Regulation of daunorubicin biosynthesis inStreptomyces peucetius -feed forward and feedback transcriptional control

Abstract

Streptomyces are a major group of soil bacteria that produce wide range of bioactive compounds including antibiotics. Daunorubicin is a chemotherapeutic agent for treatment of certain types of cancer, which is produced as a secondary metabolite by S. peucetius. Owing to the significance of this drug in treating cancer, understanding the molecular mechanism of its biosynthesis will assist in the genetic manipulation of this strain for better drug yields. Additionally, the knowledge can also be applied to design hybrid antibiotics that can be made in vivo by transferring genes from one Streptomyces species to another. Biosynthesis of daunorubicin in S. peucetius is accomplished by the function of 30 enzyme-coding genes in a sequential and coordinated fashion. In addition to these enzymes, three transcriptional regulators DnrO, DnrN and DnrI regulate this multi-step process by forming a coherent feed forward loop regulatory circuit, consequently controlling the entire enzyme coding genes. Since daunorubicin is a DNA intercalating drug, maintaining an optimal intracellular drug concentration is pivotal to prevent self-toxicity. Commencement of daunorubicin biosynthesis also activates the feedback mechanisms mediated by the metabolite. At exceeding intracellular concentrations, daunorubicin intercalates into DNA sequences and impedes the binding of these transcription factors. This feedback repression is relieved by a group of self-resistance genes, which concurrently efflux the excess intracellular daunorubicin. This review will discuss the mechanistic role of each transcription factor and their interplay in initiating and maintaining the biosynthesis of daunorubicin in S. peucetius.

Cardio-Oncology

“…7 Anthracyclines are derived from Streptomyces bacterium and are among the most effective anticancer drugs to date. 8 Commonly used anthracyclines include doxorubicin, mitoxantrone, epirubicin, idarubicin, and daunorubicin. Anthracyclines exhibit anti-neoplastic properties by 4 main mechanisms.…”

Steps towards the synthetic biology of polyketide biosynthesis

“…Polyketides represent an important class of compounds that are extremely diverse in structure and function. Natural screening strategies have brought more than 20 drugs to market, including the immunosuppressants FK506 and rapamycin (Park et al ., ; Goranovic et al ., ); hypocholesterolemics, such as lovastatin (Ma & Tang, ); anticancer agents, such as doxorubicin (Vasanthakumar et al ., ); and a host of antimicrobials, including tetracycline and erythromycin (Weissman & Leadlay, ; Lesnik et al ., ). Furthermore, it is predicted that more than 1% of polyketides described have potential drug activity (Koskinen & Karisalmi, ), and as a result of this, polyketides have received tremendous attention in efforts to unearth new compounds with bioactive properties.…”

Challenges and Advances in Genome Editing Technologies in Streptomyces

“…Streptomyces are Gram-positive bacteria that can produce high amounts of secondary metabolites, such as antibiotics (e.g., pristinamycin [1] and daptomycin [2]), immunosuppressants (e.g., rapamycin [3] and FK506 [4]), insecticides (e.g., avermectin [5] and milbemycin [6]) and anti-tumor drugs (e.g., daunorubicin [7] and bleomycin [8]), which are widely used in agriculture and veterinary/human medicine. In the last few decades, the traditional strategy for the discovery of novel natural products (NPs) with medicinal properties has not been effective, which is mainly due to the repeated rediscovery of known chemical compounds [9].…”