Department of Biochemistry and Biotechnology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Akademicka 19, 20-033 Lublin, Poland.
Int J Mol Sci. 2021 Dec 10;22(24):13309. doi: 10.3390/ijms222413309.
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.
泛素-蛋白酶体系统（UPS）是真核生物中负责细胞内蛋白质的调节降解的主要非溶酶体途径。作为细胞质和细胞核中的主要蛋白水解途径，UPS 具有两个主要功能：质量控制功能（即去除受损、错误折叠和功能失调的蛋白质）和主要调节功能（即靶向降解各种参与细胞周期控制、信号转导级联和基因表达及代谢途径调节的短寿命调节蛋白）。UPS 的异常与许多人类疾病有关，如癌症、神经退行性疾病、自身免疫、炎症或传染病。因此，UPS 已成为药物发现和开发的有吸引力的目标。在过去的二十年中，大量的研究集中在鉴定和开发靶向 UPS 特定成分的化合物上。人们致力于开发第二代蛋白酶体抑制剂和泛素化/去泛素化酶抑制剂。具有独特结构和生物活性的次生代谢物（天然产物）是开发新治疗药物的先导化合物。本文首次总结了真菌次生代谢物作为 UPS 成分抑制剂的作用。
