Engineering Streptomyces peucetius for Doxorubicin and Daunorubicin Biosynthesis
Doxorubicin and daunorubicin are notable members of the type II polyketide synthase family and clinically important cancer chemotherapeutic agents and are produced by a mutant strain S. peucetius ATCC 27952. They belong to the anthracycline-type antitumor drugs. Doxorubicin remains one of the most widely used antitumor drugs for the treatment of various cancers because of its broad spectrum of activity. As a result, numerous works have been carried to unravel the biosynthetic pathway and the underlying regulatory mechanisms to gain insight into the mechanisms of the genes involved. Consenquently, there is a need to develop an overproducing strain at the industrial scale, to produce doxorubicin as an anticancer drug. Therefore a significant amount of progress has been made in unraveling the bottlenecks in the pathway, manipulating the biosynthesis, improving production, and generating novel derivatives by engineering S. peucetius strain.
Here we review in depth, various pathway engineering approaches and strategies that have been applied during these courses of time, since the discovery of these compounds, for the efficient production of daunorubicin and doxorubicin. The major pathway engineering approaches discussed in this chapter are divided into three parts: the first part includes the engineering of the thymidine diphosphate-l-daunosamine biosynthesis pathway genes which is important for the enhanced production of the glycone which in turn is used for the glycosylation reaction. Similarly the second part includes the engineering of the polyketide genes responsible for the production of the aglycone moiety that undergoes several modifications to generate the important compounds doxorubicin and daunorubicin. Lastly, we discuss the engineering of the several regulatory genes involved either directly or indirectly in regulation and control of the production of daunorubicin and doxorubicin.
KeywordsDaunorubicin Doxorubicin Anthracycline Anticancer drug Polyketide synthase Biosynthetic pathway Pathway engineering Streptomyces peucetius
This research was supported by a grant from the National Research Foundation of Korea to Ramesh Prasad Pandey (Grant No: 2017R1C1B5018056).
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