Anthracyclines are aromatic polyketides, or a class of natural products derived from precursor molecules consisting of a chain of alternating ketones and are produced by streptomyces. Anthracyclines are known to be potent therapeutics used for the treatment of human cancers. As a result of toxic side effects, engineering new analogues could decrease toxicity and increase potency allowing safer use. Our approach is to genetically engineer streptomyces to produce these analogues as they are native producers of polyketides. Using these bacteria, we can use enzymes to create the stereocenters needed to produce these compounds. Anthracyclines are biosynthesized through a multistep enzymatic pathway, which includes a tricyclic intermediate. The biosynthetic route for the transformation of the tricyclic intermediates nogalonic acid or aklanonic acid into tetracyclic anthracyclinones, requires three enzymes. First, nogalonic acid/aklanonic acid undergo O-methylation at the carboxylic acid functionality via nogalonic acid O-methyltranferase to form nogalonic acid methyl ester (NAME) or aklanonic acid methyl ester (AAME), respectively. Second, NAME/AAME undergoes an fourth ring cyclization to form tetracyclic anthracyclinones. Lastly, the anthracyclinone is reduced at C-7 to form nogalamycinone. In this work, we engineered S. coelicolor M1152ΔmatAB strains with different combinations of anthracyclinone biosynthetic genes to produce a comprehensive library of tetracyclic anthracyclinone core scaffolds that are useful for the elaboration of potent anticancer agents.

BioBricks® platform for engineering of diverse anthracyclinone core scaffolds

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.