Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 129, Issue 43, Pages 13082-13094Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja073275o
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Funding
- NCI NIH HHS [U19 CA113297-02, U19 CA113297, CA113297, CA1059845, CA78747, R01 CA078747-08, R01 CA078747, F32 CA105984] Funding Source: Medline
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The biosynthetic gene cluster for the enediyne antitumor antibiotic maduropeptin (MDP) from Actinomadura madurae ATCC 39144 was cloned and sequenced. Cloning of the mdp gene cluster was confirmed by heterologous complemenlation of enediyne olylelide syntlase (PKS, mutants from the C-1027 producer Streptomyces globisporus and the neocarzinostatin producer Streptomyces carzinostaticus using the MDP enediyne PKS and associated genes. Furthermore, MDP was produced, and its apoprotein was isolated and N-terminal sequenced; the encoding gene, mdpA, was found to reside within the cluster. The biosynthesis of MDP is highlighted by two iterative type I PKSs - the enediyne PKS and a 6-methylsalicylic acid PKS; generation of (S)-3-(2-chloro-3-hydroxy-4-methoxyphenyl)-3-hydroxypropionic acid derived from L-alpha-tyrosine; a unique type of enediyne apoprotein; and a convergent biosynthetic approach to the final MDP chromophore. The results demonstrate a platform for engineering new enediynes by combinatorial biosynthesis and establish a unified paradigm for the biosynthesis of enediyne polyketides.
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