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Fostriecin (FST, 1) is a natural product with promising antitumor activity produced by Streptomyces pulveraceus. Its antitumor activity is associated with the selective inhibition of protein phosphatase activities. The biosynthetic gene cluster for FST has recently been cloned and sequenced. To better understand the post-polyketide synthase (PKS) modification steps in the biosynthetic pathway of FST, we constructed and characterized three post-PKS modification gene mutants of fosG, fosK, and fosMby knockout inactivation in S. pulveraceus. As a result, we determined that a fosK-encoded cytochrome P450 monooxygenase is responsible for C-18 hydroxylation, formation of an unsaturated lactone is dependent upon FosM, and the fosGgene product is involved in hydroxylation at C-4 after the action of FosM to yield PD 113,271 from FST. The accumulated analogues from the ΔfosKand ΔfosMmutant strains possessed a malonyl ester moiety that suggested that all the post-PKS modification steps in FST biosynthesis occur with the polyketide chain bearing a malonyl ester at the C-3 position, with formation of the unsaturated six-membered lactone as the last step in FST biosynthesis.