Abstract
The ubiquitin–proteasome system (UPS) is the major non-lysosomal pathway responsible for regulated degradation of intracellular proteins in eukaryotes. As the principal proteolytic pathway in the cytosol and the nucleus, the UPS serves two main functions: the quality control function (i.e., removal of damaged, misfolded, and functionally incompetent proteins) and a major regulatory function (i.e., targeted degradation of a variety of short-lived regulatory proteins involved in cell cycle control, signal transduction cascades, and regulation of gene expression and metabolic pathways). Aberrations in the UPS are implicated in numerous human pathologies such as cancer, neurodegenerative disorders, autoimmunity, inflammation, or infectious diseases. Therefore, the UPS has become an attractive target for drug discovery and development. For the past two decades, much research has been focused on identifying and developing compounds that target specific components of the UPS. Considerable effort has been devoted to the development of both second-generation proteasome inhibitors and inhibitors of ubiquitinating/deubiquitinating enzymes. With the feature of unique structure and bioactivity, secondary metabolites (natural products) serve as the lead compounds in the development of new therapeutic drugs. This review, for the first time, summarizes fungal secondary metabolites found to act as inhibitors of the UPS components.
Highlights
The ubiquitin–proteasome system (UPS), known as the ubiquitin–proteasome pathway (UPP), is the major non-lysosomal system for degrading proteins in eukaryotic cells [1]; it is responsible for the degradation of 80–90% of all cellular proteins [2]
Some fungal secondary metabolites (SMs) were developed as essential medicines, such as antibiotics and cholesterol-lowering drugs
As the principal proteolytic pathway in eukaryotes, the ubiquitin–proteasome system plays a pivotal role in maintaining cellular proteostasis and regulates many basic cellular processes, including cell cycle progression, transcription, cell differentiation, apoptosis, signal transduction, morphogenesis, modulation of cell surface receptors and ion channels, antigen presentation, and protein quality control in the endoplasmic reticulum
Summary
The ubiquitin–proteasome system (UPS), known as the ubiquitin–proteasome pathway (UPP), is the major non-lysosomal system for degrading proteins in eukaryotic cells [1]; it is responsible for the degradation of 80–90% of all cellular proteins [2]. The human genome is estimated to encode two E1 isoforms, about 40 E2s, and more than 600 E3 ligases, which generally confer substrate specificity to the UPS [20,21]. Based on their Ub transfer mechanism and molecular structure, E3 enzymes can be subdivided into three major families: RING (Really Interesting New Gene) domain ligases, HECT (homologous to the E6AP carboxyl terminus) domain ligases, and RING-between-RING (RBR) ligases [21,22]. This review, for the first time, summarizes the fungal secondary metabolites reported to act as inhibitors of specific components of the UPS Both inhibitors of the 26S proteasome activities and inhibitors of ubiquitinating/deubiquitinating enzymes are discussed. Potential inhibitor of the p53–MDM2 interaction Induce the degradation of Skp, a subunit of the SCFSkp ubiquitin ligase that targets p27Kip and p21Cip for proteasomal destruction
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