylating Enzymes

The process of cell cycle involves many levels and aspects of regulation. As a class of important hydrolases involved in post-translational modification of proteins, deubiquitination enzymes play an important role in cell cycle regulation as follows:

• Processing ubiquitin precursors to produce free ubiquitin molecules.
• Removing the ubiquitin chain from the protein to avoid proteasome degradation, thus stabilizing the protein.
• Removing the non-degraded ubiquitination signal attached to the protein.
• Ensuring the homeostasis of ubiquitin molecules by preventing the degradation of ubiquitin molecules and substrate proteins.
• Editing the type of ubiquitin chain by cutting ubiquitin chain.
• Participating in the disintegration of intracellular free ubiquitin chains.

* PROTAC^® is a registered trademark of Arvinas Operations, Inc., and is used under license.