Biocatalytic diversification of abietic acid in Streptomyces.

Abstract

Biocatalysis provides access to synthetically challenging molecules and commercially and pharmaceutically relevant natural product analogs while adhering to principles of green chemistry. Cytochromes P450 (P450s) are among the most superlative and versatile oxidative enzymes found in nature and are desired regio- and stereoselective biocatalysts, particularly for structurally complex hydrocarbon skeletons. We used 10 genome-sequenced Streptomyces strains, selected based on their preponderance of P450s, to biotransform the bioactive diterpenoid abietic acid. We isolated and structurally characterized seven oxidized abietic acid derivatives from three different strains, including four products that are new bacterial biotransformants or enzymatic products. Oxidations (hydroxylation, dehydrogenation, and aromatization) were seen on both the B and C rings of abietic acid and five products had multiple modifications. Notable conversions observed in the study were that of abietic acid to 15-hydroxy-7-oxo-8,11,13-abietatrien-18-oic acid, 7, which involves multiple hydroxylation reactions and dehydrogenation. The findings from this study will lead to identifying P450s or other enzymes that may act as general biocatalysts to modify abietanes and other labdane-type diterpenoid skeletons.

One-sentence summary: Genome-guided biotransformation of the bioactive diterpenoid abietic acid in Streptomyces yielded seven oxidized derivatives including four that have not been previously seen from bacteria.