LAUSR.org creates dashboard-style pages of related content for over 1.5 million academic articles. Sign Up to like articles & get recommendations!

The antitumor antibiotic mithramycin: new advanced approaches in modification and production

Photo from archive.org

The aureolic acid-type polyketide mithramycin (MTM) has a remarkable cytotoxicity against a variety of human tumors and has been used for the treatment of several types of cancer, including chronic… Click to show full abstract

The aureolic acid-type polyketide mithramycin (MTM) has a remarkable cytotoxicity against a variety of human tumors and has been used for the treatment of several types of cancer, including chronic and acute myeloid leukemia, testicular carcinoma, hypercalcemia, and Paget’s disease. However, its clinical use is quite limited due to its toxicity. Recently, interest in MTM has been renewed after its identification as a top candidate for the inhibition of the aberrant fusion transcription factor EWS-FLI1, associated with malignant transformation and progression of Ewing sarcoma tumor family. The mechanism of MTM inhibition involves its reversible non-intercalative interaction with GC-rich DNA regions. As a result of this binding, MTM blocks binding of transcription factors (such as Sp1) to their GC-rich promoters and inhibits transcription of several proto-oncogenes and thus suppresses various types of cancer. Knowledge of the biosynthesis of MTM and its gene cluster has enabled genetic modifications of the gene cluster and combinatorial biosynthesis to produce new modified MTM molecules (“mithralogues”) with improved efficacy and lower toxicity, which has also renewed interest in the clinical development of MTM. However, production yields of MTM and its analogues are low in the natural production strains. Recent developments in genetic engineering approaches have made it possible to increase MTM production through more rational strategies based on genetic manipulations and heterologous expression in optimized chassis. Recent construction of various genetically modified strains of Streptomyces lividans has shown their use for efficient heterologous production of various biologically active secondary metabolites including MTM. • Discovery a novel bifunctional glycosyl hydrolase from uncultured microorganism. • Heterologous production of MTM in engineered S. lividans strains is efficient.

Keywords: production; mtm; antibiotic mithramycin; mithramycin new; antitumor antibiotic; new advanced

Journal Title: Applied Microbiology and Biotechnology
Year Published: 2020

Link to full text (if available)


Share on Social Media:                               Sign Up to like & get
recommendations!

Related content

More Information              News              Social Media              Video              Recommended



                Click one of the above tabs to view related content.