The ubiquitin-proteasomal system is critical for multiple myeloma: implications in drug discovery

Abstract

Bortezomib is a specific inhibitor of proteasomes, the most important protease complexes in protein degradation. Bortezomib can induce apoptosis of a variety of cancer cells, including leukemia, lymphoma, multiple myeloma, breast cancers, prostate cancers, lung cancers, and so on. However, extensive studies and overall evaluation suggested that multiple myeloma is the most sensitive and the best responsive disease which was later approved by Food and Drug Administration for bortezomib treatment. Because proteasomes are an essential component in the ubiquitin-proteasomal protein degradation pathway, the discovery of bortezomib implicates that the UPS is critical for myeloma pathophysiology. The UPS also contains ubiquitin, ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), ubiquitin ligases (E3) and deubiquitinases (Dubs). In this review, we examined and analyzed the recent advancements of the UPS components in multiple myeloma and its implications in drug discovery for myeloma treatment.

Keywords: Ubiquitin-proteasomal system; bortezomib; deubiquitinases; drug discovery; multiple myeloma.

Figure 1

The amino acid sequence of ubiquitin. a. Ubiquitin is highly conserved through eukaryotic organisms. b. There are 7 lysine residues out of 76 amino acids and each could be further conjugated to a specific protein based on the polyubiquitin chain.

Figure 2

E1, E2 and E3 form a enzymatic cascade for protein ubiquitination (adapted from reference 1). One single ubiquitin-activating enzyme E1 initiates the whole ubiquitination process, by activating Ub and transferring it to E2. There are around 100 E2s in human. Each E2 will deliver activated Ub to one or several E3s which are a large family of around 1000 members. E3 can specifically identify target proteins and attach Ub to individual proteins.

Figure 3

The chemical structure of Bortezomib. Bortezomib is a tripeptide made up of pyrazinoic acid, phenylalanine and leucine with boronic acid instead of a carboxylic acid.