Biosynthesis of the Terpene Phenalinolactone in Streptomyces sp. Tü6071: Analysis of the Gene Cluster and Generation of Derivatives

• Published in: Chemistry & biology Vol. 13; no. 4; pp. 365 - 377
• Main Authors: Dürr, Clemens, Schnell, Hans-Jörg, Luzhetskyy, Andriy, Murillo, Renato, Weber, Monika, Welzel, Katrin, Vente, Andreas, Bechthold, Andreas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.04.2006
• Subjects: Anti-Bacterial Agents - biosynthesis; Anti-Bacterial Agents - chemistry; Base Sequence; CHEMBIO; DNA, Bacterial - genetics; Genes, Bacterial; Glycosides - biosynthesis; Glycosides - chemistry; Hexoses - biosynthesis; Hexoses - metabolism; Lactones - chemistry; Lactones - metabolism; MICROBIO; Models, Biological; Molecular Sequence Data; Multigene Family; Mutation; Oxygenases - genetics; Oxygenases - metabolism; Pyrroles - metabolism; Streptomyces - genetics; Streptomyces - metabolism; Terpenes - chemistry; Terpenes - metabolism; CHEMBIO; MICROBIO
• ISSN: 1074-5521; 1879-1301
• DOI: 10.1016/j.chembiol.2006.01.011

Phenalinolactones are terpene glycosides with antibacterial activity. A striking structural feature is a highly oxidized γ-butyrolactone of elusive biosynthetic origin. To investigate the genetic basis of the phenalinolactones biosynthesis, we cloned and sequenced the corresponding gene cluster from the producer strain Streptomyces sp. Tü6071. Spanning a 42 kbp region, 35 candidate genes could be assigned to putatively encode biosynthetic, regulatory, and resistance-conferring functions. Targeted gene inactivations were carried out to specifically manipulate the phenalinolactones pathway. The inactivation of a sugar methyltransferase gene and a cytochrome P450 monoxygenase gene led to the production of modified phenalinolactone derivatives. The inactivation of a Fe(II)/α-ketoglutarate-dependent dioxygenase gene disrupted the biosynthetic pathway within γ-butyrolactone formation. The structure elucidation of the accumulating intermediate indicated that pyruvate is the biosynthetic precursor of the γ butyrolactone moiety.