Belactosins and cystargolides are natural product proteasome inhibitors from Actinobacteria. Both feature dipeptidic backbones and a unique β-lactone building block. Herein, we present a detailed investigation of their biosynthesis. Identification and analysis of the corresponding gene clusters indicated that both compounds are assembled by rare single-enzyme amino acid ligases. Feeding experiments with isotope-labeled precursors and in vitro biochemistry showed that the formation of the β-lactone warhead is unprecedented and reminiscent of leucine biosynthesis, and that it involves the action of isopropylmalate synthase homologues.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1002/anie.201612076 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL.
Nat Commun
January 2025
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Chronic lymphocytic leukemia is a malignant lymphoproliferative disorder for which primary or acquired drug resistance represents a major challenge. To investigate the underlying molecular mechanisms, we generate a mouse model of ibrutinib resistance, in which, after initial treatment response, relapse under therapy occurrs with an aggressive outgrowth of malignant cells, resembling observations in patients. A comparative analysis of exome, transcriptome and proteome of sorted leukemic murine cells during treatment and after relapse suggests alterations in the proteasome activity as a driver of ibrutinib resistance.
View Article and Find Full Text PDFPharmacological Modulation of the Unfolded Protein Response as a Therapeutic Approach in Cutaneous T-Cell Lymphoma.
Biomolecules
January 2025
Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Ave., MSC509, Charleston, SC 29425, USA.
Cutaneous T-cell lymphoma (CTCL) is a rare T-cell malignancy characterized by inflamed and painful rash-like skin lesions that may affect large portions of the body's surface. Patients experience recurrent infections due to a compromised skin barrier and generalized immunodeficiency resulting from a dominant Th2 immune phenotype of CTCL cells. Given the role of the unfolded protein response (UPR) in normal and malignant T-cell development, we investigated the impact of UPR-inducing drugs on the viability, transcriptional networks, and Th2 phenotype of CTCL.
View Article and Find Full Text PDFUnlocking the Therapeutic Potential of Algae-Derived Compounds in Hematological Malignancies.
Cancers (Basel)
January 2025
Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.
Algae are a rich source of bioactive compounds that have a wide range of beneficial effects on human health and can show significant potential in the treatment of hematological malignancies such as leukemia, lymphoma, and multiple myeloma. These diseases often pose a therapeutic challenge despite recent advances in treatment (e.g.
View Article and Find Full Text PDFA novel USP4 inhibitor that suppresses colorectal cancer stemness by promoting β-catenin and Twist1 degradation.
J Transl Med
January 2025
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
Background: The high mortality rate of metastatic colorectal cancer (CRC) is primarily attributed to resistance to chemotherapy, where cancer stem cells (CSCs) play a crucial role. Deubiquitinating enzymes are essential regulators of CSC maintenance, making them potential targets for eliminating CSCs and overcoming chemotherapy resistance. This study aims to identify key deubiquitinating enzymes regulating CSCs and drug resistance of CRC.
View Article and Find Full Text PDFFunctional genomics pipeline identifies CRL4 inhibition for the treatment of ovarian cancer.
Clin Transl Med
February 2025
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York, USA.
Background: The goal of precision oncology is to find effective therapeutics for every patient. Through the inclusion of emerging therapeutics in a high-throughput drug screening platform, our functional genomics pipeline inverts the common paradigm to identify patient populations that are likely to benefit from novel therapeutic strategies.
Approach: Utilizing drug screening data across a panel of 46 cancer cell lines from 11 tumor lineages, we identified an ovarian cancer-specific sensitivity to the first-in-class CRL4 inhibitors KH-4-43 and 33-11.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!