Better Biosynthesis Building Blocks

A pair of biosynthetic studies may provide information that makes it easier to access analogs of the salinosporamides, a promising class of anticancer agents. Bradley S. Moore of Scripps Institution of Oceanography and the University of California, San Diego, teamed with Kevin A. Reynolds of Portland State University and colleagues to analyze the genome of Salinispora tropica, a deep-sea-dwelling bacterium that makes salinosporamides. They found that salinosporamides are biosynthesized by an unusual polyketide synthase (PKS) enzyme (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.0901237106). The team then explored the enzyme's substrate specificity and learned that it can incorporate a broad range of substrates, including brominated and fluorinated compounds, into the salinosporamide skeleton (J. Am. Chem. Soc., DOI: 10.1021/ja9042824). PKS enzymes naturally make erythromycin, rapamycin, and a host of other drugs. They tend to accept a limited set of substrates, however, leaving few opportunities for further elaboration. In contrast, the salinosporamide-making PKS accepts substrates with functionalizable moieties, which might aid efforts to generate novel drug derivatives via fermentation, says Yi Tang, who studies biosynthesis at UCLA.