Ubiquitin activity

Ubiquitin tags proteins for protein degradation. The ubiquitination requires three different enzymatic activities, a ubiquitin-activating enzyme (El), a ubiquitin-conjugating enzyme (E2 or Ubc) and a ubiquitin ligase (E3). The action of all three enzymes leads to the establishment of a poly-ubiquitin chain on target proteins which are then recognized and proteolyzed by the 26S proteasome. 

The natural product panepophenanthrin (6/1-170), isolated in 2002 from the fermented broth of the mushroom strain Panus radus IFO 8994 [90], is the first example of an inhibitor of the ubiquitin-activating enzyme [91]. Retrosynthetic analysis based on a biomimetic analysis led to the conjugated diene 6/1-172 by a retro-Diels-Alder reaction via the hemiacetal 6/1-171. Further disconnections of 6/1-172 produces the vinyl stannane 6/1-173 and the vinyl bromide 6/1-174 [92]. 

Ubiquitin-El Ubiquitin-activating enzyme UbL Ubiquitin-like protein... 

A) Schematic comparison between MoeB, the ubiquitin-activating enzyme (UBAl) and the heterodimeric (APPBP1-UBA3) NEDD8 activator based on PSI-BLAST [54] sequence analyses. The numbers represent the sequence identities between the first 170-180 residues of MoeB (shaded) and the corresponding regions in... 

The crystal structure of MPT synthase and the simultaneously determined NMR structure of the MoaD-related ThiS protein involved in thiamine biosynthesis [37] unambiguously demonstrated the evolutionary relationship between a subset of enzymes involved in the biosynthesis of S-containing cofactors (e.g. Moco, thiamine and certain EeS-clusters) and the process of ubiquitin activation. MoaD displays significant structural homology to human ubiquitin (Figure 3.3B and C), resulting in a superposition with a root mean square (rms) deviation of 3.6 A for 68 equivalent Ca atoms out of 76 residues in ubiquitin. The key secondary structure... 

Haas, A. L. and Rose, 1. A. The mechanism of ubiquitin activating enzyme. A kinetic and equilibrium analysis, J Biol Chem 1982, 257, 10329-10337. 

Rudolph, M. J., Wuebbens, M. M., Rajagopalan, K. V., and Schindelin, H. Crystal structure of molybdopterin synthase and its evolutionary relationship to ubiquitin activation,... 

Fig. 5.1. The ubiquitin-conjugation pathway. Steps in ubiquitin activation and substrate modification. El, ubiquitin activating enzyme E2, ubiquitin-conjugating enzyme E3, ubiquitin-protein ligase. Atoms involved in the thiol ester and amide bonds are shown.

Heeshko, A., and Rose, 1. A. Ubiquitin-activating enzyme. Mechanism and role in protein-ubiquitin conjugation. J. Biol. Chem. 1982, 257, 2543-48. 

Fig. 12.1. Domain scheme of selected proteins with internal ubiquitin-like domains. Ubiquitin-like domains are indicated by black boxes. Other domains are abbreviated as follows ThiF, NAD-binding domain in ubiq-uitin activating enzymes UAct, 2nd conserved domain in ubiquitin activating enzymes ...

Increasing evidence indicates that accumulation of aberrant or misfolded proteins, protofibril formation, ubiquitin-proteasome system dysfunction, and the direct or indirect consequences of abnormal protein aggregation and accumulation represent deleterious events linked to neurodegeneration (255,256). Ubiquitination is an essential cellular process affected by a multienzyme cascade involving Els (ubiquitin-activating enzymes), E2s (ubiquitin-conjugation enzymes or UBCs), and E3s (ubiquitin-protein Ugases) (12,257) (see Fig. 10.4). 

Ciechanover, A., Elias, S., Heller, H. and Hershko, A. (1982). Covalent affinity purification of ubiquitin activating enzyme. J. Biol. Chem. 257, 2537-2542. 

Finley, D., Ciechanover, A., and Varshavsky, A. (1984). Thermolability of ubiquitin-activating enzyme from the mammalian cell cycle mutant ts85. Cell 37, 43-55. 

Ubiquitin-Activating Enzyme, Ubiquitin-Conjugating Enzymes... 

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