i) Terpendole E is an indole-diterpene compound and identified as an inhibitor of a mitotic kinesin, Eg5. The biosynthetic gene cluster (ter) of the terpendole family was cloned from the producer strain Chaunopycnis alba. The original producer strain produced only a small amount of terpendole E, but a genetically engineered strain in which terP (cytochrome P450 gene) was disrupted accumulated a high amount of terpendole E in culture broth. Moreover, the genetically engineered strain produced several new derivatives including prenylated derivatives and an oxidized derivative which was 10-fold more potent than terpendole E.
ii) Fumitremorgins are diketopiperazine compounds produced by Aspergillus fumigatus. One of the compounds, fumitremorgin C, is a potent and specific inhibitor of breast cancer resistance protein (BCRP), which is a multidrug ABC transporter. We have cloned the biosynthetic gene cluster (ftm) for the fumitremorgin family from the producer strain, Aspergillus fumigatus BM939. The cluster consists of nine genes, one NRPS gene, two prenyltransferase genes, one methyltransferase gene, four oxygenase genes, three of which are cytochrome P450 genes, and a hypothetical protein gene. The structure-relationship study using the metabolites associated with the ftm gene cluster demonstrates that fumitremorgin C is the most potent BCRP inhibitor among the metabolites tested.
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