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Small Molecule Inhibitors Targeting Biosynthesis of Ceramide, the Central Hub of the Sphingolipid Network.

ABSTRACT: Ceramides are composed of a sphingosine and a single fatty acid connected by an amide linkage. As one of the major classes of biologically active lipids, ceramides and their upstream and downstream metabolites have been implicated in several pathological conditions including cancer, neurodegeneration, diabetes, microbial pathogenesis, obesity, and inflammation. Consequently, tremendous efforts have been devoted to deciphering the dynamics of metabolic pathways involved in ceramide biosynthesis. Given that several distinct enzymes can produce ceramide, different enzyme targets have been pursued depending on the underlying disease mechanism. The main objective of this review is to provide a comprehensive overview of small molecule inhibitors reported to date for each of these ceramide-producing enzymes from a medicinal chemistry perspective.

SUBMITTER: Skacel J

PROVIDER: S-EPMC8023021 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Small Molecule Inhibitors Targeting Biosynthesis of Ceramide, the Central Hub of the Sphingolipid Network.

Skácel Jan J Slusher Barbara S BS Tsukamoto Takashi T

Journal of medicinal chemistry 20210104 1

Ceramides are composed of a sphingosine and a single fatty acid connected by an amide linkage. As one of the major classes of biologically active lipids, ceramides and their upstream and downstream metabolites have been implicated in several pathological conditions including cancer, neurodegeneration, diabetes, microbial pathogenesis, obesity, and inflammation. Consequently, tremendous efforts have been devoted to deciphering the dynamics of metabolic pathways involved in ceramide biosynthesis. ...[more]

PMID: 33395289

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Project description:The 26S proteasome is the principal protease for regulated intracellular proteolysis. This multi-subunit complex is also pivotal for clearance of harmful proteins that are produced throughout the lifetime of eukaryotes. Recent structural and kinetic studies have revealed a multitude of conformational states of the proteasome in substrate-free and substrate-engaged forms. These conformational transitions demonstrate that proteasome is a highly dynamic machinery during substrate processing that can be also controlled by a number of proteasome-associated factors. Essentially, three distinct family of deubiquitinases-USP14, RPN11, and UCH37-are associated with the 19S regulatory particle of human proteasome. USP14 and UCH37 are capable of editing ubiquitin conjugates during the process of their dynamic engagement into the proteasome prior to the catalytic commitment. In contrast, RPN11-mediated deubiquitination is directly coupled to substrate degradation by sensing the proteasome's conformational switch into the commitment steps. Therefore, proteasome-bound deubiquitinases are likely to tailor the degradation events in accordance with substrate processing steps and for dynamic proteolysis outcomes. Recent chemical screening efforts have yielded highly selective small-molecule inhibitors for targeting proteasomal deubiquitinases, such as USP14 and RPN11. USP14 inhibitors, IU1 and its progeny, were found to promote the degradation of a subset of substrates probably by overriding USP14-imposed checkpoint on the proteasome. On the other hand, capzimin, a RPN11 inhibitor, stabilized the proteasome substrates and showed the anti-proliferative effects on cancer cells. It is highly conceivable that these specific inhibitors will aid to dissect the role of each deubiquitinase on the proteasome. Moreover, customized targeting of proteasome-associated deubiquitinases may also provide versatile therapeutic strategies for induced or repressed protein degradation depending on proteolytic demand and cellular context.

Dataset Information

Small Molecule Inhibitors Targeting Biosynthesis of Ceramide, the Central Hub of the Sphingolipid Network.

Publications

Small Molecule Inhibitors Targeting Biosynthesis of Ceramide, the Central Hub of the Sphingolipid Network.

Similar Datasets

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