Biotechnological doxorubicin production: pathway and regulation engineering of strains for enhanced production

Abstract

Doxorubicin (DXR) is an anthracycline-type polyketide, typically produced by Streptomyces peucetius ATCC 27952. Like the biosynthesis of other secondary metabolites in Streptomyces species, DXR biosynthesis is tightly regulated, and a very low level of DXR production is maintained in the wild-type strain. Despite that DXR is one of the most broadly used and clinically important anticancer drugs, a traditional strain improvement strategy has long been practiced via recursive random mutagenesis, with little understanding of the molecular genetic basis underlying such enhanced DXR production. Since DXR titer enhancement is imperative in the fermentation industry, attaining a comprehensive understanding and its application of the specific regulatory systems that govern secondary metabolite production is an important aspect of metabolic engineering that can efficiently improve fermentation titers. In this mini-review, various efforts to improve the titers of DXR have been summarized based on biosynthetic and regulatory studies including transcriptional and product analyses.

Current Approaches for Enhanced Expression of Secondary Metabolites as Bioactive Compounds in Plants for Agronomic and Human Health Purposes

“…In most cases the cultures of differentiated cells have been able to get productions of the desired compounds in levels comparable to the mother plant. However the culture of such differentiated tissues on a large-scale in bioreactors is a major constraint, but for studies of the secondary metabolites biosynthesis such systems are very useful [Niraula et al, 2010]. The second approach is mentioned as the use of elicitors, this technique has been successfully reported in several cases.…”

“…Different strategies using cell cultures systems have been extensively studied with the objective of improving the production of bioactive secondary metabolites and cell culture systems could be used for the large scale culturing of plant cells from which secondary metabolites can be extracted. The advantage of this method is that it can provide a continuous, reliable source of natural products [Niraula et al, 2010].…”

“…The use of natural compounds as inhibitory agents for virulence factor production is a new approach to overcome increased antimicrobial resistance in pathogenic bacteria [Niraula et al, 2010]. Medicinal plants are the most exclusive source of lifesaving drugs for majority of the world's population.…”

Transcriptome Analysis of an Antibiotic Downregulator Mutant and Synergistic Actinorhodin Stimulation via Disruption of a Precursor Flux Regulator in Streptomyces coelicolor

“…It has been proposed that the expression of antibiotic-biosynthetic genes is tightly controlled through multiple different regulatory networks in Streptomyces species (18,19). Traditionally, random mutation has been one of the most widely used strategies for Streptomyces strain improvement with regard to the generation of secondary-metabolite-overproducing industrial mutants, even though the molecular genetic basis underlying such enhanced production remains largely unknown (17,20,21,23).…”

Metabolic Engineering of Microorganisms for Biosynthesis of Antibiotics

“…DXR biosynthesis is tightly regulated, and a very low level of DXR production is maintained in the wild-type strain. DXR is one of the most broadly used and clinically important anticancer drugs; a traditional strain improvement strategy has been practiced via random mutagenesis that enhanced production (Niraula et al 2010). There is some rule for the selection of host strain and genetic tools required for drug production are essential.…”