The ubiquitin pathway is a complex multi-stage enzyme cascade, in which the small cofactor ubiquitin becomes bound to a protein substrate, initiating catalytic destruction by a series of proteases. We at Novus Biologicals have an expansive antibody database devoted to the ubiquitin protease system. However, many of the proteins targeted by the enzymes remain a mystery, with their linkage sites and molecular mechanisms poorly understood.
Ubiquitination, or modification of protein substrates is dependent upon three enzyme classes: E1 (activating); E2 (conjugating) and E3 (ligase) enzymes. Substrate modification takes place via either mono or poly-ubiquitination, involving one or many ubiquitin molecules. Modifications are highly distinct and specific.
The E1 activating enzyme initializes the first step of the pathway, transporting activated ubiquitin to the reaction site. The E2 conjugating enzyme then delivers the ubiquitin to the target protein, assisted by E3 ligase whose role it is to dictate substrate specificity and ensure a bridge is created between the E2 ligase and its target. The major number of ligase antibodies belong to the E3 family, which consist of both single proteins and complexes. They can be further subdivided depending on their structural domains, which include the HECT, RING and U-box modified-RING domain.
E3 ligases are a complex super-family with a high level of specificity, and have been implemented in disorders of the human ubiquitin protease system. Antibody suppliers are hopeful that in the future E3 ligases may become an attractive proposition for drug therapy. However, as yet no compounds have reached the clinical stage.
There are a number of reasons for this. Currently there are upwards of 500 E3 enzymes, with an extensive range of corresponding antibodies. Each E3 ligase has a number of protein targets for ubiquitination; however, the exact identity of the substrates is often unknown. In addition, most E3 enzymes have multiple binding domains, with many able to bind to hundred of other proteins and enzymes. Among the E3 ligase products of interest in our antibody catalog are the APC1, RNF2, TRIM32 and the NEDD4 antibody.
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