Ubiquitin

The ubiquitin-proteasome system (UPS) targets numerous cellular proteins for degradation. It is a highly complex, temporally controlled, and tightly regulated process that plays major roles in a variety of basic cellular processes[1]. Degradation of a protein via the ubiquitin-proteasome pathway involves two discrete and successive steps: (1) tagging of the substrate by covalent attachment of multiple ubiquitin molecules to synthesize the polyubiquitin chain proteolytic signal and (2) degradation of the tagged protein by the 26S proteasome complex with release of free and reusable ubiquitin catalyzed by ubiquitin-recycling enzymes (DUBs)[2]. Conjugation of ubiquitin to the protein substrate proceeds via a three-step cascade mechanism. Initially, the ubiquitin-activating enzyme E1 activates ubiquitin in an ATP-requiring reaction resulting in a high-energy thiol ester intermediate. Subsequently, this intermediate is transferred to a member of the ubiquitin-carrier proteins family of enzymes, E2 (also known as a ubiquitin-conjugating enzyme [UBC]). Finally, from E2, the activated ubiquitin moiety is attached to the substrate that is specifically bound to an E3, a member of the ubiquitin-protein ligase family of proteins[3]. By successively adding additional activated ubiquitin moieties to internal Lys residues on the previously conjugated ubiquitin molecule, a polyubiquitin chain is synthesized. The degradation signal that is recognized by the 26S proteasome complex is made of a Lys48 polyubiquitin chain. In contrast, monoubiquitination or polyubiquitination with chains linked together via Lys63 serve as nonproteolytic signals in intracellular trafficking, DNA repair, activation of transcription and other signal transduction pathways[4].


[1] Drug discovery in the ubiquitin–proteasome system. G. Nalepa, M. Rolfe, J.W.Harper. Nature Reviews Drug Discovery2006, 5, 596-613.
[2] Mechanisms of Proteasome Inhibitor PS-341-induced G2-M-Phase Arrest and Apoptosis in Human Non-Small Cell Lung Cancer Cell Lines. Y Ling et al. Clin. Cancer Res. 2003, 9, 1145-1154.
[3] R.J. Deshaies, C.A.P. Joazeiro. RING Domain E3 Ubiquitin Ligases. Annu. Rev. Biochem. 2009, 78, 399-434.
[4] The Ubiquitin Proteasome System in Neurodegenerative Diseases: Sometimes the Chicken, Sometimes the Egg. A.Ciechanover, P. Brundin. Neuron 2003, 40, 427–446.

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Axon ID Name Description From price
2639 AMG 232 Potent, selective, and orally bioavailable MDM2-p53 inhibitor €115.00
2251 Apoptozole Inhibitor of ATPase activity of Hsc70 and Hsp70 €95.00
5051 Axon Ligands™ Cell signaling and Oncology compound library Axon Ligands™ Cell signaling and Oncology compound library Inquire
1810 Bortezomib Inhibitor of 26S proteasome €85.00
2645 CC-885 Cereblon (CRBN) modulator with potent anti-tumour activity €145.00
1826 DBeQ Inhibitor of p97 ATPase €90.00
1798 Eeyarestatin I Inhibitor of endoplasmic reticulum associated protein degradation (ERAD) €80.00
2348 GNE 7915 Potent, selective, metabolically stable, and brain-penetrable LRRK2 inhibitor €110.00
2181 GSK 2578215A Potent and highly selective LRRK2 inhibitor €125.00
2713 GSK 2982772 Specific inhibitor of RIP1 kinase  Recently added €115.00
2608 GSK481 Potent inhibitor of RIP1 kinase and TNF induced inflammation €95.00
1643 HLI 373 HDM2 inhibitor €95.00
1538 JNJ 26854165 HDM2 inhibitor €105.00
1586 JNJ 26854165 dihydrochloride HDM2 inhibitor €105.00
2449 LDN 57444 Reversible, competitive inhibitor of UCH-L1 deubiquitinase €95.00

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