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  • A prominent example of such enzyme


    A prominent example of such enzyme is the proteasome, a highly promising target not only in cancer, but also in inflammatory and autoimmune diseases. Circulating proteasomes and respective anti-proteasome autoantibodies were detected in serum samples from patients with autoimmune diseases such as multiple sclerosis (MS), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) [7]. Selective proteasome inhibition is a mechanism of action demonstrated by FDA-approved anticancer drugs Carfilzomib and Bortezomib, both of which are also being considered as potential drug candidates for modulation of immune response. For example, Bortezomib that was initially approved for treatment of multiple myeloma now undergoes clinical trials against several autoimmune diseases such as proliferative lupus nephritis, refractory cold agglutinin disease and IgA nephropathy. This prospective therapeutic strategy is also supported by clinical data showing that refractory SLE patients indeed respond to the Bortezomib-based therapy [8]. In addition, both Bortezomib and Carfilzomib were tested in SLE animal models and demonstrated decreased levels of autoantibodies and retarded disease development [9]. The therapeutic effect was accompanied by diminished number of plasma Bax inhibitor peptide V5 synthesis and suppressed production of interferon alpha (IFNα) by plasmacytoid dendritic cells (PDCs). An emerging and highly promising drug discovery approach is to target multiple levels of ubiquitination cascade upstream of proteasome - E1, E2 and, particularly, E3 enzymes [10]. High interest towards E3 ubiquitin ligases is caused by their function to confer substrate specificity of whole UPS. E3s act via two primary mechanisms - intermediary catalytic transfer of ubiquitins from E2∼Ub conjugate to the substrate or, alternatively, direct ubiquitin transfer bypassing the E3 ligase itself. The first mechanism is common for Homologous to E6-AP Carboxy Terminus (HECT)-type E3s, whereas the second one is typical for really interesting new gene (RING)-type E3s. Development of potent small molecule modulators for these enzymes is a risky and challenging task complicated by diverse protein-protein interfaces of the multi-component complexes, common lack of a classical enzymatic/catalytic active site and specificity problems stipulated by a variety of potential substrates. Conserved RING finger domain constitutes the core of E3 ligase catalytic activity by serving as docking platform for E2 enzyme. RING motif was initially identified in RING1 protein and later confirmed as a structural element of Rbx1, an E2-recruiting subunit of E3 ligase [[11], [12], [13], [14]]. The canonical RING finger motif can be represented as Cys–X2-Cys-X(9–39)-Cys-X(1–3)-His-X(2–3)-Cys-X2-Cys-X(4–48)-Cys-X2-Cys, where X is any other amino acid [15]. The motif includes two Zn2+-coordinated loops and intervening central α-helix that together form a conserved structural platform for anchoring the E2 conjugating enzyme. RING E3s can be categorized into subclasses according to the form of subunit organization: 1) mono-subunit ligases, i.e. murine double minute (MDM); and 2) multi-subunit complexes, i.e. Cullin RING ligase (CRL), anaphase promoting complex/cyclosome (APC/C) [16] and Fanconi anemia ligase (FANC) [17]. Another important RING family members are RING-between RING-RING ligases (RBRs), the single subunit enzymes with multiple RING domains [18]. In addition, worth mentioning are U-box ligases, containing atypical RING domains without coordinated Zn2+ ions, that are often featured as separate from canonical RING E3s [19]. Inflammation and autoimmunity is often described as defective response of adaptive immune system due to deregulated activation of B or T cells, and is accompanied by immune tolerance towards self-antigens and tissue damage. Cell-mediated immunity is based on functions and signaling of T lymphocytes that includes maturation of CD4+ helper and CD8+ cytotoxic T cells in thymus, then migration to peripheral tissues and activation through a process in which T cell receptor (TCR) binds to antigen presented by major histocompatibility complex (MHC) of antigen-presenting cells (APCs). This is followed by CD8+ cells attacking and destroying pathogen-infected host cells, CD4+ T cells activating phagocytes and facilitating differentiation of various immune cells, antibody-producing memory B cells providing strong pathogen-specific immune response [20]. Understanding molecular principles underlying the initiation and progression of inflammation has long been a major priority in the field. Therefore, identification of disease-associated proteins and subsequent design of small-molecule modulators to target those proteins represents a highly attractive route to develop new treatments.